Materiały źródłowe

• #1 Autoimmune encephalitis: clinical spectrum and management | Practical Neurology

  https://pn.bmj.com/content/21/5/412

  Autoimmune encephalitis defines brain inflammation caused by a misdirected immune response against self-antigens expressed in the central nervous system. […] The rapid and ongoing expansion of this field has been driven by the identification of several pathogenic autoantibodies that cause polysymptomatic neurological and neuropsychiatric diseases. […] These autoantibodies are considered pathogenic because they are directed against the extracellular and hence in vivo exposed domains of their target antigens. […] This fundamental property has led to much interest and excitement surrounding this rapidly expanding field, with new autoantibody targets described most years. […] Many established antigens are key synaptic proteins, ion channels or receptors, meaning that the extracellular domain-targeting autoantibodies are likely to directly modulate critical physiological processes.

• #2

  https://link.springer.com/article/10.1007/s00234-024-03318-x

  Autoimmune encephalitis is a relatively novel nosological entity characterized by an immune-mediated damage of the central nervous system. […] Autoimmune encephalitis (AE) refers to a spectrum of disorders characterized by inflammatory processes affecting the brain tissue and originating from an immune-mediated pathophysiological mechanism targeting neurons. […] AE was originally described as a paraneoplastic phenomenon affecting limbic structures, and causing subacute onset of behavior and memory disturbances, along with seizures, in the presence of an underlying neoplasms. […] Subsequent evidence led to the detection of autoantibodies linked with AE, and contributed to the recognition that non-paraneoplastic instances are relatively common. […] Currently, AE includes a number of subtypes, that can be classified based on the associated autoantibody (Ab) found in the serum and/or CSF.

• #3 Autoimmune Encephalitis: Pathophysiology and Imaging Review of an Overlooked Diagnosis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7960083/

  Autoimmune encephalitis is a relatively new category of immune-mediated disease involving the central nervous system that demonstrates a widely variable spectrum of clinical presentations, ranging from the relatively mild or insidious onset of cognitive impairment to more complex forms of encephalopathy with refractory seizure. […] The term autoimmune encephalitis generally refers to a family of closely related disease processes that share overlapping clinical features and neuroimaging findings but are ultimately differentiated by the specific antibody subtypes driving the underlying immune-mediated attack on different CNS structures. […] This antibody-mediated attack on neuronal structures results in a localized inflammatory response. Thus, the clinical and imaging manifestations are dictated by the specific location of the underlying immune response within the nervous system, which leads to substantial variability.

• #4 Autoimmune Encephalitis: Pathophysiology and Imaging Review of an Overlooked Diagnosis | American Journal of Neuroradiology

  http://www.ajnr.org/content/38/6/1070

  Autoimmune encephalitis is a relatively new category of immune-mediated disease involving the central nervous system that demonstrates a widely variable spectrum of clinical presentations, ranging from the relatively mild or insidious onset of cognitive impairment to more complex forms of encephalopathy with refractory seizure. […] The term autoimmune encephalitis generally refers to a family of closely related disease processes that share overlapping clinical features and neuroimaging findings but are ultimately differentiated by the specific antibody subtypes driving the underlying immune-mediated attack on different CNS structures. […] This antibody-mediated attack on neuronal structures results in a localized inflammatory response. […] While limbic dysfunction is the single most consistent finding in autoimmune encephalitis, varying degrees of involvement are seen within the neocortex, striatum, hindbrain, spine, and peripheral nervous system based on the unique antibody profile.

• #5 Autoimmune Encephalitis: Pathophysiology and Imaging Review of an Overlooked Diagnosis | American Journal of Neuroradiology

  http://www.ajnr.org/content/38/6/1070

  Autoimmune encephalitis is a relatively new category of immune-mediated disease involving the central nervous system that demonstrates a widely variable spectrum of clinical presentations, ranging from the relatively mild or insidious onset of cognitive impairment to more complex forms of encephalopathy with refractory seizure. […] The term autoimmune encephalitis generally refers to a family of closely related disease processes that share overlapping clinical features and neuroimaging findings but are ultimately differentiated by the specific antibody subtypes driving the underlying immune-mediated attack on different CNS structures. […] This antibody-mediated attack on neuronal structures results in a localized inflammatory response. […] While limbic dysfunction is the single most consistent finding in autoimmune encephalitis, varying degrees of involvement are seen within the neocortex, striatum, hindbrain, spine, and peripheral nervous system based on the unique antibody profile.

• #6 SciELO Brazil – A critical review and update on autoimmune encephalitis: understanding the alphabet soup A critical review and update on autoimmune encephalitis: understanding the alphabet soup

  https://www.scielo.br/j/anp/a/gXJNV7zDM4BPfxwd3LPpbxh/

  Autoimmune encephalitis (AE) comprises a group of diseases mediated by antibodies against neuronal cell surface or synaptic antigens, such as ion channels or neurotransmitter receptors. […] Autoimmune encephalitis (AE) is a group of recently recognized diseases where antibodies believed to be pathogenic target neuronal proteins localized in cell surface and/or synapses, disrupting their function and provoking a peculiar symptomatology. […] Recognition of autoimmune encephalitis is crucial, because AE often presents with rapidly progressive severe and debilitating symptoms which, if promptly and adequately treated, can lead to good outcomes, including full recovery in many cases. […] The term autoimmune encephalitis has been little by little adopted to describe those disorders associated the last class of antibodies, despite the fact that, strictly speaking, autoimmune encephalitis can refer to any given target central nervous system cell (neurons, glial cells: astrocytes, oligodendrocytes and microglia) caused by any given immune mechanism (humoral: antibodies and complement, cellular: B and T cells, innate and adaptive).

• #7 Autoimmune encephalitis – Wikipedia

  https://en.wikipedia.org/wiki/Autoimmune_encephalitis

  Autoimmune encephalitis commonly presents an immune response against neuronal autoantigens with production of antibodies. […] Anti-neuronal antibodies are classified into antibodies against cell surface antigens (CSAab), antibodies against synaptic antigens (SyAab) and antibodies against intraneuronal antigens (INAab), also known as onconeural antibodies.

• #8 :: Journal of Epilepsy Research

  https://www.j-epilepsy.org/m/journal/view.php?doi=10.14581/jer.16010

  Autoimmune encephalitis is a group of encephalitis syndromes that cause altered mentality, memory decline, or seizures in association with the presence of serum and cerebrospinal fluid (CSF) autoantibodies (auto-Abs). […] Autoimmune encephalitis is a group of syndromes that occur in association with autoantibodies (auto-Abs), which are presumed to be responsible, or partly responsible, for the development of epilepsy and encephalitis. […] Many series of patients with autoimmune encephalitis involve B-cell-mediated autoimmunity. However, some syndromes may also involve T-cell-mediated immunity. […] The various types of autoimmune encephalitis antibodies can be categorized into three groups: intracellular paraneoplastic Ab, cell-surface or synaptic Ab, and with Ab of unclear significance.

• #9 SciELO Brazil – Autoimmune encephalitis: a review of diagnosis and treatment Autoimmune encephalitis: a review of diagnosis and treatment

  https://www.scielo.br/j/anp/a/mqLMtVDZLLF566CwstHwyhy/

  Autoimmune encephalitis presents an immune response against neuronal autoantigens with production of antibodies. Anti-neuronal antibodies are classified into antibodies against cell surface antigens (CSAab), antibodies against synaptic antigens (SyAab) and antibodies against intraneuronal antigens (INAab), also known as onconeural antibodies. The CSAab (i.e., anti-NMDAR antibodies) target molecules involved in neurotransmission leading to neuronal dysfunction. They may have agonistic or antagonistic effects on the receptors, block ion channel pores or disrupt the interaction with neighboring molecules. They could also alter receptor localization at the membrane or cause receptor internalization, thus reducing cell surface expression of receptors. Moreover, they could lead to complement deposition and activation of natural killer cells resulting in cell death. The SyAab are believed to contribute to alteration of neurotransmitter release. In contrast, INAab (i.e., anti-Hu, anti-Yo, anti-Ma) are most likely not directly pathogenic and probably an epiphenomenon of T-cell-mediated immune response. The term AIE is used to describe a group of neurological disorders with symptoms of limbic and extra-limbic dysfunction in association with CSAab or SyAab. Patients may have antibodies of more than one type, and CSAab and SyAab may be present together with anti-INAab, especially in paraneoplastic AIE. Patients with AIE associated with CSAab have a more favorable prognosis. In contrast, those with AIE associated with INAab often show limited response to immunotherapy and their symptoms are mostly irreversible due to T-cell-mediated neuronal damage.

• #10 SciELO Brazil – Autoimmune encephalitis: a review of diagnosis and treatment Autoimmune encephalitis: a review of diagnosis and treatment

  https://www.scielo.br/j/anp/a/mqLMtVDZLLF566CwstHwyhy/

  Autoimmune encephalitis presents an immune response against neuronal autoantigens with production of antibodies. Anti-neuronal antibodies are classified into antibodies against cell surface antigens (CSAab), antibodies against synaptic antigens (SyAab) and antibodies against intraneuronal antigens (INAab), also known as onconeural antibodies. The CSAab (i.e., anti-NMDAR antibodies) target molecules involved in neurotransmission leading to neuronal dysfunction. They may have agonistic or antagonistic effects on the receptors, block ion channel pores or disrupt the interaction with neighboring molecules. They could also alter receptor localization at the membrane or cause receptor internalization, thus reducing cell surface expression of receptors. Moreover, they could lead to complement deposition and activation of natural killer cells resulting in cell death. The SyAab are believed to contribute to alteration of neurotransmitter release. In contrast, INAab (i.e., anti-Hu, anti-Yo, anti-Ma) are most likely not directly pathogenic and probably an epiphenomenon of T-cell-mediated immune response. The term AIE is used to describe a group of neurological disorders with symptoms of limbic and extra-limbic dysfunction in association with CSAab or SyAab. Patients may have antibodies of more than one type, and CSAab and SyAab may be present together with anti-INAab, especially in paraneoplastic AIE. Patients with AIE associated with CSAab have a more favorable prognosis. In contrast, those with AIE associated with INAab often show limited response to immunotherapy and their symptoms are mostly irreversible due to T-cell-mediated neuronal damage.

• #11 SciELO Brazil – Autoimmune encephalitis: a review of diagnosis and treatment Autoimmune encephalitis: a review of diagnosis and treatment

  https://www.scielo.br/j/anp/a/mqLMtVDZLLF566CwstHwyhy/

  Autoimmune encephalitis presents an immune response against neuronal autoantigens with production of antibodies. Anti-neuronal antibodies are classified into antibodies against cell surface antigens (CSAab), antibodies against synaptic antigens (SyAab) and antibodies against intraneuronal antigens (INAab), also known as onconeural antibodies. The CSAab (i.e., anti-NMDAR antibodies) target molecules involved in neurotransmission leading to neuronal dysfunction. They may have agonistic or antagonistic effects on the receptors, block ion channel pores or disrupt the interaction with neighboring molecules. They could also alter receptor localization at the membrane or cause receptor internalization, thus reducing cell surface expression of receptors. Moreover, they could lead to complement deposition and activation of natural killer cells resulting in cell death. The SyAab are believed to contribute to alteration of neurotransmitter release. In contrast, INAab (i.e., anti-Hu, anti-Yo, anti-Ma) are most likely not directly pathogenic and probably an epiphenomenon of T-cell-mediated immune response. The term AIE is used to describe a group of neurological disorders with symptoms of limbic and extra-limbic dysfunction in association with CSAab or SyAab. Patients may have antibodies of more than one type, and CSAab and SyAab may be present together with anti-INAab, especially in paraneoplastic AIE. Patients with AIE associated with CSAab have a more favorable prognosis. In contrast, those with AIE associated with INAab often show limited response to immunotherapy and their symptoms are mostly irreversible due to T-cell-mediated neuronal damage.

• #12 Autoimmune Encephalitis: Pathophysiology and Imaging Review of an Overlooked Diagnosis | American Journal of Neuroradiology

  http://www.ajnr.org/content/38/6/1070

  Antibody-mediated CNS disorders can be classified into 2 broad categories, paraneoplastic or nonparaneoplastic, based on the presence or absence of an underlying malignancy, respectively. […] Paraneoplastic syndromes affecting the CNS are generally thought to develop in cancer when antigens shared by tumor cells and native nonneoplastic neuronal cells result in an antibody-mediated attack on previously immune-privileged neuronal structures. […] Regardless of the etiology and antibody profile, there is a clear predilection in autoimmune encephalitis for antigens within the limbic system. […] Group I antibodies target intracellular neuronal antigens, are more closely associated with an underlying malignancy, and use the same cytotoxic T-cell mechanisms when targeting the intracellular neuronal antigens and onconeuronal antigens as part of the immune response to cancer.

• #13 Autoimmune (including paraneoplastic) encephalitis: Clinical features and diagnosis – UpToDate

  https://www.uptodate.com/contents/autoimmune-including-paraneoplastic-encephalitis-clinical-features-and-diagnosis

  Encephalitis is an inflammatory condition of the brain with many etiologies. There are several types of encephalitis that are immune mediated (autoimmune), including the encephalitis syndromes associated with antibodies against neuronal cell-surface/synaptic proteins and those associated with antibodies against intracellular neuronal proteins. […] Although both categories of autoimmune encephalitis can occur as paraneoplastic manifestations of an underlying cancer, the frequency of cancer association varies depending on the autoantibodies. Most neuronal antibodies typically associated with paraneoplastic encephalitis (eg, >70 percent of cases occur with a cancer association) are directed against intracellular neuronal proteins (onconeuronal proteins). […] Thus, many autoimmune encephalitides associated with antibodies against neuronal cell-surface proteins can occur in the presence or absence of cancer, and a few encephalitides associated with antibodies against intracellular neuronal proteins (eg, glutamic-acid decarboxylase 65 kilodalton isoform [GAD65] or adenylate kinase 5 [AK5]) rarely or almost never occur with cancer.

• #14 Autoimmune Encephalitis – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK578203/

  Autoimmune encephalitis refers to acute to subacute, progressive inflammation of the brain associated with antibodies against neuronal cell surface and synaptic protein, most commonly being anti-N-methyl-D-aspartate receptor encephalitis. […] While the exact mechanism of AIE is unknown, current literature suggests that autoimmune antibodies target synaptic proteins, leading to widespread inflammation. […] Although the exact mechanism is currently under investigation, autoimmune encephalitis is thought to be an autoimmune process with an exaggerated response to a neuronal self-antigen. […] When bound to target proteins, these antibodies induce conformational changes that lead to an inflammatory response. […] To this date, the exact mechanism of the collapse of immune tolerance in AIE largely remains unknown.

• #15

  https://europepmc.org/books/n/statpearls/article-140572/?extid=31536295&src=med

  Autoimmune encephalitis refers to acute to subacute, progressive inflammation of the brain associated with antibodies against neuronal cell surface and synaptic protein, most commonly being anti-N-methyl-D-aspartate receptor encephalitis. […] While the exact mechanism of AIE is unknown, current literature suggests that autoimmune antibodies target synaptic proteins, leading to widespread inflammation. […] Although the exact mechanism is currently under investigation, autoimmune encephalitis is thought to be an autoimmune process with an exaggerated response to a neuronal self-antigen. […] Antibodies in AIE are intrinsically pathogenic. They induce inflammation by targeting specific neuronal proteins. […] When bound to target proteins, these antibodies induce conformational changes that lead to an inflammatory response.

• #16 Autoimmune Encephalitis: A Physician’s Guide to the Clinical Spectrum Diagnosis and Management

  https://www.mdpi.com/2076-3425/12/9/1130

  The rapidly expanding spectrum of autoimmune encephalitis in the last fifteen years is largely due to ongoing discovery of many neuronal autoantibodies. […] Autoimmune encephalitis is among the most common form of encephalitis of non-infectious etiologies caused by autoantibodies targeting neural epitopes such as synaptic surface structures (e.g., receptors, ionic channels, or supporting proteins) or intracellular antigens such as onconeural antigens. […] Increased familiarity with the neurobiology and the diverse presenting neuropsychiatric symptoms of autoimmune encephalitis among physicians of all disciplines, and not only neurology, is pivotal for early detection. […] There are two proposed immune mechanisms in autoimmune encephalitis. The first involves autoantibodies against synaptic surface structures (e.g., receptors, ionic channels, or supporting proteins).

• #17 Autoimmune Encephalitis: A Physician’s Guide to the Clinical Spectrum Diagnosis and Management

  https://www.mdpi.com/2076-3425/12/9/1130

  The second mechanism involves cytotoxic T cell-mediated neuronal destruction associated with antibodies against cytoplasmic or nuclear onconeural antigens. […] It is unclear whether humoral or cytotoxic mechanisms account for the pathogenesis of GAD autoantibodies associated autoimmunity. […] There is a consensus that circulating neuronal autoantibodies must gain access to the CNS through the tightly regulated blood-brain or blood-CSF barriers to exert their harmful pathogenic effects. […] Other possibilities include inflammation-induced hyperpermeability of BBB or BCSF that can expose and re-expose the brain’s self-antigens to the peripheral adaptive immunity, which in turn can trigger the formation of pathogenic neuronal autoantibodies, leading to a breakdown in immune tolerance. […] BBB disruption associated with perivascular neuroinflammation involving both innate and adaptive immune cells has been documented in brain biopsies and post-mortem studies from individuals with etiologically diverse autoimmune encephalitis. […] Collectively, these findings support the potential contributory role of BBB disruption to the pathophysiology of autoimmune encephalitis.

