Materiały źródłowe

• #1

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5241505/

  Multiple sclerosis (MS) is a chronic inflammatory disease characterized by central nervous system (CNS) lesions that can lead to severe physical or cognitive disability as well as neurological defects. […] Although the etiology and pathogenesis of MS remains unclear, the present documents illustrate that the cause of MS is multifactorial and include genetic predisposition together with environmental factors such as exposure to infectious agents, vitamin deficiencies, and smoking. […] Inflammation of the white and gray matter tissues in the CNS due to focal immune cell infiltration and their cytokines are the incipient cause of damage in MS. […] Many studies have suggested T helper (Th) cell (also known as CD4+ T cells) intervention and adaptive immune responses which initiated by interaction between antigen presenting cells (APCs) with T lymphocytes play an important role in the initiation and progression of MS.

• #2 Multiple sclerosis – Wikipedia

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

  Multiple sclerosis (MS) is an autoimmune disease resulting in damage to myelin the insulating covers of nerve cells in the brain and spinal cord. As a demyelinating disease, MS disrupts the nervous system’s ability to transmit signals, resulting in a range of signs and symptoms, including physical, mental, and sometimes psychiatric problems. While its cause is unclear, the underlying mechanism is thought to be due to either destruction by the immune system or inactivation of myelin-producing cells. Proposed causes for this include immune dysregulation, genetics, and environmental factors, such as viral infections. MS is the most common immune-mediated disorder affecting the central nervous system (CNS). […] MS is an autoimmune disease with a combination of genetic and environmental causes underlying it. Both T-cells and B-cells are involved, although T-cells are often considered to be the driving force of the disease. The causes of the disease are not fully understood. The Epstein-Barr Virus (EBV) has been shown to be directly present in the brain of most cases of MS and the virus is transcriptionally active in infected cells. EBV nuclear antigens are believed to be involved in the pathogenesis of multiple sclerosis, but not all people with MS have signs of EBV infection.

• #3 Multiple Sclerosis: Pathogenesis and Treatment

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3151595/

  Multiple sclerosis (MS) is a chronic inflammatory autoimmune demyelinating disease of the central nervous system. The main mechanism of injury appears to be inflammation and 8 agents are now FDA approved to help control MS. […] Inflammation of central nervous system is the primary cause of damage in MS. The specific elements that start this inflammation are still unknown. Studies have suggested that genetic, environmental and infectious agents may be among the factors influencing the development of MS. […] The innate immune response is initiated by microbial products that activate specific receptors, mainly toll-like receptors (TLRs) in an antigen nonspecific manner. […] The adaptive response is initiated by the presentation of a specific antigen to T lymphocytes by antigen presenting cells (APCs).

• #4 Multiple sclerosis – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/multiple-sclerosis/symptoms-causes/syc-20350269

  Multiple sclerosis is a disorder in which the body’s immune system attacks the protective covering of the nerve cells in the brain, optic nerve and spinal cord, called the myelin sheath. […] In MS, the immune system attacks the protective sheath that covers nerve fibers, known as myelin. This interrupts communication between the brain and the rest of the body. Eventually, the disease can cause permanent damage of the nerve fibers. […] The cause of multiple sclerosis is not known. It’s considered an immune-mediated disease in which the body’s immune system attacks its own tissues. In MS, the immune system attacks and destroys the fatty substance that coats and protects nerve fibers in the brain and spinal cord. This fatty substance is called myelin. […] It isn’t clear why MS develops in some people and not others. A combination of genetics and environmental factors may increase the risk of MS.

• #5 Multiple sclerosis – Wikipedia

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

  MS is a heterogeneous disease. The three main characteristics of MS are the formation of lesions in the central nervous system (also called plaques), inflammation, and the destruction of myelin sheaths of neurons. These features interact in a complex and not yet fully understood manner to produce the breakdown of nerve tissue, and in turn, the signs and symptoms of the disease. Damage is believed to be caused, at least in part, by attack on the nervous system by a person’s own immune system.

• #6 The Pathologic Foundations of Multiple Sclerosis: Current Considerations

  https://www.ajmc.com/view/the-pathologic-foundations-of-multiple-sclerosis-current-considerations

  Multiple sclerosis (MS) is a chronic immune-mediated demyelinating disease of the central nervous system (CNS). MS appears to involve a complex combination of genetic susceptibility and nongenetic triggers, such as environmental factors, that result in a steady or rapid progression of neurological symptoms. The main characteristics of MS pathology include inflammatory demyelination, axonal injury, and development of CNS lesions. The interaction of these pathologic events produces diffuse, irreversible neurodegeneration. […] Understanding the neurodegenerative processes involved in MS, particularly the role of white matter (WM) and grey matter (GM), may help clinicians to diagnose the disease earlier and maximize opportunities to preserve neurological reserve. […] The pathogenesis of MS involves the initiation and perpetuation of inflammatory mediators, which leads to apoptosis of oligodendrocytes and damage to the myelin sheath of the axon. Myelin is essential for impulse conduction from one nerve cell body to another. Reduced conduction ability causes deficiencies in sensation, movement, cognition, or other functions depending on which nerves are damaged. Remyelination occurs; however, repeated attacks on the myelin lead to successively less effective remyelination until a scar-like lesion, a plaque, forms around the damaged axon.

• #7 Pathophysiology of multiple sclerosis – Wikipedia

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

  In multiple sclerosis, inflammation, demyelination, and neurodegeneration are observed together. Some clinical trials have shown that the inflammation produces both the relapses and the demyelination, and that neurodegeneration (axonal transection) is independent from inflammation, produces the accumulative disability, and advances even when inflammation and demyelination are delayed. […] Current models can be divided into two categories: inside-out and outside-in. In the former, it is hypothesized that a problem in CNS cells produces an immune response that destroys myelin and subsequently breaks the BBB. In latter, an external factor produces BBB leaks, enters the CNS, and destroys myelin and axons. […] The bloodbrain barrier (BBB) is a protective barrier that denies the entrance of foreign material into the nervous system. BBB disruption is the moment in which penetration of the barrier by lymphocytes occur and has been considered one of the early problems in MS lesions.

• #8 Multiple Sclerosis: Pathogenesis and Treatment

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3151595/

  Multiple sclerosis (MS) is a chronic inflammatory autoimmune demyelinating disease of the central nervous system. The main mechanism of injury appears to be inflammation and 8 agents are now FDA approved to help control MS. […] Inflammation of central nervous system is