• #18 Autoimmune Encephalitis—A Multifaceted Pathology

  https://www.mdpi.com/2227-9059/11/8/2176

  It is important to recognize that autoimmune encephalitis is a complex condition, and treatment plans should be customized to each individual based on their specific symptoms, antibody findings, and response to therapy. Early diagnosis and appropriate treatment can lead to substantial improvement in symptoms and a positive prognosis for many individuals with autoimmune encephalitis. However, some cases may present greater challenges in treatment, and long-term neurological complications can arise. Therefore, a personalized approach to treatment and ongoing medical management is essential for individuals affected by this disorder. […] Two immune mechanisms have been proposed in autoimmune encephalitis. One of the proposed immune mechanisms in autoimmune encephalitis is the presence of autoantibodies targeting synaptic surface structures, such as receptors, ionic channels, or supporting proteins. These antibodies play a role in causing neuronal dysfunction by affecting synaptic transmission in various ways. For example, anti-NMDAR antibodies can cross-link and internalize receptors, leading to altered synaptic transmission. Antibodies like anti-GABAB receptor antibodies may interfere with neurotransmitter binding, while antibodies such as anti-VGKC and anti-LGI1 antibodies can disrupt ion channel function. It is important to note that these antibodies do not directly damage neuronal structures or cause significant neuronal apoptosis, so the clinical outcome is generally favorable.

• #19 Autoimmune Encephalitis—A Multifaceted Pathology

  https://www.mdpi.com/2227-9059/11/8/2176

  It is important to recognize that autoimmune encephalitis is a complex condition, and treatment plans should be customized to each individual based on their specific symptoms, antibody findings, and response to therapy. Early diagnosis and appropriate treatment can lead to substantial improvement in symptoms and a positive prognosis for many individuals with autoimmune encephalitis. However, some cases may present greater challenges in treatment, and long-term neurological complications can arise. Therefore, a personalized approach to treatment and ongoing medical management is essential for individuals affected by this disorder. […] Two immune mechanisms have been proposed in autoimmune encephalitis. One of the proposed immune mechanisms in autoimmune encephalitis is the presence of autoantibodies targeting synaptic surface structures, such as receptors, ionic channels, or supporting proteins. These antibodies play a role in causing neuronal dysfunction by affecting synaptic transmission in various ways. For example, anti-NMDAR antibodies can cross-link and internalize receptors, leading to altered synaptic transmission. Antibodies like anti-GABAB receptor antibodies may interfere with neurotransmitter binding, while antibodies such as anti-VGKC and anti-LGI1 antibodies can disrupt ion channel function. It is important to note that these antibodies do not directly damage neuronal structures or cause significant neuronal apoptosis, so the clinical outcome is generally favorable.

• #20 Autoimmune Encephalitis—A Multifaceted Pathology

  https://www.mdpi.com/2227-9059/11/8/2176

  The second mechanism in autoimmune encephalitis involves cytotoxic T cell-mediated neuronal destruction. This mechanism is associated with the presence of antibodies targeting cytoplasmic antigens or nuclear onconeural antigens. These antibodies are markers for the concurrent pathogenic cytotoxic T cell response, which leads to the destruction of neurons. This immune response is typically associated with a limited response to treatment and can result in a worse neurological outcome due to the rapid destruction of neurons. […] It is widely accepted that circulating neuronal autoantibodies need to penetrate the tightly regulated blood-brain barrier in order to exert their pathogenic effects within the central nervous system. However, the specific mechanisms by which these antibodies gain access to the CNS are still not well understood and remain largely unknown. Despite ongoing research, the precise mechanisms involved in allowing these autoantibodies to cross the blood-brain barrier have not been fully elucidated. In recent times, the relationship between the brain’s “glymphatic” system and dual lymphatic channels has been discovered. The glymphatic system involves the flow of cerebrospinal fluid (CSF) through periarteriolar and parenchymal extracellular spaces, facilitated by glial cells. This system allows for the passage of small molecules, including central nervous system (CNS) proteins. This discovery challenges the long-held belief in the immune privilege status of the CNS, as intracranial antigens can potentially interact with the immune system through these pathways. The implications of this relationship on the mechanisms by which circulating neuronal autoantibodies access the CNS are still being investigated. Additional possibilities for the access of circulating neuronal autoantibodies to the central nervous system include inflammation-induced hyperpermeability of the blood-brain barrier. Inflammatory processes can disrupt the integrity of the BBB, allowing exposure and re-exposure of the brain’s self-antigens to the peripheral adaptive immune system. This exposure can trigger the formation of pathogenic neuronal autoantibodies, leading to a breakdown in immune tolerance. The inflammatory response and increased permeability of the BBB create an environment where self-antigens are more accessible to the immune system, potentially contributing to the development of autoimmune responses within the CNS. Viral infections are believed to play a role as immune triggers in certain cases of autoimmune encephalitis. These infections can promote the production of cross-reactive autoantibodies that target neuronal self-antigens. Additionally, viral infections can facilitate the entry of these autoantibodies into the central nervous system through mechanisms involving proinflammatory cytokines, particularly interleukin-17 produced by Th17 cells. These cytokines contribute to the proinflammatory response, which can lead to increased permeability of the blood-brain barrier and allow the passage of autoantibodies into the CNS. The cross-reactivity between viral antigens and self-antigens, coupled with the proinflammatory environment created by the viral infection, can trigger an autoimmune response targeting the neurons in the CNS. However, the specific mechanisms and viral triggers involved can vary among different cases of autoimmune encephalitis.

• #21

  https://link.springer.com/article/10.1007/s00234-024-03318-x

  More in general, different antibodies have a different likelihood of tumor associations, and the updated 2021 diagnostic criteria for AE propose to stratify AE-related antibodies in low-, intermediate- and high-risk, based on the likelihood of tumor associations. […] In addition to a worse prognosis due to the underlying malignancies, Group I AE are generally characterized by a worse treatment response and are more likely to induce irreversible tissue damage. […] Such differences are related to the underpinning pathophysiological mechanisms. […] While in Group II the autoantibodies are believed to serve a pathogenetic function, in Group I the immune-mediated damage is sustained by CD8+T-cells and the extent of the antibody contribution to the neural damage is still being evaluated. […] As a general rule, in Group I antitumoral immune response cross-reacts with neural antigens causing lymphocyte-mediated neuronal killing.

• #22 Diagnosis and Management of Autoimmune Encephalitis | Cleveland Clinic

  https://my.clevelandclinic.org/departments/neurological/depts/multiple-sclerosis/ms-approaches/diagnosis-and-management-of-autoimmune-encephalitis

  Autoimmune encephalitis (AE) is a heterogeneous group of non-infectious, immune-mediated inflammatory disorders that primarily affect the brain but can also have multifocal involvement of the spinal cord, peripheral nervous system and/or systemic manifestations. […] An increasing number of neuroglial autoantibodies (NAAs) targeting glial, extracellular/synaptic or intracellular neuronal antigens have been identified with characteristic clinical presentations and epidemiological features. […] Autoantibodies targeting extracellular antigens have been shown to be pathogenic in disease models whereas intracellular antigens, often paraneoplastic, seem to reflect T-cell mediated inflammation and, with few exceptions, do not seem to be directly pathogenic. […] Broadly speaking, AE associated with intracellular antigens portends a poor outcome and are less responsive to immune therapies. Conversely, patients with NAA targeting cell surface or synaptic antigens have a better response to immune therapy and if treated in a timely fashion show good long-term functional outcomes.

• #23

  https://link.springer.com/article/10.1007/s00234-024-03318-x

  This distinction bears significant clinical, prognostic, and pathophysiological implications, a general rule being that Group I AE are associated with a worse prognosis than Group II AE. […] Group I AE are more likely associated with an underlying malignancy (Group I Ab are also referred to as onconeural antibodies). […] For instance, anti-Hu AE the most common paraneoplastic AE with a reported incidence of 0.4/million person-years is associated with tumors in 7580% of cases (mainly small cell lung carcinoma, SCLC). […] On the other hand, Group II AE are more commonly non-paraneoplastic conditions that can affect patients belonging to a wide age range, including younger and sometimes pediatric patients. […] Despite the abovementioned rule of thumb for neoplastic associations is overall valid, some AE subtypes represent notable exceptions.

• #24 Autoimmune Encephalitis: Pathophysiology and Imaging Review of an Overlooked Diagnosis | American Journal of Neuroradiology

  http://www.ajnr.org/content/38/6/1070

  Antibody-mediated CNS disorders can be classified into 2 broad categories, paraneoplastic or nonparaneoplastic, based on the presence or absence of an underlying malignancy, respectively. […] Paraneoplastic syndromes affecting the CNS are generally thought to develop in cancer when antigens shared by tumor cells and native nonneoplastic neuronal cells result in an antibody-mediated attack on previously immune-privileged neuronal structures. […] Regardless of the etiology and antibody profile, there is a clear predilection in autoimmune encephalitis for antigens within the limbic system. […] Group I antibodies target intracellular neuronal antigens, are more closely associated with an underlying malignancy, and use the same cytotoxic T-cell mechanisms when targeting the intracellular neuronal antigens and onconeuronal antigens as part of the immune response to cancer.

• #25 Autoimmune Encephalitis: Pathophysiology and Imaging Review of an Overlooked Diagnosis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7960083/

  Group I antibodies are also associated with poor clinical outcomes, characterized by a decreased response to immunomodulatory therapy and an increased prevalence of irreversible neuronal damage, and often have the additional burden of an underlying malignancy. […] Group II antibodies target cell-surface neuronal antigens, are less likely to be associated with an underlying malignancy, and use more restricted humoral immune mechanisms of neurotoxicity that typically respond better to early immunomodulatory therapy. […] Group II antibodies also represent a more specific clinical marker of disease for antibody-mediated encephalitis, with reduction in serum antibody titers following treatment directly associated with improved neurologic outcomes. […] N-methyl D-aspartate receptor (NMDAr) encephalitis is one of the most common and best characterized subtypes of autoimmune encephalitis classically seen in young women and children with autoimmunity not associated with cancer.

• #26 Autoimmune Encephalitis – EMCrit Project

  https://emcrit.org/ibcc/ae/

  Autoimmune encephalitis refers to a group of disorders which vary along numerous dimensions, as shown in the table below. This includes disorders associated with malignancy (paraneoplastic encephalitides), as well as postinfectious and idiopathic disorders. […] Our understanding of autoimmune encephalitis has advanced enormously in the past two decades. It is currently estimated that autoimmune encephalitis is as common as viral encephalitis (although historically, most cases of autoimmune encephalitis have eluded accurate diagnosis). With the increasing use of checkpoint inhibitors for treatment of malignancy, it’s conceivable that autoimmune encephalitis could become the most common form of encephalitis. […] These antibodies are not directly pathogenic, but rather they are merely immunological markers that correspond to autoimmune illness. The pathogenesis of these processes involves cellular damage due to a cytotoxic T-cell response.

• #27 Autoimmune Encephalitis: Pathophysiology and Imaging Review of an Overlooked Diagnosis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7960083/

  Group I antibodies are also associated with poor clinical outcomes, characterized by a decreased response to immunomodulatory therapy and an increased prevalence of irreversible neuronal damage, and often have the additional burden of an underlying malignancy. […] Group II antibodies target cell-surface neuronal antigens, are less likely to be associated with an underlying malignancy, and use more restricted humoral immune mechanisms of neurotoxicity that typically respond better to early immunomodulatory therapy. […] Group II antibodies also represent a more specific clinical marker of disease for antibody-mediated encephalitis, with reduction in serum antibody titers following treatment directly associated with improved neurologic outcomes. […] N-methyl D-aspartate receptor (NMDAr) encephalitis is one of the most common and best characterized subtypes of autoimmune encephalitis classically seen in young women and children with autoimmunity not associated with cancer.

• #28 Autoimmune Encephalitis: Pathophysiology and Imaging Review of an Overlooked Diagnosis | American Journal of Neuroradiology

  http://www.ajnr.org/content/38/6/1070

  Group II antibodies target cell-surface neuronal antigens, are less likely to be associated with an underlying malignancy, and use more restricted humoral immune mechanisms of neurotoxicity that typically respond better to early immunomodulatory therapy. […] N-methyl D-aspartate receptor (NMDAr) encephalitis is one of the most common and best characterized subtypes of autoimmune encephalitis classically seen in young women and children with autoimmunity not associated with cancer. […] This subtype is mediated by immunoglobulin G antibodies against the GluN1 subunit of the neuronal NMDAr, with inflammatory neuronal dysfunction that is thought to be initially reversible but potentially progresses to permanent neuronal destruction if untreated, due to prolonged inflammation and N-methyl D-aspartate (NMDA)-mediated glutamate excitotoxicity.

• #29 Autoimmune Encephalitis: Pathophysiology and Imaging Review of an Overlooked Diagnosis | American Journal of Neuroradiology

  http://www.ajnr.org/content/38/6/1070

  Group II antibodies target cell-surface neuronal antigens, are less likely to be associated with an underlying malignancy, and use more restricted humoral immune mechanisms of neurotoxicity that typically respond better to early immunomodulatory therapy. […] N-methyl D-aspartate receptor (NMDAr) encephalitis is one of the most common and best characterized subtypes of autoimmune encephalitis classically seen in young women and children with autoimmunity not associated with cancer. […] This subtype is mediated by immunoglobulin G antibodies against the GluN1 subunit of the neuronal NMDAr, with inflammatory neuronal dysfunction that is thought to be initially reversible but potentially progresses to permanent neuronal destruction if untreated, due to prolonged inflammation and N-methyl D-aspartate (NMDA)-mediated glutamate excitotoxicity.

• #30 Autoimmune Encephalitis – EMCrit Project

  https://emcrit.org/ibcc/ae/

  Since these disorders are T-cell mediated, they respond less well to immunotherapies such as plasmapheresis or IVIG. […] Overall, these disorders are often more closely linked to malignancy. […] Antibodies are directly pathologic in these disorders. […] Since antibodies are the culprit, patients respond better to immunotherapy and plasma exchange. However, patients can often relapse following recovery. […] Overall, these disorders are often less closely linked to malignancy. For example, some may be triggered by immunological mimicry following viral infection. […] The ability to recover function is better, since dysfunction often reflects transient neuronal dysfunction (rather than cellular destruction). Patients can make stunning recoveries, despite initially being entirely debilitated.

• #31 Autoimmune Encephalitis: Pathophysiology and Imaging Review of an Overlooked Diagnosis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7960083/

  Group I antibodies are also associated with poor clinical outcomes, characterized by a decreased response to immunomodulatory therapy and an increased prevalence of irreversible neuronal damage, and often have the additional burden of an underlying malignancy. […] Group II antibodies target cell-surface neuronal antigens, are less likely to be associated with an underlying malignancy, and use more restricted humoral immune mechanisms of neurotoxicity that typically respond better to early immunomodulatory therapy. […] Group II antibodies also represent a more specific clinical marker of disease for antibody-mediated encephalitis, with reduction in serum antibody titers following treatment directly associated with improved neurologic outcomes. […] N-methyl D-aspartate receptor (NMDAr) encephalitis is one of the most common and best characterized subtypes of autoimmune encephalitis classically seen in young women and children with autoimmunity not associated with cancer.

• #32 SciELO Brazil – Autoimmune encephalitis: a review of diagnosis and treatment Autoimmune encephalitis: a review of diagnosis and treatment

  https://www.scielo.br/j/anp/a/mqLMtVDZLLF566CwstHwyhy/

  Autoimmune encephalitis presents an immune response against neuronal autoantigens with production of antibodies. Anti-neuronal antibodies are classified into antibodies against cell surface antigens (CSAab), antibodies against synaptic antigens (SyAab) and antibodies against intraneuronal antigens (INAab), also known as onconeural antibodies. The CSAab (i.e., anti-NMDAR antibodies) target molecules involved in neurotransmission leading to neuronal dysfunction. They may have agonistic or antagonistic effects on the receptors, block ion channel pores or disrupt the interaction with neighboring molecules. They could also alter receptor localization at the membrane or cause receptor internalization, thus reducing cell surface expression of receptors. Moreover, they could lead to complement deposition and activation of natural killer cells resulting in cell death. The SyAab are believed to contribute to alteration of neurotransmitter release. In contrast, INAab (i.e., anti-Hu, anti-Yo, anti-Ma) are most likely not directly pathogenic and probably an epiphenomenon of T-cell-mediated immune response. The term AIE is used to describe a group of neurological disorders with symptoms of limbic and extra-limbic dysfunction in association with CSAab or SyAab. Patients may have antibodies of more than one type, and CSAab and SyAab may be present together with anti-INAab, especially in paraneoplastic AIE. Patients with AIE associated with CSAab have a more favorable prognosis. In contrast, those with AIE associated with INAab often show limited response to immunotherapy and their symptoms are mostly irreversible due to T-cell-mediated neuronal damage.

• #33 SciELO Brazil – Autoimmune encephalitis: a review of diagnosis and treatment Autoimmune encephalitis: a review of diagnosis and treatment

  https://www.scielo.br/j/anp/a/mqLMtVDZLLF566CwstHwyhy/

  Autoimmune encephalitis presents an immune response against neuronal autoantigens with production of antibodies. Anti-neuronal antibodies are classified into antibodies against cell surface antigens (CSAab), antibodies against synaptic antigens (SyAab) and antibodies against intraneuronal antigens (INAab), also known as onconeural antibodies. The CSAab (i.e., anti-NMDAR antibodies) target molecules involved in neurotransmission leading to neuronal dysfunction. They may have agonistic or antagonistic effects on the receptors, block ion channel pores or disrupt the interaction with neighboring molecules. They could also alter receptor localization at the membrane or cause receptor internalization, thus reducing cell surface expression of receptors. Moreover, they could lead to complement deposition and activation of natural killer cells resulting in cell death. The SyAab are believed to contribute to alteration of neurotransmitter release. In contrast, INAab (i.e., anti-Hu, anti-Yo, anti-Ma) are most likely not directly pathogenic and probably an epiphenomenon of T-cell-mediated immune response. The term AIE is used to describe a group of neurological disorders with symptoms of limbic and extra-limbic dysfunction in association with CSAab or SyAab. Patients may have antibodies of more than one type, and CSAab and SyAab may be present together with anti-INAab, especially in paraneoplastic AIE. Patients with AIE associated with CSAab have a more favorable prognosis. In contrast, those with AIE associated with INAab often show limited response to immunotherapy and their symptoms are mostly irreversible due to T-cell-mediated neuronal damage.

• #34 SciELO Brazil – Autoimmune encephalitis: a review of diagnosis and treatment Autoimmune encephalitis: a review of diagnosis and treatment

  https://www.scielo.br/j/anp/a/mqLMtVDZLLF566CwstHwyhy/

  Autoimmune encephalitis presents an immune response against neuronal autoantigens with production of antibodies. Anti-neuronal antibodies are classified into antibodies against cell surface antigens (CSAab), antibodies against synaptic antigens (SyAab) and antibodies against intraneuronal antigens (INAab), also known as onconeural antibodies. The CSAab (i.e., anti-NMDAR antibodies) target molecules involved in neurotransmission leading to neuronal dysfunction. They may have agonistic or antagonistic effects on the receptors, block ion channel pores or disrupt the interaction with neighboring molecules. They could also alter receptor localization at the membrane or cause receptor internalization, thus reducing cell surface expression of receptors. Moreover, they could lead to complement deposition and activation of natural killer cells resulting in cell death. The SyAab are believed to contribute to alteration of neurotransmitter release. In contrast, INAab (i.e., anti-Hu, anti-Yo, anti-Ma) are most likely not directly pathogenic and probably an epiphenomenon of T-cell-mediated immune response. The term AIE is used to describe a group of neurological disorders with symptoms of limbic and extra-limbic dysfunction in association with CSAab or SyAab. Patients may have antibodies of more than one type, and CSAab and SyAab may be present together with anti-INAab, especially in paraneoplastic AIE. Patients with AIE associated with CSAab have a more favorable prognosis. In contrast, those with AIE associated with INAab often show limited response to immunotherapy and their symptoms are mostly irreversible due to T-cell-mediated neuronal damage.

• #35 SciELO Brazil – Autoimmune encephalitis: a review of diagnosis and treatment Autoimmune encephalitis: a review of diagnosis and treatment

  https://www.scielo.br/j/anp/a/mqLMtVDZLLF566CwstHwyhy/

  Autoimmune encephalitis presents an immune response against neuronal autoantigens with production of antibodies. Anti-neuronal antibodies are classified into antibodies against cell surface antigens (CSAab), antibodies against synaptic antigens (SyAab) and antibodies against intraneuronal antigens (INAab), also known as onconeural antibodies. The CSAab (i.e., anti-NMDAR antibodies) target molecules involved in neurotransmission leading to neuronal dysfunction. They may have agonistic or antagonistic effects on the receptors, block ion channel pores or disrupt the interaction with neighboring molecules. They could also alter receptor localization at the membrane or cause receptor internalization, thus reducing cell surface expression of receptors. Moreover, they could lead to complement deposition and activation of natural killer cells resulting in cell death. The SyAab are believed to contribute to alteration of neurotransmitter release. In contrast, INAab (i.e., anti-Hu, anti-Yo, anti-Ma) are most likely not directly pathogenic and probably an epiphenomenon of T-cell-mediated immune response. The term AIE is used to describe a group of neurological disorders with symptoms of limbic and extra-limbic dysfunction in association with CSAab or SyAab. Patients may have antibodies of more than one type, and CSAab and SyAab may be present together with anti-INAab, especially in paraneoplastic AIE. Patients with AIE associated with CSAab have a more favorable prognosis. In contrast, those with AIE associated with INAab often show limited response to immunotherapy and their symptoms are mostly irreversible due to T-cell-mediated neuronal damage.

• #36 SciELO Brazil – Autoimmune encephalitis: a review of diagnosis and treatment Autoimmune encephalitis: a review of diagnosis and treatment

  https://www.scielo.br/j/anp/a/mqLMtVDZLLF566CwstHwyhy/

  Autoimmune encephalitis presents an immune response against neuronal autoantigens with production of antibodies. Anti-neuronal antibodies are classified into antibodies against cell surface antigens (CSAab), antibodies against synaptic antigens (SyAab) and antibodies against intraneuronal antigens (INAab), also known as onconeural antibodies. The CSAab (i.e., anti-NMDAR antibodies) target molecules involved in neurotransmission leading to neuronal dysfunction. They may have agonistic or antagonistic effects on the receptors, block ion channel pores or disrupt the interaction with neighboring molecules. They could also alter receptor localization at the membrane or cause receptor internalization, thus reducing cell surface expression of receptors. Moreover, they could lead to complement deposition and activation of natural killer cells resulting in cell death. The SyAab are believed to contribute to alteration of neurotransmitter release. In contrast, INAab (i.e., anti-Hu, anti-Yo, anti-Ma) are most likely not directly pathogenic and probably an epiphenomenon of T-cell-mediated immune response. The term AIE is used to describe a group of neurological disorders with symptoms of limbic and extra-limbic dysfunction in association with CSAab or SyAab. Patients may have antibodies of more than one type, and CSAab and SyAab may be present together with anti-INAab, especially in paraneoplastic AIE. Patients with AIE associated with CSAab have a more favorable prognosis. In contrast, those with AIE associated with INAab often show limited response to immunotherapy and their symptoms are mostly irreversible due to T-cell-mediated neuronal damage.

• #37 SciELO Brazil – Autoimmune encephalitis: a review of diagnosis and treatment Autoimmune encephalitis: a review of diagnosis and treatment

  https://www.scielo.br/j/anp/a/mqLMtVDZLLF566CwstHwyhy/

  Autoimmune encephalitis presents an immune response against neuronal autoantigens with production of antibodies. Anti-neuronal antibodies are classified into antibodies against cell surface antigens (CSAab), antibodies against synaptic antigens (SyAab) and antibodies against intraneuronal antigens (INAab), also known as onconeural antibodies. The CSAab (i.e., anti-NMDAR antibodies) target molecules involved in neurotransmission leading to neuronal dysfunction. They may have agonistic or antagonistic effects on the receptors, block ion channel pores or disrupt the interaction with neighboring molecules. They could also alter receptor localization at the membrane or cause receptor internalization, thus reducing cell surface expression of receptors. Moreover, they could lead to complement deposition and activation of natural killer cells resulting in cell death. The SyAab are believed to contribute to alteration of neurotransmitter release. In contrast, INAab (i.e., anti-Hu, anti-Yo, anti-Ma) are most likely not directly pathogenic and probably an epiphenomenon of T-cell-mediated immune response. The term AIE is used to describe a group of neurological disorders with symptoms of limbic and extra-limbic dysfunction in association with CSAab or SyAab. Patients may have antibodies of more than one type, and CSAab and SyAab may be present together with anti-INAab, especially in paraneoplastic AIE. Patients with AIE associated with CSAab have a more favorable prognosis. In contrast, those with AIE associated with INAab often show limited response to immunotherapy and their symptoms are mostly irreversible due to T-cell-mediated neuronal damage.

• #38 SciELO Brazil – Autoimmune encephalitis: a review of diagnosis and treatment Autoimmune encephalitis: a review of diagnosis and treatment

  https://www.scielo.br/j/anp/a/mqLMtVDZLLF566CwstHwyhy/

  Autoimmune encephalitis presents an immune response against neuronal autoantigens with production of antibodies. Anti-neuronal antibodies are classified into antibodies against cell surface antigens (CSAab), antibodies against synaptic antigens (SyAab) and antibodies against intraneuronal antigens (INAab), also known as onconeural antibodies. The CSAab (i.e., anti-NMDAR antibodies) target molecules involved in neurotransmission leading to neuronal dysfunction. They may have agonistic or antagonistic effects on the receptors, block ion channel pores or disrupt the interaction with neighboring molecules. They could also alter receptor localization at the membrane or cause receptor internalization, thus reducing cell surface expression of receptors. Moreover, they could lead to complement deposition and activation of natural killer cells resulting in cell death. The SyAab are believed to contribute to alteration of neurotransmitter release. In contrast, INAab (i.e., anti-Hu, anti-Yo, anti-Ma) are most likely not directly pathogenic and probably an epiphenomenon of T-cell-mediated immune response. The term AIE is used to describe a group of neurological disorders with symptoms of limbic and extra-limbic dysfunction in association with CSAab or SyAab. Patients may have antibodies of more than one type, and CSAab and SyAab may be present together with anti-INAab, especially in paraneoplastic AIE. Patients with AIE associated with CSAab have a more favorable prognosis. In contrast, those with AIE associated with INAab often show limited response to immunotherapy and their symptoms are mostly irreversible due to T-cell-mediated neuronal damage.

• #39 Autoimmune Encephalitis: Pathophysiology and Imaging Review of an Overlooked Diagnosis | American Journal of Neuroradiology

  http://www.ajnr.org/content/38/6/1070

  Group II antibodies target cell-surface neuronal antigens, are less likely to be associated with an underlying malignancy, and use more restricted humoral immune mechanisms of neurotoxicity that typically respond better to early immunomodulatory therapy. […] N-methyl D-aspartate receptor (NMDAr) encephalitis is one of the most common and best characterized subtypes of autoimmune encephalitis classically seen in young women and children with autoimmunity not associated with cancer. […] This subtype is mediated by immunoglobulin G antibodies against the GluN1 subunit of the neuronal NMDAr, with inflammatory neuronal dysfunction that is thought to be initially reversible but potentially progresses to permanent neuronal destruction if untreated, due to prolonged inflammation and N-methyl D-aspartate (NMDA)-mediated glutamate excitotoxicity.

• #40 Structural basis for antibody-mediated NMDA receptor clustering and endocytosis in autoimmune encephalitis | Nature Structural & Molecular Biology

  https://www.nature.com/articles/s41594-024-01387-3

  Antibodies against N-methyl-d-aspartate receptors (NMDARs) are most frequently detected in persons with autoimmune encephalitis (AE) and used as diagnostic biomarkers. […] Here, we reconstructed nanodiscs containing green fluorescent protein-fused NMDARs to label and sort individual immune B cells from persons with AE and further cloned and identified mAbs against NMDARs. […] Importantly, these mAbs reduced the surface NMDARs and NMDAR-mediated currents, without tonically affecting NMDAR channel gating. […] These structural and functional findings imply that the design of neutralizing antibody binding to the R1 lobe of NMDARs represents a potential therapy for AE treatment. […] Clinical evidence indicates that viral infection or peripheral tumorigenesis could initiate the immune process and production of autoantibodies, which cross the blood-brain barrier and directly bind to NMDARs on the synaptic membrane.

• #41 Anti-NMDA receptor encephalitis – Wikipedia

  https://en.wikipedia.org/wiki/Anti-NMDA_receptor_encephalitis

  Autoimmune encephalitis is a type of brain inflammation caused by antibodies. […] The underlying mechanism is autoimmune, with the primary target being the GluN1 subunit of the N-methyl-D-aspartate receptors (NMDAR) in the brain. […] The condition is mediated by autoantibodies that target NMDA receptors in the brain. […] These can be produced by cross reactivity with NMDA receptors in teratomas, which contain many cell types, including brain cells, and thus present a window in which a breakdown in immunological tolerance can occur. […] Other autoimmune mechanisms are suspected for patients who do not have tumors. […] Passive access involves the diffusion of antibodies from the blood across a pathologically disrupted blood-brain barrier (BBB). […] Intrathecal production (production of antibodies in the intrathecal space) is also a possible mechanism.

• #42 Anti-NMDA receptor encephalitis – Wikipedia

  https://en.wikipedia.org/wiki/Anti-NMDA_receptor_encephalitis

  Once the antibodies have entered the CSF, they bind to the NR1 subunit of the NMDA receptor. […] A reduction in the density of NMDA receptors on the post synaptic knob, due to receptor internalization once the antibody has bound. […] The direct antagonism of the NMDA receptor by the antibody, similar to the action of the classic dissociative anesthetics phencyclidine and ketamine. […] The recruitment of the complement cascade via the classical pathway (antibody-antigen interaction).

• #43 Autoimmune Encephalitis: Pathophysiology and Imaging Review of an Overlooked Diagnosis | American Journal of Neuroradiology

  http://www.ajnr.org/content/38/6/1070

  Group II antibodies target cell-surface neuronal antigens, are less likely to be associated with an underlying malignancy, and use more restricted humoral immune mechanisms of neurotoxicity that typically respond better to early immunomodulatory therapy. […] N-methyl D-aspartate receptor (NMDAr) encephalitis is one of the most common and best characterized subtypes of autoimmune encephalitis classically seen in young women and children with autoimmunity not associated with cancer. […] This subtype is mediated by immunoglobulin G antibodies against the GluN1 subunit of the neuronal NMDAr, with inflammatory neuronal dysfunction that is thought to be initially reversible but potentially progresses to permanent neuronal destruction if untreated, due to prolonged inflammation and N-methyl D-aspartate (NMDA)-mediated glutamate excitotoxicity.

• #44

  https://link.springer.com/article/10.1007/s00415-023-11685-3

  Rather, in most presentations, an abrupt onset together with the canonical diffuse and multimodal clinical features described above should be considered as the core features of NMDAR-AbE. […] In NMDAR-AbE, antibodies are reported to bind the extracellular amino-terminal domain of the NR1 subunit. […] Patient serum and CSF have been shown in vitro to reduce the size of NMDAR clusters giving rise to impaired glutamatergic signaling. […] The reduction of NMDAR cluster density is likely driven by two phenomena: internalization of NMDARs and their lateral dispersion from key synaptic signaling areas. […] In LGI1- and CASPR2-antibody encephalitis, there is an evolving neuroscientific understanding of the role of AMPA receptors in disease manifestations. […] In vitro and in vivo data demonstrated that LGI1-antibodies disrupt the binding of LGI1 to ADAM22/23, leading to a reduction of post-synaptic AMPA receptors with consequent excess network excitability and seizures. […] In CASPR2-antibody encephalitis, evidence from animal models suggests that similar mechanisms are in operation, with silencing of CASPR2 either genetically or with autoantibodies resulting in altered AMPA receptor function and subsequent disruption of cortical excitatory transmission.

• #45

  https://link.springer.com/article/10.1007/s00415-023-11685-3

  Rather, in most presentations, an abrupt onset together with the canonical diffuse and multimodal clinical features described above should be considered as the core features of NMDAR-AbE. […] In NMDAR-AbE, antibodies are reported to bind the extracellular amino-terminal domain of the NR1 subunit. […] Patient serum and CSF have been shown in vitro to reduce the size of NMDAR clusters giving rise to impaired glutamatergic signaling. […] The reduction of NMDAR cluster density is likely driven by two phenomena: internalization of NMDARs and their lateral dispersion from key synaptic signaling areas. […] In LGI1- and CASPR2-antibody encephalitis, there is an evolving neuroscientific understanding of the role of AMPA receptors in disease manifestations. […] In vitro and in vivo data demonstrated that LGI1-antibodies disrupt the binding of LGI1 to ADAM22/23, leading to a reduction of post-synaptic AMPA receptors with consequent excess network excitability and seizures. […] In CASPR2-antibody encephalitis, evidence from animal models suggests that similar mechanisms are in operation, with silencing of CASPR2 either genetically or with autoantibodies resulting in altered AMPA receptor function and subsequent disruption of cortical excitatory transmission.

• #46 :: JCN :: Journal of Clinical Neurology

  https://www.thejcn.com/DOIx.php?id=10.3988/jcn.2016.12.1.1

  The mechanisms of NMDAR antibodies have been extensively studied: these antibodies cross-link and internalize the target receptors, depleting NMDARs from synapses. […] The antibodies are clearly directly pathogenic; passive transfer into the brains of rodents produced neurological symptoms that correlate with reduction in surface NMDARs on neurons.

• #47

  https://link.springer.com/article/10.1007/s00415-023-11685-3

  Rather, in most presentations, an abrupt onset together with the canonical diffuse and multimodal clinical features described above should be considered as the core features of NMDAR-AbE. […] In NMDAR-AbE, antibodies are reported to bind the extracellular amino-terminal domain of the NR1 subunit. […] Patient serum and CSF have been shown in vitro to reduce the size of NMDAR clusters giving rise to impaired glutamatergic signaling. […] The reduction of NMDAR cluster density is likely driven by two phenomena: internalization of NMDARs and their lateral dispersion from key synaptic signaling areas. […] In LGI1- and CASPR2-antibody encephalitis, there is an evolving neuroscientific understanding of the role of AMPA receptors in disease manifestations. […] In vitro and in vivo data demonstrated that LGI1-antibodies disrupt the binding of LGI1 to ADAM22/23, leading to a reduction of post-synaptic AMPA receptors with consequent excess network excitability and seizures. […] In CASPR2-antibody encephalitis, evidence from animal models suggests that similar mechanisms are in operation, with silencing of CASPR2 either genetically or with autoantibodies resulting in altered AMPA receptor function and subsequent disruption of cortical excitatory transmission.

• #48 Structural basis for antibody-mediated NMDA receptor clustering and endocytosis in autoimmune encephalitis | Nature Structural & Molecular Biology

  https://www.nature.com/articles/s41594-024-01387-3

  Our results showed that mAbs interacted with the peripheral GluN1-NTDs of NMDAR, which varies from the LBD or ion channel gate, without acutely changing the channel activity as seen with anti-GABAA receptor antibodies. […] The binding of these autoantibodies to various ion channels including excitatory glutamate receptors and inhibitory GABAA and glycine receptors altered the synaptic neurotransmission and excitatory-inhibitory balance. […] These data suggested that patient-derived mAbs clustered NMDARs with different interaction patterns in solution and presumably induced receptor clustering on the neuronal surface.

• #49 Autoimmune Encephalitis: Pathophysiology and Imaging Review of an Overlooked Diagnosis | American Journal of Neuroradiology

  http://www.ajnr.org/content/38/6/1070

  Group II antibodies target cell-surface neuronal antigens, are less likely to be associated with an underlying malignancy, and use more restricted humoral immune mechanisms of neurotoxicity that typically respond better to early immunomodulatory therapy. […] N-methyl D-aspartate receptor (NMDAr) encephalitis is one of the most common and best characterized subtypes of autoimmune encephalitis classically seen in young women and children with autoimmunity not associated with cancer. […] This subtype is mediated by immunoglobulin G antibodies against the GluN1 subunit of the neuronal NMDAr, with inflammatory neuronal dysfunction that is thought to be initially reversible but potentially progresses to permanent neuronal destruction if untreated, due to prolonged inflammation and N-methyl D-aspartate (NMDA)-mediated glutamate excitotoxicity.

• #50 SciELO Brazil – Autoimmune encephalitis: a review of diagnosis and treatment Autoimmune encephalitis: a review of diagnosis and treatment

  https://www.scielo.br/j/anp/a/mqLMtVDZLLF566CwstHwyhy/

  Autoimmune encephalitis is typically an acute or subacute onset and that may become chronic later. Suggested mechanisms that may trigger AIE include tumors (paraneoplastic), infections (parainfectious), or it may be cryptogenic. […] Autoimmune encephalitis has a wide variety of clinical manifestations including behavioral and psychiatric symptoms, autonomic disturbances, movement disorders and seizures. We reviewed common causes of AIE and discuss their pathophysiology, diagnostic approach and management.

• #51 Autoimmune Encephalitis: Pathophysiology and Imaging Review of an Overlooked Diagnosis | American Journal of Neuroradiology

  http://www.ajnr.org/content/38/6/1070

  Antibody-mediated CNS disorders can be classified into 2 broad categories, paraneoplastic or nonparaneoplastic, based on the presence or absence of an underlying malignancy, respectively. […] Paraneoplastic syndromes affecting the CNS are generally thought to develop in cancer when antigens shared by tumor cells and native nonneoplastic neuronal cells result in an antibody-mediated attack on previously immune-privileged neuronal structures. […] Regardless of the etiology and antibody profile, there is a clear predilection in autoimmune encephalitis for antigens within the limbic system. […] Group I antibodies target intracellular neuronal antigens, are more closely associated with an underlying malignancy, and use the same cytotoxic T-cell mechanisms when targeting the intracellular neuronal antigens and onconeuronal antigens as part of the immune response to cancer.

• #52 Azthena logo with the word Azthena

  https://www.news-medical.net/health/Autoimmune-Encephalitis-Pathophysiology.aspx

  In general, these antibodies themselves cause the clinical manifestations by disrupting synaptic processing in the affected neurons, but not causing neuronal destruction. […] The antibody titer thus determines the extent of depletion of receptors. […] How these autoantibodies arise is a question being asked. […] The tumor, if present, usually expresses the same antigen that is bound on the neuronal surface, and this is responsible for breaching the immunologic tolerance and raising an immune reaction against the neurons in question. […] Antagonism of the NMDA receptors leads to deficits in cognitive, psychological and sensory processing. […] IgG antibodies to NMDAR occur in both serum and (more reliably) CSF in association with acute psychotic features in anti-NMDAR encephalitis. […] Frontal and temporal lobe atrophy is prominent in this condition, which is suggestive because of the high density of NMDAR in this region of the brain.

• #53 Azthena logo with the word Azthena

  https://www.news-medical.net/health/Autoimmune-Encephalitis-Pathophysiology.aspx

  In general, these antibodies themselves cause the clinical manifestations by disrupting synaptic processing in the affected neurons, but not causing neuronal destruction. […] The antibody titer thus determines the extent of depletion of receptors. […] How these autoantibodies arise is a question being asked. […] The tumor, if present, usually expresses the same antigen that is bound on the neuronal surface, and this is responsible for breaching the immunologic tolerance and raising an immune reaction against the neurons in question. […] Antagonism of the NMDA receptors leads to deficits in cognitive, psychological and sensory processing. […] IgG antibodies to NMDAR occur in both serum and (more reliably) CSF in association with acute psychotic features in anti-NMDAR encephalitis. […] Frontal and temporal lobe atrophy is prominent in this condition, which is suggestive because of the high density of NMDAR in this region of the brain.

• #54

  https://link.springer.com/article/10.1007/s00234-024-03318-x

  More in general, different antibodies have a different likelihood of tumor associations, and the updated 2021 diagnostic criteria for AE propose to stratify AE-related antibodies in low-, intermediate- and high-risk, based on the likelihood of tumor associations. […] In addition to a worse prognosis due to the underlying malignancies, Group I AE are generally characterized by a worse treatment response and are more likely to induce irreversible tissue damage. […] Such differences are related to the underpinning pathophysiological mechanisms. […] While in Group II the autoantibodies are believed to serve a pathogenetic function, in Group I the immune-mediated damage is sustained by CD8+T-cells and the extent of the antibody contribution to the neural damage is still being evaluated. […] As a general rule, in Group I antitumoral immune response cross-reacts with neural antigens causing lymphocyte-mediated neuronal killing.

• #55

  https://link.springer.com/article/10.1007/s00234-024-03318-x

  More in general, different antibodies have a different likelihood of tumor associations, and the updated 2021 diagnostic criteria for AE propose to stratify AE-related antibodies in low-, intermediate- and high-risk, based on the likelihood of tumor associations. […] In addition to a worse prognosis due to the underlying malignancies, Group I AE are generally characterized by a worse treatment response and are more likely to induce irreversible tissue damage. […] Such differences are related to the underpinning pathophysiological mechanisms. […] While in Group II the autoantibodies are believed to serve a pathogenetic function, in Group I the immune-mediated damage is sustained by CD8+T-cells and the extent of the antibody contribution to the neural damage is still being evaluated. […] As a general rule, in Group I antitumoral immune response cross-reacts with neural antigens causing lymphocyte-mediated neuronal killing.

• #56

  https://link.springer.com/article/10.1007/s00234-024-03318-x

  This distinction bears significant clinical, prognostic, and pathophysiological implications, a general rule being that Group I AE are associated with a worse prognosis than Group II AE. […] Group I AE are more likely associated with an underlying malignancy (Group I Ab are also referred to as onconeural antibodies). […] For instance, anti-Hu AE the most common paraneoplastic AE with a reported incidence of 0.4/million person-years is associated with tumors in 7580% of cases (mainly small cell lung carcinoma, SCLC). […] On the other hand, Group II AE are more commonly non-paraneoplastic conditions that can affect patients belonging to a wide age range, including younger and sometimes pediatric patients. […] Despite the abovementioned rule of thumb for neoplastic associations is overall valid, some AE subtypes represent notable exceptions.

• #57 Autoimmune Encephalitis in Rural Central Illinois | IntechOpen

  https://www.intechopen.com/chapters/38018

  A practical classification of autoimmune encephalitis can be based on pathogenic mechanism. In some instances, autoimmunity is triggered by a known or occult neoplasm, however in the absence of malignancy, auto-antibodies are directed against intracellular or neural membrane receptors. The cause of autoimmunity in non-PNS cases is unclear. Antibodies may be directed against intracellular antigens: (anti-Hu and anti-Ma), or antibodies against neuronal antigens (VGKC, NMDA receptor and Gamma-amino butyric acid (GABA) type b receptors) (1-25). Identification of these antibodies may provide a clue as to the possible associated neoplasm. For instance, anti-NMDA encephalitis is frequently associated with germ-cell tumors of the ovary and may rarely be seen in men, as was the case we reported. Anti-Ma antibodies are often present among patients with germ cell tumors of the testis. The anti-Hu is frequently present in small cell lung carcinoma (SCLC). Recent autoimmune encephalitis with antibodies against the alpha-amino-3 hydroxi-isoxazole propionic acid (AMPA) receptor have been reported reported [24]. Practically, the entire gamut of known auto-antibodies should be ordered in this group of patients as there is significant clinical overlap despite diverse neuronal antigenic targets. Once herpes virus encephalitis is ruled out, an investigation with auto-antibodies evaluation and immunosuppressive therapy can be initiated (Table 1). Given that reports from the immunologic testing usually take anywhere from two to three weeks, treatment should be initiated even before a diagnosis is confirmed. The initial therapy consists of high-dose intravenous Methyl-prednisolone, 1 gm daily for five days, followed by intravenous human Ig, usually at a dose of 0.4 gm/ kg per day for five additional days. Following a definitive diagnosis of autoimmune encephalitis, a plan of prolonged immunosuppressive treatment may be designed. […] The neuropathologic findings in patients with paraneoplastic (PNS) autoimmune encephalitis include perivascular and interstitial lymphocytic cuffing, microglial proliferation, gliosis and neuronal degeneration. It is likely that non-PNS autoimmune encephalitis is associated with similar findings.

• #58 Autoimmune Encephalitis – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK578203/

  There have been case reports and observational studies to suggest that herpes simplex virus encephalitis (HSVE) triggers an immune response, causing anti-NMDAR encephalitis. […] Genetic factors like human leukocyte antigen (HLA) were strongly associated with certain antibody production causing autoimmune responses, eg, IgLON 5 antibody encephalitis.

• #59 Autoimmune Encephalitis – Autoimmune Encephalitis

  https://autoimmune-encephalitis.org/autoimmune-encephalitis/

  Most importantly, Autoimmune Encephalitis IS TREATABLE and almost invariably responds to immunotherapies with considerable potential to reverse the impairments caused by these attacking antibodies. Immunotherapies can slow down the progression of the disease, stop the antibodies from attacking and with some treatments kill the attacking antibody which may sometimes leads to complete recovery. […] Autoimmune Encephalitis is caused by a tumor or viral trigger. Antibodies are created through a process of molecular mimicry and epitope spreading against either infectious or neoplastic agent. Research has proven that patients can experience a virus triggering synaptic autoimmunity in the case of herpes simplex virus and possibly other viral encephalitides. […] While several infectious agents have been implicated in anti-NMDA encephalitis, with the exception of HSV’s proven link, these cases are novel and suggestive that it is likely science will show other cases in the future where neurotropic viruses can induce similar pathology. […] Presently in 2020, findings suggest that SARS-CoV-2 (COVID-19) has also triggered secondary autoimmune encephalitis. The following months will show whether such autoreactivity can cause persisting neurological morbidity even after clearance of SARS-CoV-2 and remission of COVID-19.

• #60 Autoimmune Encephalitis – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK578203/

  There have been case reports and observational studies to suggest that herpes simplex virus encephalitis (HSVE) triggers an immune response, causing anti-NMDAR encephalitis. […] Genetic factors like human leukocyte antigen (HLA) were strongly associated with certain antibody production causing autoimmune responses, eg, IgLON 5 antibody encephalitis.

• #61 Encephalitis – Neurologic Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/neurologic-disorders/brain-infections/encephalitis

  Encephalitis can occur as a secondary immunologic complication of certain viral infections or vaccinations. Inflammatory demyelination of the brain and spinal cord can occur 1 to 3 weeks later (as acute disseminated encephalomyelitis); the immune system attacks one or more central nervous system (CNS) antigens that resemble proteins of the infectious agent. […] Immunologically mediated encephalitis also occurs in patients with cancer and other autoimmune disorders. […] Rarely, apparent encephalitis has developed in patients with COVID-19, caused by the novel pandemic severe acute respiratory syndrome coronavirus (SARS-CoV2); the mechanism is not clear, but an immunologic contribution to the mechanism of apparent encephalitis is possible. […] Encephalopathies caused by autoantibodies to neuronal membrane proteins (eg, N-methyl-d-aspartate receptors [NMDAR]) may mimic viral encephalitis. Studies indicate that anti-NMDAR encephalitis is more common than viral encephalitides. […] Anti-NMDAR encephalitis also occurs as a postinfectious complication of HSV encephalitis, resulting in clinical decline within weeks of the HSV infection.

• #62 Autoimmune Encephalitis—A Multifaceted Pathology

  https://www.mdpi.com/2227-9059/11/8/2176

  The second mechanism in autoimmune encephalitis involves cytotoxic T cell-mediated neuronal destruction. This mechanism is associated with the presence of antibodies targeting cytoplasmic antigens or nuclear onconeural antigens. These antibodies are markers for the concurrent pathogenic cytotoxic T cell response, which leads to the destruction of neurons. This immune response is typically associated with a limited response to treatment and can result in a worse neurological outcome due to the rapid destruction of neurons. […] It is widely accepted that circulating neuronal autoantibodies need to penetrate the tightly regulated blood-brain barrier in order to exert their pathogenic effects within the central nervous system. However, the specific mechanisms by which these antibodies gain access to the CNS are still not well understood and remain largely unknown. Despite ongoing research, the precise mechanisms involved in allowing these autoantibodies to cross the blood-brain barrier have not been fully elucidated. In recent times, the relationship between the brain’s “glymphatic” system and dual lymphatic channels has been discovered. The glymphatic system involves the flow of cerebrospinal fluid (CSF) through periarteriolar and parenchymal extracellular spaces, facilitated by glial cells. This system allows for the passage of small molecules, including central nervous system (CNS) proteins. This discovery challenges the long-held belief in the immune privilege status of the CNS, as intracranial antigens can potentially interact with the immune system through these pathways. The implications of this relationship on the mechanisms by which circulating neuronal autoantibodies access the CNS are still being investigated. Additional possibilities for the access of circulating neuronal autoantibodies to the central nervous system include inflammation-induced hyperpermeability of the blood-brain barrier. Inflammatory processes can disrupt the integrity of the BBB, allowing exposure and re-exposure of the brain’s self-antigens to the peripheral adaptive immune system. This exposure can trigger the formation of pathogenic neuronal autoantibodies, leading to a breakdown in immune tolerance. The inflammatory response and increased permeability of the BBB create an environment where self-antigens are more accessible to the immune system, potentially contributing to the development of autoimmune responses within the CNS. Viral infections are believed to play a role as immune triggers in certain cases of autoimmune encephalitis. These infections can promote the production of cross-reactive autoantibodies that target neuronal self-antigens. Additionally, viral infections can facilitate the entry of these autoantibodies into the central nervous system through mechanisms involving proinflammatory cytokines, particularly interleukin-17 produced by Th17 cells. These cytokines contribute to the proinflammatory response, which can lead to increased permeability of the blood-brain barrier and allow the passage of autoantibodies into the CNS. The cross-reactivity between viral antigens and self-antigens, coupled with the proinflammatory environment created by the viral infection, can trigger an autoimmune response targeting the neurons in the CNS. However, the specific mechanisms and viral triggers involved can vary among different cases of autoimmune encephalitis.

• #63 Autoimmune Encephalitis – Autoimmune Encephalitis

  https://autoimmune-encephalitis.org/autoimmune-encephalitis/

  Most importantly, Autoimmune Encephalitis IS TREATABLE and almost invariably responds to immunotherapies with considerable potential to reverse the impairments caused by these attacking antibodies. Immunotherapies can slow down the progression of the disease, stop the antibodies from attacking and with some treatments kill the attacking antibody which may sometimes leads to complete recovery. […] Autoimmune Encephalitis is caused by a tumor or viral trigger. Antibodies are created through a process of molecular mimicry and epitope spreading against either infectious or neoplastic agent. Research has proven that patients can experience a virus triggering synaptic autoimmunity in the case of herpes simplex virus and possibly other viral encephalitides. […] While several infectious agents have been implicated in anti-NMDA encephalitis, with the exception of HSV’s proven link, these cases are novel and suggestive that it is likely science will show other cases in the future where neurotropic viruses can induce similar pathology. […] Presently in 2020, findings suggest that SARS-CoV-2 (COVID-19) has also triggered secondary autoimmune encephalitis. The following months will show whether such autoreactivity can cause persisting neurological morbidity even after clearance of SARS-CoV-2 and remission of COVID-19.

• #64 Autoimmune Encephalitis—A Multifaceted Pathology

  https://www.mdpi.com/2227-9059/11/8/2176

  The second mechanism in autoimmune encephalitis involves cytotoxic T cell-mediated neuronal destruction. This mechanism is associated with the presence of antibodies targeting cytoplasmic antigens or nuclear onconeural antigens. These antibodies are markers for the concurrent pathogenic cytotoxic T cell response, which leads to the destruction of neurons. This immune response is typically associated with a limited response to treatment and can result in a worse neurological outcome due to the rapid destruction of neurons. […] It is widely accepted that circulating neuronal autoantibodies need to penetrate the tightly regulated blood-brain barrier in order to exert their pathogenic effects within the central nervous system. However, the specific mechanisms by which these antibodies gain access to the CNS are still not well understood and remain largely unknown. Despite ongoing research, the precise mechanisms involved in allowing these autoantibodies to cross the blood-brain barrier have not been fully elucidated. In recent times, the relationship between the brain’s “glymphatic” system and dual lymphatic channels has been discovered. The glymphatic system involves the flow of cerebrospinal fluid (CSF) through periarteriolar and parenchymal extracellular spaces, facilitated by glial cells. This system allows for the passage of small molecules, including central nervous system (CNS) proteins. This discovery challenges the long-held belief in the immune privilege status of the CNS, as intracranial antigens can potentially interact with the immune system through these pathways. The implications of this relationship on the mechanisms by which circulating neuronal autoantibodies access the CNS are still being investigated. Additional possibilities for the access of circulating neuronal autoantibodies to the central nervous system include inflammation-induced hyperpermeability of the blood-brain barrier. Inflammatory processes can disrupt the integrity of the BBB, allowing exposure and re-exposure of the brain’s self-antigens to the peripheral adaptive immune system. This exposure can trigger the formation of pathogenic neuronal autoantibodies, leading to a breakdown in immune tolerance. The inflammatory response and increased permeability of the BBB create an environment where self-antigens are more accessible to the immune system, potentially contributing to the development of autoimmune responses within the CNS. Viral infections are believed to play a role as immune triggers in certain cases of autoimmune encephalitis. These infections can promote the production of cross-reactive autoantibodies that target neuronal self-antigens. Additionally, viral infections can facilitate the entry of these autoantibodies into the central nervous system through mechanisms involving proinflammatory cytokines, particularly interleukin-17 produced by Th17 cells. These cytokines contribute to the proinflammatory response, which can lead to increased permeability of the blood-brain barrier and allow the passage of autoantibodies into the CNS. The cross-reactivity between viral antigens and self-antigens, coupled with the proinflammatory environment created by the viral infection, can trigger an autoimmune response targeting the neurons in the CNS. However, the specific mechanisms and viral triggers involved can vary among different cases of autoimmune encephalitis.

• #65 Antibody Responses to Mycoplasma pneumoniae: Role in Pathogenesis and Diagnosis of Encephalitis? | PLOS Pathogens

  https://journals.plos.org/plospathogens/article%3Fid%3D10.1371/journal.ppat.1003983

  The pathogenesis of encephalitis associated with the respiratory pathogen Mycoplasma pneumoniae is not well understood. A direct infection of the central nervous system (CNS) and an immune-mediated process have been discussed. […] Recent observations suggest that intrathecally detectable antibodies against the bacterium, which can serve to establish the etiology of encephalitis, may indeed mediate the disease. […] M. pneumoniae infection is established in 5%10% of pediatric encephalitis patients, and up to 60% of them show neurologic sequelae. […] These cases indicate that M. pneumoniae encephalitis may exemplify a postinfectious phenomenon that manifests after clearance of the bacteria from the CNS or respiratory tract by the immune system. The immune response to M. pneumoniae in the CNS or other sites may also contribute to the encephalitis.

• #66 Antibody Responses to Mycoplasma pneumoniae: Role in Pathogenesis and Diagnosis of Encephalitis? | PLOS Pathogens

  https://journals.plos.org/plospathogens/article%3Fid%3D10.1371/journal.ppat.1003983

  Interestingly, a promising diagnostic marker for M. pneumoniae encephalitis has recently emerged from a few case studies. In one study, intrathecal synthesis of antibodies to M. pneumoniae was reported in 14 cases of M. pneumoniae encephalitis (74%). […] The intrathecal production of antibodies is generally considered a highly specific marker for infection of the CNS. […] In another study, it was reported that intrathecal antibodies to M. pneumoniae were found to cross-react with galactocerebroside C (GalC) in eight out of 21 (38%) of M. pneumoniae encephalitis cases. […] Such antibodies may also be involved in demyelination of central nerve cells in M. pneumoniae encephalitis, as a significant correlation was found between the presence of anti-GalC antibodies in the CSF and demyelination.

• #67 Autoimmune Encephalitis – Autoimmune Encephalitis

  https://autoimmune-encephalitis.org/autoimmune-encephalitis/

  Most importantly, Autoimmune Encephalitis IS TREATABLE and almost invariably responds to immunotherapies with considerable potential to reverse the impairments caused by these attacking antibodies. Immunotherapies can slow down the progression of the disease, stop the antibodies from attacking and with some treatments kill the attacking antibody which may sometimes leads to complete recovery. […] Autoimmune Encephalitis is caused by a tumor or viral trigger. Antibodies are created through a process of molecular mimicry and epitope spreading against either infectious or neoplastic agent. Research has proven that patients can experience a virus triggering synaptic autoimmunity in the case of herpes simplex virus and possibly other viral encephalitides. […] While several infectious agents have been implicated in anti-NMDA encephalitis, with the exception of HSV’s proven link, these cases are novel and suggestive that it is likely science will show other cases in the future where neurotropic viruses can induce similar pathology. […] Presently in 2020, findings suggest that SARS-CoV-2 (COVID-19) has also triggered secondary autoimmune encephalitis. The following months will show whether such autoreactivity can cause persisting neurological morbidity even after clearance of SARS-CoV-2 and remission of COVID-19.

• #68 Encephalitis – Neurologic Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/neurologic-disorders/brain-infections/encephalitis

  Encephalitis can occur as a secondary immunologic complication of certain viral infections or vaccinations. Inflammatory demyelination of the brain and spinal cord can occur 1 to 3 weeks later (as acute disseminated encephalomyelitis); the immune system attacks one or more central nervous system (CNS) antigens that resemble proteins of the infectious agent. […] Immunologically mediated encephalitis also occurs in patients with cancer and other autoimmune disorders. […] Rarely, apparent encephalitis has developed in patients with COVID-19, caused by the novel pandemic severe acute respiratory syndrome coronavirus (SARS-CoV2); the mechanism is not clear, but an immunologic contribution to the mechanism of apparent encephalitis is possible. […] Encephalopathies caused by autoantibodies to neuronal membrane proteins (eg, N-methyl-d-aspartate receptors [NMDAR]) may mimic viral encephalitis. Studies indicate that anti-NMDAR encephalitis is more common than viral encephalitides. […] Anti-NMDAR encephalitis also occurs as a postinfectious complication of HSV encephalitis, resulting in clinical decline within weeks of the HSV infection.

• #69 Autoimmune Encephalitis – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK578203/

  There have been case reports and observational studies to suggest that herpes simplex virus encephalitis (HSVE) triggers an immune response, causing anti-NMDAR encephalitis. […] Genetic factors like human leukocyte antigen (HLA) were strongly associated with certain antibody production causing autoimmune responses, eg, IgLON 5 antibody encephalitis.

• #70

  https://europepmc.org/books/n/statpearls/article-140572/?extid=31536295&src=med

  To this date, the exact mechanism of the collapse of immune tolerance in AIE largely remains unknown. […] Cases with AIE often have an infection as a preceding event, causing inflammation leading to neurological symptoms. […] There have been case reports and observational studies to suggest that herpes simplex virus encephalitis (HSVE) triggers an immune response, causing anti-NMDAR encephalitis. […] Also, genetic factors like human leukocyte antigen (HLA) were strongly associated with certain antibody production causing autoimmune responses, eg, IgLON 5 antibody encephalitis.

• #71 Autoimmune Encephalitis – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK578203/

  There have been case reports and observational studies to suggest that herpes simplex virus encephalitis (HSVE) triggers an immune response, causing anti-NMDAR encephalitis. […] Genetic factors like human leukocyte antigen (HLA) were strongly associated with certain antibody production causing autoimmune responses, eg, IgLON 5 antibody encephalitis.

• #72

  https://europepmc.org/books/n/statpearls/article-140572/?extid=31536295&src=med

  To this date, the exact mechanism of the collapse of immune tolerance in AIE largely remains unknown. […] Cases with AIE often have an infection as a preceding event, causing inflammation leading to neurological symptoms. […] There have been case reports and observational studies to suggest that herpes simplex virus encephalitis (HSVE) triggers an immune response, causing anti-NMDAR encephalitis. […] Also, genetic factors like human leukocyte antigen (HLA) were strongly associated with certain antibody production causing autoimmune responses, eg, IgLON 5 antibody encephalitis.

• #73 Autoimmune Encephalitis – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK578203/

  There have been case reports and observational studies to suggest that herpes simplex virus encephalitis (HSVE) triggers an immune response, causing anti-NMDAR encephalitis. […] Genetic factors like human leukocyte antigen (HLA) were strongly associated with certain antibody production causing autoimmune responses, eg, IgLON 5 antibody encephalitis.

• #74

  https://europepmc.org/books/n/statpearls/article-140572/?extid=31536295&src=med

  To this date, the exact mechanism of the collapse of immune tolerance in AIE largely remains unknown. […] Cases with AIE often have an infection as a preceding event, causing inflammation leading to neurological symptoms. […] There have been case reports and observational studies to suggest that herpes simplex virus encephalitis (HSVE) triggers an immune response, causing anti-NMDAR encephalitis. […] Also, genetic factors like human leukocyte antigen (HLA) were strongly associated with certain antibody production causing autoimmune responses, eg, IgLON 5 antibody encephalitis.

• #75 An Autopsy-proven Case-based Review of Autoimmune Encephalitis

  https://www.en-journal.org/journal/view.html?uid=650

  This article aims to provide an overview of AIE to improve understanding of the disease through an autopsy-proven case. […] The inflammatory infiltrates were primarily perivascular and extended into the parenchyma. […] Most of the inflammatory infiltrates consisted of CD8+ T-cells, suggesting AIE. […] CD8+ T cells play a crucial role as mediators of cytotoxic effector functions in various contexts, including infection, cancer, and autoimmunity. […] Understanding the role of HLA molecules in AIE might open doors to novel treatments. […] The presence of anti-LGI1 autoantibody. […] Hyponatremia can affect the function of the blood-brain barrier through the action of cytokines, leading to increased permeability and potentially contributing to AIE.

• #76 Autoimmune Encephalitis: A Physician’s Guide to the Clinical Spectrum Diagnosis and Management

  https://www.mdpi.com/2076-3425/12/9/1130

  The second mechanism involves cytotoxic T cell-mediated neuronal destruction associated with antibodies against cytoplasmic or nuclear onconeural antigens. […] It is unclear whether humoral or cytotoxic mechanisms account for the pathogenesis of GAD autoantibodies associated autoimmunity. […] There is a consensus that circulating neuronal autoantibodies must gain access to the CNS through the tightly regulated blood-brain or blood-CSF barriers to exert their harmful pathogenic effects. […] Other possibilities include inflammation-induced hyperpermeability of BBB or BCSF that can expose and re-expose the brain’s self-antigens to the peripheral adaptive immunity, which in turn can trigger the formation of pathogenic neuronal autoantibodies, leading to a breakdown in immune tolerance. […] BBB disruption associated with perivascular neuroinflammation involving both innate and adaptive immune cells has been documented in brain biopsies and post-mortem studies from individuals with etiologically diverse autoimmune encephalitis. […] Collectively, these findings support the potential contributory role of BBB disruption to the pathophysiology of autoimmune encephalitis.

• #77 Autoimmune Encephalitis—A Multifaceted Pathology

  https://www.mdpi.com/2227-9059/11/8/2176

  The second mechanism in autoimmune encephalitis involves cytotoxic T cell-mediated neuronal destruction. This mechanism is associated with the presence of antibodies targeting cytoplasmic antigens or nuclear onconeural antigens. These antibodies are markers for the concurrent pathogenic cytotoxic T cell response, which leads to the destruction of neurons. This immune response is typically associated with a limited response to treatment and can result in a worse neurological outcome due to the rapid destruction of neurons. […] It is widely accepted that circulating neuronal autoantibodies need to penetrate the tightly regulated blood-brain barrier in order to exert their pathogenic effects within the central nervous system. However, the specific mechanisms by which these antibodies gain access to the CNS are still not well understood and remain largely unknown. Despite ongoing research, the precise mechanisms involved in allowing these autoantibodies to cross the blood-brain barrier have not been fully elucidated. In recent times, the relationship between the brain’s “glymphatic” system and dual lymphatic channels has been discovered. The glymphatic system involves the flow of cerebrospinal fluid (CSF) through periarteriolar and parenchymal extracellular spaces, facilitated by glial cells. This system allows for the passage of small molecules, including central nervous system (CNS) proteins. This discovery challenges the long-held belief in the immune privilege status of the CNS, as intracranial antigens can potentially interact with the immune system through these pathways. The implications of this relationship on the mechanisms by which circulating neuronal autoantibodies access the CNS are still being investigated. Additional possibilities for the access of circulating neuronal autoantibodies to the central nervous system include inflammation-induced hyperpermeability of the blood-brain barrier. Inflammatory processes can disrupt the integrity of the BBB, allowing exposure and re-exposure of the brain’s self-antigens to the peripheral adaptive immune system. This exposure can trigger the formation of pathogenic neuronal autoantibodies, leading to a breakdown in immune tolerance. The inflammatory response and increased permeability of the BBB create an environment where self-antigens are more accessible to the immune system, potentially contributing to the development of autoimmune responses within the CNS. Viral infections are believed to play a role as immune triggers in certain cases of autoimmune encephalitis. These infections can promote the production of cross-reactive autoantibodies that target neuronal self-antigens. Additionally, viral infections can facilitate the entry of these autoantibodies into the central nervous system through mechanisms involving proinflammatory cytokines, particularly interleukin-17 produced by Th17 cells. These cytokines contribute to the proinflammatory response, which can lead to increased permeability of the blood-brain barrier and allow the passage of autoantibodies into the CNS. The cross-reactivity between viral antigens and self-antigens, coupled with the proinflammatory environment created by the viral infection, can trigger an autoimmune response targeting the neurons in the CNS. However, the specific mechanisms and viral triggers involved can vary among different cases of autoimmune encephalitis.

• #78 Anti-NMDA receptor encephalitis – Wikipedia

  https://en.wikipedia.org/wiki/Anti-NMDA_receptor_encephalitis

  Autoimmune encephalitis is a type of brain inflammation caused by antibodies. […] The underlying mechanism is autoimmune, with the primary target being the GluN1 subunit of the N-methyl-D-aspartate receptors (NMDAR) in the brain. […] The condition is mediated by autoantibodies that target NMDA receptors in the brain. […] These can be produced by cross reactivity with NMDA receptors in teratomas, which contain many cell types, including brain cells, and thus present a window in which a breakdown in immunological tolerance can occur. […] Other autoimmune mechanisms are suspected for patients who do not have tumors. […] Passive access involves the diffusion of antibodies from the blood across a pathologically disrupted blood-brain barrier (BBB). […] Intrathecal production (production of antibodies in the intrathecal space) is also a possible mechanism.

• #79 Anti-NMDA receptor encephalitis – Wikipedia

  https://en.wikipedia.org/wiki/Anti-NMDA_receptor_encephalitis

  Autoimmune encephalitis is a type of brain inflammation caused by antibodies. […] The underlying mechanism is autoimmune, with the primary target being the GluN1 subunit of the N-methyl-D-aspartate receptors (NMDAR) in the brain. […] The condition is mediated by autoantibodies that target NMDA receptors in the brain. […] These can be produced by cross reactivity with NMDA receptors in teratomas, which contain many cell types, including brain cells, and thus present a window in which a breakdown in immunological tolerance can occur. […] Other autoimmune mechanisms are suspected for patients who do not have tumors. […] Passive access involves the diffusion of antibodies from the blood across a pathologically disrupted blood-brain barrier (BBB). […] Intrathecal production (production of antibodies in the intrathecal space) is also a possible mechanism.

• #80 Anti-NMDA receptor encephalitis – Wikipedia

  https://en.wikipedia.org/wiki/Anti-NMDA_receptor_encephalitis

  Autoimmune encephalitis is a type of brain inflammation caused by antibodies. […] The underlying mechanism is autoimmune, with the primary target being the GluN1 subunit of the N-methyl-D-aspartate receptors (NMDAR) in the brain. […] The condition is mediated by autoantibodies that target NMDA receptors in the brain. […] These can be produced by cross reactivity with NMDA receptors in teratomas, which contain many cell types, including brain cells, and thus present a window in which a breakdown in immunological tolerance can occur. […] Other autoimmune mechanisms are suspected for patients who do not have tumors. […] Passive access involves the diffusion of antibodies from the blood across a pathologically disrupted blood-brain barrier (BBB). […] Intrathecal production (production of antibodies in the intrathecal space) is also a possible mechanism.

• #81 Autoimmune encephalitis: clinical spectrum and management | Practical Neurology

  https://pn.bmj.com/content/21/5/412

  The ability to detect CNS-directed autoantibodies that target the extracellular domains of neuroglial proteins has revolutionised our ability to diagnose and classify this nascent group of autoantibody-mediated disorders. […] An understanding of the basic immunobiology helps to appreciate nuances around diagnostic testing, suspected mechanisms of pathogenesis and offer a rationale for administration of therapies. […] As these diseases are associated with pathogenic autoantibodies, a focus on the B cell immunobiology may be the key to understanding autoimmune encephalitis. […] After B cell autoreactivities originate in the periphery, autoantibody access to the CNS is likely to play a major role in pathogenesis. […] The autoantibodies must gain access to the brain. […] Recent studies show these patients have an enrichment of autoantigen-reactive B cells in the CSF, providing direct evidence of intrathecal autoantibody production. […] Hence, drugs that prevent lymphocyte transmigration into the CNS may yet be effective agents in these disorders.

• #82 Autoimmune Encephalitis: A Physician’s Guide to the Clinical Spectrum Diagnosis and Management

  https://www.mdpi.com/2076-3425/12/9/1130

  The second mechanism involves cytotoxic T cell-mediated neuronal destruction associated with antibodies against cytoplasmic or nuclear onconeural antigens. […] It is unclear whether humoral or cytotoxic mechanisms account for the pathogenesis of GAD autoantibodies associated autoimmunity. […] There is a consensus that circulating neuronal autoantibodies must gain access to the CNS through the tightly regulated blood-brain or blood-CSF barriers to exert their harmful pathogenic effects. […] Other possibilities include inflammation-induced hyperpermeability of BBB or BCSF that can expose and re-expose the brain’s self-antigens to the peripheral adaptive immunity, which in turn can trigger the formation of pathogenic neuronal autoantibodies, leading to a breakdown in immune tolerance. […] BBB disruption associated with perivascular neuroinflammation involving both innate and adaptive immune cells has been documented in brain biopsies and post-mortem studies from individuals with etiologically diverse autoimmune encephalitis. […] Collectively, these findings support the potential contributory role of BBB disruption to the pathophysiology of autoimmune encephalitis.

• #83 Autoimmune Encephalitis—A Multifaceted Pathology

  https://www.mdpi.com/2227-9059/11/8/2176

  The second mechanism in autoimmune encephalitis involves cytotoxic T cell-mediated neuronal destruction. This mechanism is associated with the presence of antibodies targeting cytoplasmic antigens or nuclear onconeural antigens. These antibodies are markers for the concurrent pathogenic cytotoxic T cell response, which leads to the destruction of neurons. This immune response is typically associated with a limited response to treatment and can result in a worse neurological outcome due to the rapid destruction of neurons. […] It is widely accepted that circulating neuronal autoantibodies need to penetrate the tightly regulated blood-brain barrier in order to exert their pathogenic effects within the central nervous system. However, the specific mechanisms by which these antibodies gain access to the CNS are still not well understood and remain largely unknown. Despite ongoing research, the precise mechanisms involved in allowing these autoantibodies to cross the blood-brain barrier have not been fully elucidated. In recent times, the relationship between the brain’s “glymphatic” system and dual lymphatic channels has been discovered. The glymphatic system involves the flow of cerebrospinal fluid (CSF) through periarteriolar and parenchymal extracellular spaces, facilitated by glial cells. This system allows for the passage of small molecules, including central nervous system (CNS) proteins. This discovery challenges the long-held belief in the immune privilege status of the CNS, as intracranial antigens can potentially interact with the immune system through these pathways. The implications of this relationship on the mechanisms by which circulating neuronal autoantibodies access the CNS are still being investigated. Additional possibilities for the access of circulating neuronal autoantibodies to the central nervous system include inflammation-induced hyperpermeability of the blood-brain barrier. Inflammatory processes can disrupt the integrity of the BBB, allowing exposure and re-exposure of the brain’s self-antigens to the peripheral adaptive immune system. This exposure can trigger the formation of pathogenic neuronal autoantibodies, leading to a breakdown in immune tolerance. The inflammatory response and increased permeability of the BBB create an environment where self-antigens are more accessible to the immune system, potentially contributing to the development of autoimmune responses within the CNS. Viral infections are believed to play a role as immune triggers in certain cases of autoimmune encephalitis. These infections can promote the production of cross-reactive autoantibodies that target neuronal self-antigens. Additionally, viral infections can facilitate the entry of these autoantibodies into the central nervous system through mechanisms involving proinflammatory cytokines, particularly interleukin-17 produced by Th17 cells. These cytokines contribute to the proinflammatory response, which can lead to increased permeability of the blood-brain barrier and allow the passage of autoantibodies into the CNS. The cross-reactivity between viral antigens and self-antigens, coupled with the proinflammatory environment created by the viral infection, can trigger an autoimmune response targeting the neurons in the CNS. However, the specific mechanisms and viral triggers involved can vary among different cases of autoimmune encephalitis.

• #84 Autoimmune Encephalitis—A Multifaceted Pathology

  https://www.mdpi.com/2227-9059/11/8/2176

  The second mechanism in autoimmune encephalitis involves cytotoxic T cell-mediated neuronal destruction. This mechanism is associated with the presence of antibodies targeting cytoplasmic antigens or nuclear onconeural antigens. These antibodies are markers for the concurrent pathogenic cytotoxic T cell response, which leads to the destruction of neurons. This immune response is typically associated with a limited response to treatment and can result in a worse neurological outcome due to the rapid destruction of neurons. […] It is widely accepted that circulating neuronal autoantibodies need to penetrate the tightly regulated blood-brain barrier in order to exert their pathogenic effects within the central nervous system. However, the specific mechanisms by which these antibodies gain access to the CNS are still not well understood and remain largely unknown. Despite ongoing research, the precise mechanisms involved in allowing these autoantibodies to cross the blood-brain barrier have not been fully elucidated. In recent times, the relationship between the brain’s “glymphatic” system and dual lymphatic channels has been discovered. The glymphatic system involves the flow of cerebrospinal fluid (CSF) through periarteriolar and parenchymal extracellular spaces, facilitated by glial cells. This system allows for the passage of small molecules, including central nervous system (CNS) proteins. This discovery challenges the long-held belief in the immune privilege status of the CNS, as intracranial antigens can potentially interact with the immune system through these pathways. The implications of this relationship on the mechanisms by which circulating neuronal autoantibodies access the CNS are still being investigated. Additional possibilities for the access of circulating neuronal autoantibodies to the central nervous system include inflammation-induced hyperpermeability of the blood-brain barrier. Inflammatory processes can disrupt the integrity of the BBB, allowing exposure and re-exposure of the brain’s self-antigens to the peripheral adaptive immune system. This exposure can trigger the formation of pathogenic neuronal autoantibodies, leading to a breakdown in immune tolerance. The inflammatory response and increased permeability of the BBB create an environment where self-antigens are more accessible to the immune system, potentially contributing to the development of autoimmune responses within the CNS. Viral infections are believed to play a role as immune triggers in certain cases of autoimmune encephalitis. These infections can promote the production of cross-reactive autoantibodies that target neuronal self-antigens. Additionally, viral infections can facilitate the entry of these autoantibodies into the central nervous system through mechanisms involving proinflammatory cytokines, particularly interleukin-17 produced by Th17 cells. These cytokines contribute to the proinflammatory response, which can lead to increased permeability of the blood-brain barrier and allow the passage of autoantibodies into the CNS. The cross-reactivity between viral antigens and self-antigens, coupled with the proinflammatory environment created by the viral infection, can trigger an autoimmune response targeting the neurons in the CNS. However, the specific mechanisms and viral triggers involved can vary among different cases of autoimmune encephalitis.

• #85 Autoimmune Encephalitis: A Physician’s Guide to the Clinical Spectrum Diagnosis and Management

  https://www.mdpi.com/2076-3425/12/9/1130

  The second mechanism involves cytotoxic T cell-mediated neuronal destruction associated with antibodies against cytoplasmic or nuclear onconeural antigens. […] It is unclear whether humoral or cytotoxic mechanisms account for the pathogenesis of GAD autoantibodies associated autoimmunity. […] There is a consensus that circulating neuronal autoantibodies must gain access to the CNS through the tightly regulated blood-brain or blood-CSF barriers to exert their harmful pathogenic effects. […] Other possibilities include inflammation-induced hyperpermeability of BBB or BCSF that can expose and re-expose the brain’s self-antigens to the peripheral adaptive immunity, which in turn can trigger the formation of pathogenic neuronal autoantibodies, leading to a breakdown in immune tolerance. […] BBB disruption associated with perivascular neuroinflammation involving both innate and adaptive immune cells has been documented in brain biopsies and post-mortem studies from individuals with etiologically diverse autoimmune encephalitis. […] Collectively, these findings support the potential contributory role of BBB disruption to the pathophysiology of autoimmune encephalitis.

• #86 Autoimmune Encephalitis: A Physician’s Guide to the Clinical Spectrum Diagnosis and Management

  https://www.mdpi.com/2076-3425/12/9/1130

  The second mechanism involves cytotoxic T cell-mediated neuronal destruction associated with antibodies against cytoplasmic or nuclear onconeural antigens. […] It is unclear whether humoral or cytotoxic mechanisms account for the pathogenesis of GAD autoantibodies associated autoimmunity. […] There is a consensus that circulating neuronal autoantibodies must gain access to the CNS through the tightly regulated blood-brain or blood-CSF barriers to exert their harmful pathogenic effects. […] Other possibilities include inflammation-induced hyperpermeability of BBB or BCSF that can expose and re-expose the brain’s self-antigens to the peripheral adaptive immunity, which in turn can trigger the formation of pathogenic neuronal autoantibodies, leading to a breakdown in immune tolerance. […] BBB disruption associated with perivascular neuroinflammation involving both innate and adaptive immune cells has been documented in brain biopsies and post-mortem studies from individuals with etiologically diverse autoimmune encephalitis. […] Collectively, these findings support the potential contributory role of BBB disruption to the pathophysiology of autoimmune encephalitis.

• #87 Autoimmune encephalitis: clinical spectrum and management | Practical Neurology

  https://pn.bmj.com/content/21/5/412

  The ability to detect CNS-directed autoantibodies that target the extracellular domains of neuroglial proteins has revolutionised our ability to diagnose and classify this nascent group of autoantibody-mediated disorders. […] An understanding of the basic immunobiology helps to appreciate nuances around diagnostic testing, suspected mechanisms of pathogenesis and offer a rationale for administration of therapies. […] As these diseases are associated with pathogenic autoantibodies, a focus on the B cell immunobiology may be the key to understanding autoimmune encephalitis. […] After B cell autoreactivities originate in the periphery, autoantibody access to the CNS is likely to play a major role in pathogenesis. […] The autoantibodies must gain access to the brain. […] Recent studies show these patients have an enrichment of autoantigen-reactive B cells in the CSF, providing direct evidence of intrathecal autoantibody production. […] Hence, drugs that prevent lymphocyte transmigration into the CNS may yet be effective agents in these disorders.

• #88 Autoimmune Encephalitis – touchNEUROLOGY

  https://touchneurology.com/brain-trauma/journal-articles/autoimmune-encephalitis/

  The term autoimmune encephalitis is used to describe a group of disorders characterised by symptoms of limbic and extra-limbic dysfunction occurring in association with antibodies against synaptic antigens and proteins localised on the neuronal cell surface. […] In contrast, the neuronal surface antibodies so far studied exert a direct effect on their target antigens. In anti-NMDA-receptor and AMPA-receptor encephalitis, the antibodies result in a specific decrease of the corresponding synaptic receptors. The best studied disorder is anti-NMDA-receptor encephalitis, in which the antibodies produce a titre-dependent decrease of receptors by a mechanism of capping, cross-linking and internalisation of the receptors. […] To exert their direct pathogenic effect, the antibodies have to reach the target antigens in the central nervous system (CNS). In anti-NMDA-receptor encephalitis there is evidence of local production of antibodies in brain and meninges, supported by the demonstration of intrathecally produced antibodies and the presence of infiltrating B-cells and plasma cells in autopsy studies.

• #89 An Autopsy-proven Case-based Review of Autoimmune Encephalitis

  https://www.en-journal.org/journal/view.html?uid=650

  This article aims to provide an overview of AIE to improve understanding of the disease through an autopsy-proven case. […] The inflammatory infiltrates were primarily perivascular and extended into the parenchyma. […] Most of the inflammatory infiltrates consisted of CD8+ T-cells, suggesting AIE. […] CD8+ T cells play a crucial role as mediators of cytotoxic effector functions in various contexts, including infection, cancer, and autoimmunity. […] Understanding the role of HLA molecules in AIE might open doors to novel treatments. […] The presence of anti-LGI1 autoantibody. […] Hyponatremia can affect the function of the blood-brain barrier through the action of cytokines, leading to increased permeability and potentially contributing to AIE.

• #90 The role of dendritic cells and their interactions in the pathogenesis of antibody-associated autoimmune encephalitis | Journal of Neuroinflammation | Full Text

  https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-021-02310-z

  Autoimmune encephalitis (AE) is an inflammatory brain disease which is frequently associated with antibodies (Abs) against cell-surface, synaptic or intracellular neuronal proteins. […] There is increasing evidence that dendritic cells (DCs) are implicated as key modulators in keeping the balance between immune response and tolerance in the CNS. […] Genetic polymorphisms together with other triggers such as systemic or cerebral viral infection, or systemic malignancies could contribute to the dysbalance of regulatory and encephalitogenic DCs with subsequent dysregulated T and B cell reactions in AE. […] Novel in vivo models with implantation of mature DCs containing neuronal antigens could help to study the pathogenesis and perhaps to understand the origin of AE. […] Investigations of DCs in human blood, lymphoid tissues, CSF, and brain parenchyma of patients with AE are necessary to deepen our knowledge about the complex interactions between DCs, T and B cells during neuroinflammation in AE.

• #91 Autoimmune encephalitis: clinical spectrum and management | Practical Neurology

  https://pn.bmj.com/content/21/5/412

  The ability to detect CNS-directed autoantibodies that target the extracellular domains of neuroglial proteins has revolutionised our ability to diagnose and classify this nascent group of autoantibody-mediated disorders. […] An understanding of the basic immunobiology helps to appreciate nuances around diagnostic testing, suspected mechanisms of pathogenesis and offer a rationale for administration of therapies. […] As these diseases are associated with pathogenic autoantibodies, a focus on the B cell immunobiology may be the key to understanding autoimmune encephalitis. […] After B cell autoreactivities originate in the periphery, autoantibody access to the CNS is likely to play a major role in pathogenesis. […] The autoantibodies must gain access to the brain. […] Recent studies show these patients have an enrichment of autoantigen-reactive B cells in the CSF, providing direct evidence of intrathecal autoantibody production. […] Hence, drugs that prevent lymphocyte transmigration into the CNS may yet be effective agents in these disorders.

• #92 The “Immune” in Autoimmune Encephalitis: The Role of T and B Cells – Autoimmune Encephalitis

  https://autoimmune-encephalitis.org/the-immune-in-autoimmune-encephalitis-the-role-of-t-and-b-cells/

  Antibodies from B cells that have matured into plasma cells can also be produced in response to the tumor, but they do not contribute to AE symptoms. […] Antibodies do have a strong role in producing AE symptoms when the antigen comes from the outside surface of a neuron, like the NMDA receptor for instance. […] Research on NMDAR encephalitis, in particular, has revealed the presence of B cells and antibody-secreting plasma cells in the brain. […] In the case of NMDAR encephalitis, it’s thought that the antibodies cause the receptors, which normally are exposed to the outside of the cell, to be taken back inside so that they can’t function properly. […] Overall, the type of immune response the body produces appears to be dependent on the specific antigen. In general, diseases with antibodies that target intracellular proteins like Hu, Yo, or Ma2 involve cytotoxic T cells that kill neurons. In contrast, diseases with antibodies that target cell surface proteins like NMDAR, LGI1, and GABAR involve B cells in symptom production. In this second category, the role of T cells and complement may vary depending on the particular antigen.

• #93 :: JCN :: Journal of Clinical Neurology

  https://thejcn.com/DOIx.php?id=10.3988/jcn.2020.16.4.519

  The pathogenesis of autoimmune encephalitis caused by synaptic antibodies are mediated by B cells. Thus, therapeutics against B cells can be an efficient strategy for this disease, with IVIg, high-dose corticosteroids, and PLEX being the first treatment of choice for immunotherapy, and rituximab and tocilizumab being the next treatment choices.

• #94 The “Immune” in Autoimmune Encephalitis: The Role of T and B Cells – Autoimmune Encephalitis

  https://autoimmune-encephalitis.org/the-immune-in-autoimmune-encephalitis-the-role-of-t-and-b-cells/

  Antibodies from B cells that have matured into plasma cells can also be produced in response to the tumor, but they do not contribute to AE symptoms. […] Antibodies do have a strong role in producing AE symptoms when the antigen comes from the outside surface of a neuron, like the NMDA receptor for instance. […] Research on NMDAR encephalitis, in particular, has revealed the presence of B cells and antibody-secreting plasma cells in the brain. […] In the case of NMDAR encephalitis, it’s thought that the antibodies cause the receptors, which normally are exposed to the outside of the cell, to be taken back inside so that they can’t function properly. […] Overall, the type of immune response the body produces appears to be dependent on the specific antigen. In general, diseases with antibodies that target intracellular proteins like Hu, Yo, or Ma2 involve cytotoxic T cells that kill neurons. In contrast, diseases with antibodies that target cell surface proteins like NMDAR, LGI1, and GABAR involve B cells in symptom production. In this second category, the role of T cells and complement may vary depending on the particular antigen.

• #95 :: JCN :: Journal of Clinical Neurology

  https://thejcn.com/DOIx.php?id=10.3988/jcn.2020.16.4.519

  The pathogenesis of autoimmune encephalitis caused by synaptic antibodies are mediated by B cells. Thus, therapeutics against B cells can be an efficient strategy for this disease, with IVIg, high-dose corticosteroids, and PLEX being the first treatment of choice for immunotherapy, and rituximab and tocilizumab being the next treatment choices.

• #96 Simplified regimen of combined low-dose rituximab for autoimmune encephalitis with neuronal surface antibodies | Journal of Neuroinflammation | Full Text

  https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-022-02622-8

  Autoimmune encephalitis (AE) with neuronal surface antibodies (NSAbs) presents pathogenesis mediated by B cell-secreting antibodies. […] Rituximab is a second-line choice for the treatment for AE with NSAbs, which can cause B cell depletion via targeting CD20. […] The underlying autoimmune processes may also lead to irreversible structural damages, as well as severe, progressive and refractory symptoms. […] NSAbs against surface antigens, such as NMDAR, LGI1 and CASPR2, may directly affect the targeted protein and cause clinical disturbances by blocking functions, interfering with synaptic protein interactions, or subsequent alterations of synaptic density. […] Several mechanisms may contribute to the loss of B cell tolerance in peripheral lymph nodes in the context of tumor ectopic expressions or potential viral infections, particularly by inducing B cell-intrinsic Toll-like receptor (TLR) signal together with B cell receptor (BCR) ligation, or activating T helper (Th) cell with same antigen stimulation, thereby leading to consecutive B cell clonal expansion, class switch, affinity maturation and NSAbs production.

• #97 Simplified regimen of combined low-dose rituximab for autoimmune encephalitis with neuronal surface antibodies | Journal of Neuroinflammation | Full Text

  https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-022-02622-8

  Rituximab exerts therapeutic effect through its target, cluster of differentiation 20 (CD20), an integral membrane protein mainly expressed on B lymphocytes. […] Therefore, rituximab may inhibit neuroinflammation via targeting CD20+B lymphocytes, which results in beneficial effects for AE treatment. […] The previously complex regimen for AE might be simplified and refined as combination of regular rituximab infusions with conventional first-line therapy. […] Altogether, in present study, the simplified regimen of combined low-dose rituximab (100 mg once) with common first-line therapy for AE with NSAbs, to our knowledge, firstly showed effective for short-term and long-term improvement, in parallel with reduced immunosuppressant and relapses, suggesting the advantages and benefits for combination of low-dose rituximab in the disease course.

• #98 An Autopsy-proven Case-based Review of Autoimmune Encephalitis

  https://www.en-journal.org/journal/view.html?uid=650

  This article aims to provide an overview of AIE to improve understanding of the disease through an autopsy-proven case. […] The inflammatory infiltrates were primarily perivascular and extended into the parenchyma. […] Most of the inflammatory infiltrates consisted of CD8+ T-cells, suggesting AIE. […] CD8+ T cells play a crucial role as mediators of cytotoxic effector functions in various contexts, including infection, cancer, and autoimmunity. […] Understanding the role of HLA molecules in AIE might open doors to novel treatments. […] The presence of anti-LGI1 autoantibody. […] Hyponatremia can affect the function of the blood-brain barrier through the action of cytokines, leading to increased permeability and potentially contributing to AIE.

• #99 The “Immune” in Autoimmune Encephalitis: The Role of T and B Cells – Autoimmune Encephalitis

  https://autoimmune-encephalitis.org/the-immune-in-autoimmune-encephalitis-the-role-of-t-and-b-cells/

  The Immune System: An Explainer […] In order to specifically target particular offenders, the body uses its second way of responding: the adaptive immune system. […] So what happens in autoimmune encephalitis (AE)? In this and other autoimmune diseases, the body mistakenly recognizes part of itself as a foreign invader and mounts an attack. Scientists believe that AE starts when a tumor or virus causes proteins from neurons to be exposed to the immune system. […] The proteins get picked up by immune cells outside the brain that go on to activate T and B cells in lymphoid tissue. These activated cells then make their way into the brain where they cause AE. […] In cases where the antigen comes from inside a cell, cytotoxic T cells are the culprits. […] Cytotoxic T cells fighting the tumor can make their way into the brain and kill neurons.

• #100 An Autopsy-proven Case-based Review of Autoimmune Encephalitis

  https://www.en-journal.org/journal/view.html?uid=650

  This article aims to provide an overview of AIE to improve understanding of the disease through an autopsy-proven case. […] The inflammatory infiltrates were primarily perivascular and extended into the parenchyma. […] Most of the inflammatory infiltrates consisted of CD8+ T-cells, suggesting AIE. […] CD8+ T cells play a crucial role as mediators of cytotoxic effector functions in various contexts, including infection, cancer, and autoimmunity. […] Understanding the role of HLA molecules in AIE might open doors to novel treatments. […] The presence of anti-LGI1 autoantibody. […] Hyponatremia can affect the function of the blood-brain barrier through the action of cytokines, leading to increased permeability and potentially contributing to AIE.

• #101 An Autopsy-proven Case-based Review of Autoimmune Encephalitis

  https://www.en-journal.org/journal/view.html?uid=650

  This article aims to provide an overview of AIE to improve understanding of the disease through an autopsy-proven case. […] The inflammatory infiltrates were primarily perivascular and extended into the parenchyma. […] Most of the inflammatory infiltrates consisted of CD8+ T-cells, suggesting AIE. […] CD8+ T cells play a crucial role as mediators of cytotoxic effector functions in various contexts, including infection, cancer, and autoimmunity. […] Understanding the role of HLA molecules in AIE might open doors to novel treatments. […] The presence of anti-LGI1 autoantibody. […] Hyponatremia can affect the function of the blood-brain barrier through the action of cytokines, leading to increased permeability and potentially contributing to AIE.

• #102 Diagnosis and Clinical Features in Autoimmune-Mediated Movement Disorders

  https://www.e-jmd.org/journal/view.php?number=394

  The possible pathophysiology of N-methyl-D-aspartate (NMDA) receptor encephalitis may be caused by autoantibodies targeting neuron surface antigens. The alteration of the receptor that may induce internalized NMDA receptors causes NMDA receptor hypofunction. […] The possible pathophysiological mechanism related to ataxia is an imbalance between GABA and glutamate, which causes excitotoxicity to neuronal cells. […] The pathophysiological mechanism for this group of diseases is that onconeural antigen-specific CD4 T-cells may recruit tumor antigen-specific cytotoxic CD8 T cells and activate plasma cells to produce onconeural antibodies. […] The underlying mechanisms of pathogenesis causing nervous system dysfunction remain unclear.

• #103 The role of dendritic cells and their interactions in the pathogenesis of antibody-associated autoimmune encephalitis | Journal of Neuroinflammation | Full Text

  https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-021-02310-z

  Autoimmune encephalitis (AE) is an inflammatory brain disease which is frequently associated with antibodies (Abs) against cell-surface, synaptic or intracellular neuronal proteins. […] There is increasing evidence that dendritic cells (DCs) are implicated as key modulators in keeping the balance between immune response and tolerance in the CNS. […] Genetic polymorphisms together with other triggers such as systemic or cerebral viral infection, or systemic malignancies could contribute to the dysbalance of regulatory and encephalitogenic DCs with subsequent dysregulated T and B cell reactions in AE. […] Novel in vivo models with implantation of mature DCs containing neuronal antigens could help to study the pathogenesis and perhaps to understand the origin of AE. […] Investigations of DCs in human blood, lymphoid tissues, CSF, and brain parenchyma of patients with AE are necessary to deepen our knowledge about the complex interactions between DCs, T and B cells during neuroinflammation in AE.

• #104 The role of dendritic cells and their interactions in the pathogenesis of antibody-associated autoimmune encephalitis | Journal of Neuroinflammation | Full Text

  https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-021-02310-z

  Based on the above-mentioned findings and proposed models, DCs and their interactions may play a crucial role in loss of self-tolerance and initiation of CNS autoimmune inflammation in Ab-associated AE. […] We assume that a dysbalance of regulatory and pro-inflammatory/encephalitogenic DCs with dysfunction of their interactions with the T and indirectly also B cells may lead to disease pathogenesis in AE. […] In conclusion, we hypothesize that DCs play a crucial, dominant role in the balance between immune response and tolerance during the development and progression of AE. […] Thus, explaining the migratory routes of DCs to and from the brain and the mechanisms of modulation of CNS immune responses by DCs could contribute to understand initiating and maintaining the CNS autoimmunity and developing new therapy strategies.

• #105 The role of dendritic cells and their interactions in the pathogenesis of antibody-associated autoimmune encephalitis | Journal of Neuroinflammation | Full Text

  https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-021-02310-z

  Dendritic cells as APCs exposed to auto-antigen-encoding, non-inflammatory mRNA could induce antigen-specific T cell tolerance to avoid B cell activation and differentiation into Ab-producing plasma cells, supporting our hypothesis that DCs are key modulators in the immunopathogenesis of Ab-associated AE, but also maybe key players in future treatment perspectives.

• #106 :: KJR :: Korean Journal of Radiology

  https://www.kjronline.org/DOIx.php?id=10.3348/kjr.2023.1307

  Autoimmune encephalitis (AE) is a category of immune-mediated disorders of the central nervous system (CNS) affecting children and adults. […] AE is mediated by autoantibodies targeting specific surface components or intracytoplasmic antigens in the CNS, leading to functional or structural alterations. […] Broadly, two major immune mechanisms can cause AE. The first is autoimmunity to synaptic surface components (receptors, ionic channels, and supporting proteins). […] Autoantibodies targeting glial antigens (e.g., aquaporin 4 [AQP4], myelin oligodendrocyte glycoprotein [MOG]) cause CNS demyelination or perivascular inflammation, leading to neuronal loss through oligodendrocyte or astrocyte disruption. […] In the second group, antibodies induce cytotoxic T-cell-mediated damage. […] Microglia, the primary immune effector cells in the CNS, are thought to play a key role in the pathophysiology of AE.

• #107 An Autopsy-proven Case-based Review of Autoimmune Encephalitis

  https://www.en-journal.org/journal/view.html?uid=650

  This article aims to provide an overview of AIE to improve understanding of the disease through an autopsy-proven case. […] The inflammatory infiltrates were primarily perivascular and extended into the parenchyma. […] Most of the inflammatory infiltrates consisted of CD8+ T-cells, suggesting AIE. […] CD8+ T cells play a crucial role as mediators of cytotoxic effector functions in various contexts, including infection, cancer, and autoimmunity. […] Understanding the role of HLA molecules in AIE might open doors to novel treatments. […] The presence of anti-LGI1 autoantibody. […] Hyponatremia can affect the function of the blood-brain barrier through the action of cytokines, leading to increased permeability and potentially contributing to AIE.

• #108 The “Immune” in Autoimmune Encephalitis: The Role of T and B Cells – Autoimmune Encephalitis

  https://autoimmune-encephalitis.org/the-immune-in-autoimmune-encephalitis-the-role-of-t-and-b-cells/

  The Immune System: An Explainer […] In order to specifically target particular offenders, the body uses its second way of responding: the adaptive immune system. […] So what happens in autoimmune encephalitis (AE)? In this and other autoimmune diseases, the body mistakenly recognizes part of itself as a foreign invader and mounts an attack. Scientists believe that AE starts when a tumor or virus causes proteins from neurons to be exposed to the immune system. […] The proteins get picked up by immune cells outside the brain that go on to activate T and B cells in lymphoid tissue. These activated cells then make their way into the brain where they cause AE. […] In cases where the antigen comes from inside a cell, cytotoxic T cells are the culprits. […] Cytotoxic T cells fighting the tumor can make their way into the brain and kill neurons.

• #109 The “Immune” in Autoimmune Encephalitis: The Role of T and B Cells – Autoimmune Encephalitis

  https://autoimmune-encephalitis.org/the-immune-in-autoimmune-encephalitis-the-role-of-t-and-b-cells/

  The Immune System: An Explainer […] In order to specifically target particular offenders, the body uses its second way of responding: the adaptive immune system. […] So what happens in autoimmune encephalitis (AE)? In this and other autoimmune diseases, the body mistakenly recognizes part of itself as a foreign invader and mounts an attack. Scientists believe that AE starts when a tumor or virus causes proteins from neurons to be exposed to the immune system. […] The proteins get picked up by immune cells outside the brain that go on to activate T and B cells in lymphoid tissue. These activated cells then make their way into the brain where they cause AE. […] In cases where the antigen comes from inside a cell, cytotoxic T cells are the culprits. […] Cytotoxic T cells fighting the tumor can make their way into the brain and kill neurons.

• #110 The “Immune” in Autoimmune Encephalitis: The Role of T and B Cells – Autoimmune Encephalitis

  https://autoimmune-encephalitis.org/the-immune-in-autoimmune-encephalitis-the-role-of-t-and-b-cells/

  The Immune System: An Explainer […] In order to specifically target particular offenders, the body uses its second way of responding: the adaptive immune system. […] So what happens in autoimmune encephalitis (AE)? In this and other autoimmune diseases, the body mistakenly recognizes part of itself as a foreign invader and mounts an attack. Scientists believe that AE starts when a tumor or virus causes proteins from neurons to be exposed to the immune system. […] The proteins get picked up by immune cells outside the brain that go on to activate T and B cells in lymphoid tissue. These activated cells then make their way into the brain where they cause AE. […] In cases where the antigen comes from inside a cell, cytotoxic T cells are the culprits. […] Cytotoxic T cells fighting the tumor can make their way into the brain and kill neurons.

• #111 Autoimmune Encephalitis – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK578203/

  There have been case reports and observational studies to suggest that herpes simplex virus encephalitis (HSVE) triggers an immune response, causing anti-NMDAR encephalitis. […] Genetic factors like human leukocyte antigen (HLA) were strongly associated with certain antibody production causing autoimmune responses, eg, IgLON 5 antibody encephalitis.

• #112 The “Immune” in Autoimmune Encephalitis: The Role of T and B Cells – Autoimmune Encephalitis

  https://autoimmune-encephalitis.org/the-immune-in-autoimmune-encephalitis-the-role-of-t-and-b-cells/

  The Immune System: An Explainer […] In order to specifically target particular offenders, the body uses its second way of responding: the adaptive immune system. […] So what happens in autoimmune encephalitis (AE)? In this and other autoimmune diseases, the body mistakenly recognizes part of itself as a foreign invader and mounts an attack. Scientists believe that AE starts when a tumor or virus causes proteins from neurons to be exposed to the immune system. […] The proteins get picked up by immune cells outside the brain that go on to activate T and B cells in lymphoid tissue. These activated cells then make their way into the brain where they cause AE. […] In cases where the antigen comes from inside a cell, cytotoxic T cells are the culprits. […] Cytotoxic T cells fighting the tumor can make their way into the brain and kill neurons.

• #113 The “Immune” in Autoimmune Encephalitis: The Role of T and B Cells – Autoimmune Encephalitis

  https://autoimmune-encephalitis.org/the-immune-in-autoimmune-encephalitis-the-role-of-t-and-b-cells/

  The Immune System: An Explainer […] In order to specifically target particular offenders, the body uses its second way of responding: the adaptive immune system. […] So what happens in autoimmune encephalitis (AE)? In this and other autoimmune diseases, the body mistakenly recognizes part of itself as a foreign invader and mounts an attack. Scientists believe that AE starts when a tumor or virus causes proteins from neurons to be exposed to the immune system. […] The proteins get picked up by immune cells outside the brain that go on to activate T and B cells in lymphoid tissue. These activated cells then make their way into the brain where they cause AE. […] In cases where the antigen comes from inside a cell, cytotoxic T cells are the culprits. […] Cytotoxic T cells fighting the tumor can make their way into the brain and kill neurons.

• #114 The “Immune” in Autoimmune Encephalitis: The Role of T and B Cells – Autoimmune Encephalitis

  https://autoimmune-encephalitis.org/the-immune-in-autoimmune-encephalitis-the-role-of-t-and-b-cells/

  The Immune System: An Explainer […] In order to specifically target particular offenders, the body uses its second way of responding: the adaptive immune system. […] So what happens in autoimmune encephalitis (AE)? In this and other autoimmune diseases, the body mistakenly recognizes part of itself as a foreign invader and mounts an attack. Scientists believe that AE starts when a tumor or virus causes proteins from neurons to be exposed to the immune system. […] The proteins get picked up by immune cells outside the brain that go on to activate T and B cells in lymphoid tissue. These activated cells then make their way into the brain where they cause AE. […] In cases where the antigen comes from inside a cell, cytotoxic T cells are the culprits. […] Cytotoxic T cells fighting the tumor can make their way into the brain and kill neurons.

• #115 The “Immune” in Autoimmune Encephalitis: The Role of T and B Cells – Autoimmune Encephalitis

  https://autoimmune-encephalitis.org/the-immune-in-autoimmune-encephalitis-the-role-of-t-and-b-cells/

  Antibodies from B cells that have matured into plasma cells can also be produced in response to the tumor, but they do not contribute to AE symptoms. […] Antibodies do have a strong role in producing AE symptoms when the antigen comes from the outside surface of a neuron, like the NMDA receptor for instance. […] Research on NMDAR encephalitis, in particular, has revealed the presence of B cells and antibody-secreting plasma cells in the brain. […] In the case of NMDAR encephalitis, it’s thought that the antibodies cause the receptors, which normally are exposed to the outside of the cell, to be taken back inside so that they can’t function properly. […] Overall, the type of immune response the body produces appears to be dependent on the specific antigen. In general, diseases with antibodies that target intracellular proteins like Hu, Yo, or Ma2 involve cytotoxic T cells that kill neurons. In contrast, diseases with antibodies that target cell surface proteins like NMDAR, LGI1, and GABAR involve B cells in symptom production. In this second category, the role of T cells and complement may vary depending on the particular antigen.

• #116 Autoimmune Encephalitis: Pathophysiology and Imaging Review of an Overlooked Diagnosis | American Journal of Neuroradiology

  http://www.ajnr.org/content/38/6/1070

  Group II antibodies target cell-surface neuronal antigens, are less likely to be associated with an underlying malignancy, and use more restricted humoral immune mechanisms of neurotoxicity that typically respond better to early immunomodulatory therapy. […] N-methyl D-aspartate receptor (NMDAr) encephalitis is one of the most common and best characterized subtypes of autoimmune encephalitis classically seen in young women and children with autoimmunity not associated with cancer. […] This subtype is mediated by immunoglobulin G antibodies against the GluN1 subunit of the neuronal NMDAr, with inflammatory neuronal dysfunction that is thought to be initially reversible but potentially progresses to permanent neuronal destruction if untreated, due to prolonged inflammation and N-methyl D-aspartate (NMDA)-mediated glutamate excitotoxicity.

• #117 Autoimmune Encephalitis: Pathophysiology and Imaging Review of an Overlooked Diagnosis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7960083/

  Group I antibodies are also associated with poor clinical outcomes, characterized by a decreased response to immunomodulatory therapy and an increased prevalence of irreversible neuronal damage, and often have the additional burden of an underlying malignancy. […] Group II antibodies target cell-surface neuronal antigens, are less likely to be associated with an underlying malignancy, and use more restricted humoral immune mechanisms of neurotoxicity that typically respond better to early immunomodulatory therapy. […] Group II antibodies also represent a more specific clinical marker of disease for antibody-mediated encephalitis, with reduction in serum antibody titers following treatment directly associated with improved neurologic outcomes. […] N-methyl D-aspartate receptor (NMDAr) encephalitis is one of the most common and best characterized subtypes of autoimmune encephalitis classically seen in young women and children with autoimmunity not associated with cancer.

• #118 The “Immune” in Autoimmune Encephalitis: The Role of T and B Cells – Autoimmune Encephalitis

  https://autoimmune-encephalitis.org/the-immune-in-autoimmune-encephalitis-the-role-of-t-and-b-cells/

  Antibodies from B cells that have matured into plasma cells can also be produced in response to the tumor, but they do not contribute to AE symptoms. […] Antibodies do have a strong role in producing AE symptoms when the antigen comes from the outside surface of a neuron, like the NMDA receptor for instance. […] Research on NMDAR encephalitis, in particular, has revealed the presence of B cells and antibody-secreting plasma cells in the brain. […] In the case of NMDAR encephalitis, it’s thought that the antibodies cause the receptors, which normally are exposed to the outside of the cell, to be taken back inside so that they can’t function properly. […] Overall, the type of immune response the body produces appears to be dependent on the specific antigen. In general, diseases with antibodies that target intracellular proteins like Hu, Yo, or Ma2 involve cytotoxic T cells that kill neurons. In contrast, diseases with antibodies that target cell surface proteins like NMDAR, LGI1, and GABAR involve B cells in symptom production. In this second category, the role of T cells and complement may vary depending on the particular antigen.

• #119

  https://link.springer.com/article/10.1007/s00415-023-11685-3

  In terms of advances, there has been further crystallization of the phenotypes of many of these disorders as well as examples of phenotypic expansion […] In parallel, we have learnt more about how patients fare in the longer term, the issues they face in their recovery, and the steps we can take to provide the best possible outcome for them. […] To this end, there are some innovative immunotherapeutics on the horizon and in clinical trials. […] In addition, significant progress has been made into understanding the immunological mechanisms underlying autoantibody production in these conditions and how these autoantibodies interact with their antigenic targets to induce neuronal dysfunction. […] These advances have created potential therapeutic opportunities to intervene directly in disease pathogenesis.

• #120 Autoimmune encephalitis: proposed best practice recommendations for diagnosis and acute management | Journal of Neurology, Neurosurgery & Psychiatry

  https://jnnp.bmj.com/content/92/7/757

  Several retrospective studies have shown that early and aggressive immunotherapy is associated with better outcomes in AE patients. The 2016 AE clinical criteria emphasise the importance of starting immunotherapy once AE is highly suspected and infectious etiologies are excluded based on CSF results (cell-count, glucose, viral PCR, gram stain). It is impractical and potentially hazardous to delay immunotherapy until AE is confirmed by a positive antibody. There are no robust clinical trials comparing the different modalities of acute immunotherapy; therefore, the choice of the initial therapy may be based on anecdotal evidence and factors related to the specific syndromic presentation and comorbidities as shown in figure 4 and detailed below: […] If there is no meaningful clinical or radiological response to optimised first-line therapy after 24 weeks, the addition of a second-line agent with both rapid and sustained immunosuppressive effects can improve the outcome. However, the exact definition and timing of treatment responsiveness is not well defined and some clinicians may anecdotally choose earlier initiation of second-line agents. Both rituximab and cyclophosphamide have been used as second-line agents for rescue therapy in AE with good results.

• #121 Autoimmune encephalitis: proposed best practice recommendations for diagnosis and acute management | Journal of Neurology, Neurosurgery & Psychiatry

  https://jnnp.bmj.com/content/92/7/757

  Several retrospective studies have shown that early and aggressive immunotherapy is associated with better outcomes in AE patients. The 2016 AE clinical criteria emphasise the importance of starting immunotherapy once AE is highly suspected and infectious etiologies are excluded based on CSF results (cell-count, glucose, viral PCR, gram stain). It is impractical and potentially hazardous to delay immunotherapy until AE is confirmed by a positive antibody. There are no robust clinical trials comparing the different modalities of acute immunotherapy; therefore, the choice of the initial therapy may be based on anecdotal evidence and factors related to the specific syndromic presentation and comorbidities as shown in figure 4 and detailed below: […] If there is no meaningful clinical or radiological response to optimised first-line therapy after 24 weeks, the addition of a second-line agent with both rapid and sustained immunosuppressive effects can improve the outcome. However, the exact definition and timing of treatment responsiveness is not well defined and some clinicians may anecdotally choose earlier initiation of second-line agents. Both rituximab and cyclophosphamide have been used as second-line agents for rescue therapy in AE with good results.

• #122 Autoimmune Encephalitis – EMCrit Project

  https://emcrit.org/ibcc/ae/

  Since these disorders are T-cell mediated, they respond less well to immunotherapies such as plasmapheresis or IVIG. […] Overall, these disorders are often more closely linked to malignancy. […] Antibodies are directly pathologic in these disorders. […] Since antibodies are the culprit, patients respond better to immunotherapy and plasma exchange. However, patients can often relapse following recovery. […] Overall, these disorders are often less closely linked to malignancy. For example, some may be triggered by immunological mimicry following viral infection. […] The ability to recover function is better, since dysfunction often reflects transient neuronal dysfunction (rather than cellular destruction). Patients can make stunning recoveries, despite initially being entirely debilitated.

• #123 Autoimmune Encephalitis – EMCrit Project

  https://emcrit.org/ibcc/ae/

  Since these disorders are T-cell mediated, they respond less well to immunotherapies such as plasmapheresis or IVIG. […] Overall, these disorders are often more closely linked to malignancy. […] Antibodies are directly pathologic in these disorders. […] Since antibodies are the culprit, patients respond better to immunotherapy and plasma exchange. However, patients can often relapse following recovery. […] Overall, these disorders are often less closely linked to malignancy. For example, some may be triggered by immunological mimicry following viral infection. […] The ability to recover function is better, since dysfunction often reflects transient neuronal dysfunction (rather than cellular destruction). Patients can make stunning recoveries, despite initially being entirely debilitated.

• #124 Simplified regimen of combined low-dose rituximab for autoimmune encephalitis with neuronal surface antibodies | Journal of Neuroinflammation | Full Text

  https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-022-02622-8

  Autoimmune encephalitis (AE) with neuronal surface antibodies (NSAbs) presents pathogenesis mediated by B cell-secreting antibodies. […] Rituximab is a second-line choice for the treatment for AE with NSAbs, which can cause B cell depletion via targeting CD20. […] The underlying autoimmune processes may also lead to irreversible structural damages, as well as severe, progressive and refractory symptoms. […] NSAbs against surface antigens, such as NMDAR, LGI1 and CASPR2, may directly affect the targeted protein and cause clinical disturbances by blocking functions, interfering with synaptic protein interactions, or subsequent alterations of synaptic density. […] Several mechanisms may contribute to the loss of B cell tolerance in peripheral lymph nodes in the context of tumor ectopic expressions or potential viral infections, particularly by inducing B cell-intrinsic Toll-like receptor (TLR) signal together with B cell receptor (BCR) ligation, or activating T helper (Th) cell with same antigen stimulation, thereby leading to consecutive B cell clonal expansion, class switch, affinity maturation and NSAbs production.

• #125 Simplified regimen of combined low-dose rituximab for autoimmune encephalitis with neuronal surface antibodies | Journal of Neuroinflammation | Full Text

  https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-022-02622-8

  Rituximab exerts therapeutic effect through its target, cluster of differentiation 20 (CD20), an integral membrane protein mainly expressed on B lymphocytes. […] Therefore, rituximab may inhibit neuroinflammation via targeting CD20+B lymphocytes, which results in beneficial effects for AE treatment. […] The previously complex regimen for AE might be simplified and refined as combination of regular rituximab infusions with conventional first-line therapy. […] Altogether, in present study, the simplified regimen of combined low-dose rituximab (100 mg once) with common first-line therapy for AE with NSAbs, to our knowledge, firstly showed effective for short-term and long-term improvement, in parallel with reduced immunosuppressant and relapses, suggesting the advantages and benefits for combination of low-dose rituximab in the disease course.

• #126 Autoimmune encephalitis: clinical spectrum and management | Practical Neurology

  https://pn.bmj.com/content/21/5/412

  The ability to detect CNS-directed autoantibodies that target the extracellular domains of neuroglial proteins has revolutionised our ability to diagnose and classify this nascent group of autoantibody-mediated disorders. […] An understanding of the basic immunobiology helps to appreciate nuances around diagnostic testing, suspected mechanisms of pathogenesis and offer a rationale for administration of therapies. […] As these diseases are associated with pathogenic autoantibodies, a focus on the B cell immunobiology may be the key to understanding autoimmune encephalitis. […] After B cell autoreactivities originate in the periphery, autoantibody access to the CNS is likely to play a major role in pathogenesis. […] The autoantibodies must gain access to the brain. […] Recent studies show these patients have an enrichment of autoantigen-reactive B cells in the CSF, providing direct evidence of intrathecal autoantibody production. […] Hence, drugs that prevent lymphocyte transmigration into the CNS may yet be effective agents in these disorders.

• #127 Structural basis for antibody-mediated NMDA receptor clustering and endocytosis in autoimmune encephalitis | Nature Structural & Molecular Biology

  https://www.nature.com/articles/s41594-024-01387-3

  Antibodies against N-methyl-d-aspartate receptors (NMDARs) are most frequently detected in persons with autoimmune encephalitis (AE) and used as diagnostic biomarkers. […] Here, we reconstructed nanodiscs containing green fluorescent protein-fused NMDARs to label and sort individual immune B cells from persons with AE and further cloned and identified mAbs against NMDARs. […] Importantly, these mAbs reduced the surface NMDARs and NMDAR-mediated currents, without tonically affecting NMDAR channel gating. […] These structural and functional findings imply that the design of neutralizing antibody binding to the R1 lobe of NMDARs represents a potential therapy for AE treatment. […] Clinical evidence indicates that viral infection or peripheral tumorigenesis could initiate the immune process and production of autoantibodies, which cross the blood-brain barrier and directly bind to NMDARs on the synaptic membrane.

• #128 Autoimmune Encephalitis—A Multifaceted Pathology

  https://www.mdpi.com/2227-9059/11/8/2176

  It is important to recognize that autoimmune encephalitis is a complex condition, and treatment plans should be customized to each individual based on their specific symptoms, antibody findings, and response to therapy. Early diagnosis and appropriate treatment can lead to substantial improvement in symptoms and a positive prognosis for many individuals with autoimmune encephalitis. However, some cases may present greater challenges in treatment, and long-term neurological complications can arise. Therefore, a personalized approach to treatment and ongoing medical management is essential for individuals affected by this disorder. […] Two immune mechanisms have been proposed in autoimmune encephalitis. One of the proposed immune mechanisms in autoimmune encephalitis is the presence of autoantibodies targeting synaptic surface structures, such as receptors, ionic channels, or supporting proteins. These antibodies play a role in causing neuronal dysfunction by affecting synaptic transmission in various ways. For example, anti-NMDAR antibodies can cross-link and internalize receptors, leading to altered synaptic transmission. Antibodies like anti-GABAB receptor antibodies may interfere with neurotransmitter binding, while antibodies such as anti-VGKC and anti-LGI1 antibodies can disrupt ion channel function. It is important to note that these antibodies do not directly damage neuronal structures or cause significant neuronal apoptosis, so the clinical outcome is generally favorable.

• #129 Autoimmune Encephalitis – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK578203/

  Autoimmune encephalitis refers to acute to subacute, progressive inflammation of the brain associated with antibodies against neuronal cell surface and synaptic protein, most commonly being anti-N-methyl-D-aspartate receptor encephalitis. […] While the exact mechanism of AIE is unknown, current literature suggests that autoimmune antibodies target synaptic proteins, leading to widespread inflammation. […] Although the exact mechanism is currently under investigation, autoimmune encephalitis is thought to be an autoimmune process with an exaggerated response to a neuronal self-antigen. […] When bound to target proteins, these antibodies induce conformational changes that lead to an inflammatory response. […] To this date, the exact mechanism of the collapse of immune tolerance in AIE largely remains unknown.

• #130

  https://europepmc.org/books/n/statpearls/article-140572/?extid=31536295&src=med

  Autoimmune encephalitis refers to acute to subacute, progressive inflammation of the brain associated with antibodies against neuronal cell surface and synaptic protein, most commonly being anti-N-methyl-D-aspartate receptor encephalitis. […] While the exact mechanism of AIE is unknown, current literature suggests that autoimmune antibodies target synaptic proteins, leading to widespread inflammation. […] Although the exact mechanism is currently under investigation, autoimmune encephalitis is thought to be an autoimmune process with an exaggerated response to a neuronal self-antigen. […] Antibodies in AIE are intrinsically pathogenic. They induce inflammation by targeting specific neuronal proteins. […] When bound to target proteins, these antibodies induce conformational changes that lead to an inflammatory response.

• #131 Autoimmune Encephalitis – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK578203/

  Autoimmune encephalitis refers to acute to subacute, progressive inflammation of the brain associated with antibodies against neuronal cell surface and synaptic protein, most commonly being anti-N-methyl-D-aspartate receptor encephalitis. […] While the exact mechanism of AIE is unknown, current literature suggests that autoimmune antibodies target synaptic proteins, leading to widespread inflammation. […] Although the exact mechanism is currently under investigation, autoimmune encephalitis is thought to be an autoimmune process with an exaggerated response to a neuronal self-antigen. […] When bound to target proteins, these antibodies induce conformational changes that lead to an inflammatory response. […] To this date, the exact mechanism of the collapse of immune tolerance in AIE largely remains unknown.

• #132

  https://europepmc.org/books/n/statpearls/article-140572/?extid=31536295&src=med

  To this date, the exact mechanism of the collapse of immune tolerance in AIE largely remains unknown. […] Cases with AIE often have an infection as a preceding event, causing inflammation leading to neurological symptoms. […] There have been case reports and observational studies to suggest that herpes simplex virus encephalitis (HSVE) triggers an immune response, causing anti-NMDAR encephalitis. […] Also, genetic factors like human leukocyte antigen (HLA) were strongly associated with certain antibody production causing autoimmune responses, eg, IgLON 5 antibody encephalitis.

• #133 Autoimmune Encephalitis—A Multifaceted Pathology

  https://www.mdpi.com/2227-9059/11/8/2176

  The second mechanism in autoimmune encephalitis involves cytotoxic T cell-mediated neuronal destruction. This mechanism is associated with the presence of antibodies targeting cytoplasmic antigens or nuclear onconeural antigens. These antibodies are markers for the concurrent pathogenic cytotoxic T cell response, which leads to the destruction of neurons. This immune response is typically associated with a limited response to treatment and can result in a worse neurological outcome due to the rapid destruction of neurons. […] It is widely accepted that circulating neuronal autoantibodies need to penetrate the tightly regulated blood-brain barrier in order to exert their pathogenic effects within the central nervous system. However, the specific mechanisms by which these antibodies gain access to the CNS are still not well understood and remain largely unknown. Despite ongoing research, the precise mechanisms involved in allowing these autoantibodies to cross the blood-brain barrier have not been fully elucidated. In recent times, the relationship between the brain’s “glymphatic” system and dual lymphatic channels has been discovered. The glymphatic system involves the flow of cerebrospinal fluid (CSF) through periarteriolar and parenchymal extracellular spaces, facilitated by glial cells. This system allows for the passage of small molecules, including central nervous system (CNS) proteins. This discovery challenges the long-held belief in the immune privilege status of the CNS, as intracranial antigens can potentially interact with the immune system through these pathways. The implications of this relationship on the mechanisms by which circulating neuronal autoantibodies access the CNS are still being investigated. Additional possibilities for the access of circulating neuronal autoantibodies to the central nervous system include inflammation-induced hyperpermeability of the blood-brain barrier. Inflammatory processes can disrupt the integrity of the BBB, allowing exposure and re-exposure of the brain’s self-antigens to the peripheral adaptive immune system. This exposure can trigger the formation of pathogenic neuronal autoantibodies, leading to a breakdown in immune tolerance. The inflammatory response and increased permeability of the BBB create an environment where self-antigens are more accessible to the immune system, potentially contributing to the development of autoimmune responses within the CNS. Viral infections are believed to play a role as immune triggers in certain cases of autoimmune encephalitis. These infections can promote the production of cross-reactive autoantibodies that target neuronal self-antigens. Additionally, viral infections can facilitate the entry of these autoantibodies into the central nervous system through mechanisms involving proinflammatory cytokines, particularly interleukin-17 produced by Th17 cells. These cytokines contribute to the proinflammatory response, which can lead to increased permeability of the blood-brain barrier and allow the passage of autoantibodies into the CNS. The cross-reactivity between viral antigens and self-antigens, coupled with the proinflammatory environment created by the viral infection, can trigger an autoimmune response targeting the neurons in the CNS. However, the specific mechanisms and viral triggers involved can vary among different cases of autoimmune encephalitis.

• #134 The role of dendritic cells and their interactions in the pathogenesis of antibody-associated autoimmune encephalitis | Journal of Neuroinflammation | Full Text

  https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-021-02310-z

  Autoimmune encephalitis (AE) is an inflammatory brain disease which is frequently associated with antibodies (Abs) against cell-surface, synaptic or intracellular neuronal proteins. […] There is increasing evidence that dendritic cells (DCs) are implicated as key modulators in keeping the balance between immune response and tolerance in the CNS. […] Genetic polymorphisms together with other triggers such as systemic or cerebral viral infection, or systemic malignancies could contribute to the dysbalance of regulatory and encephalitogenic DCs with subsequent dysregulated T and B cell reactions in AE. […] Novel in vivo models with implantation of mature DCs containing neuronal antigens could help to study the pathogenesis and perhaps to understand the origin of AE. […] Investigations of DCs in human blood, lymphoid tissues, CSF, and brain parenchyma of patients with AE are necessary to deepen our knowledge about the complex interactions between DCs, T and B cells during neuroinflammation in AE.

• #135 The role of dendritic cells and their interactions in the pathogenesis of antibody-associated autoimmune encephalitis | Journal of Neuroinflammation | Full Text

  https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-021-02310-z

  Based on the above-mentioned findings and proposed models, DCs and their interactions may play a crucial role in loss of self-tolerance and initiation of CNS autoimmune inflammation in Ab-associated AE. […] We assume that a dysbalance of regulatory and pro-inflammatory/encephalitogenic DCs with dysfunction of their interactions with the T and indirectly also B cells may lead to disease pathogenesis in AE. […] In conclusion, we hypothesize that DCs play a crucial, dominant role in the balance between immune response and tolerance during the development and progression of AE. […] Thus, explaining the migratory routes of DCs to and from the brain and the mechanisms of modulation of CNS immune responses by DCs could contribute to understand initiating and maintaining the CNS autoimmunity and developing new therapy strategies.

• #136 :: Journal of Epilepsy Research

  https://www.j-epilepsy.org/m/journal/view.php?doi=10.14581/jer.16010

  The application of this technique in antibody diagnosis involves several steps, including the separation of proteins via electrophoresis, the transfer of the proteins onto a membrane, and the overlay of primary (patients sample) and secondary Abs onto the membrane, followed by detection using enzymes or radioisotopes. […] The Ab test can be negative even in the presence of autoimmune encephalitis. […] The presence of the anti-TPO Ab in Hashimotos thyroiditis is not relevant to the disease process. […] The Ab tests using both CSF and serum are necessary and CSF sometimes reflects disease activity. […] Efforts aimed at detecting new auto-Abs are needed.

• #137 Antibody Responses to Mycoplasma pneumoniae: Role in Pathogenesis and Diagnosis of Encephalitis? | PLOS Pathogens

  https://journals.plos.org/plospathogens/article%3Fid%3D10.1371/journal.ppat.1003983

  In conclusion, while PCR and serology may be of limited value in the diagnosis of M. pneumoniae encephalitis, the detection of intrathecal antibodies to M. pneumoniae, including cross-reactive antibodies against GalC and gangliosides, may be regarded as a promising new diagnostic tool. […] Furthermore, their hypothesized role in the pathogenesis might provide a basis for immunomodulatory treatment in M. pneumoniae encephalitis.

• #138

  https://link.springer.com/article/10.1007/s00415-023-11685-3

  In terms of advances, there has been further crystallization of the phenotypes of many of these disorders as well as examples of phenotypic expansion […] In parallel, we have learnt more about how patients fare in the longer term, the issues they face in their recovery, and the steps we can take to provide the best possible outcome for them. […] To this end, there are some innovative immunotherapeutics on the horizon and in clinical trials. […] In addition, significant progress has been made into understanding the immunological mechanisms underlying autoantibody production in these conditions and how these autoantibodies interact with their antigenic targets to induce neuronal dysfunction. […] These advances have created potential therapeutic opportunities to intervene directly in disease pathogenesis.

• #139

  https://link.springer.com/article/10.1007/s00415-023-11685-3

  In terms of advances, there has been further crystallization of the phenotypes of many of these disorders as well as examples of phenotypic expansion […] In parallel, we have learnt more about how patients fare in the longer term, the issues they face in their recovery, and the steps we can take to provide the best possible outcome for them. […] To this end, there are some innovative immunotherapeutics on the horizon and in clinical trials. […] In addition, significant progress has been made into understanding the immunological mechanisms underlying autoantibody production in these conditions and how these autoantibodies interact with their antigenic targets to induce neuronal dysfunction. […] These advances have created potential therapeutic opportunities to intervene directly in disease pathogenesis.

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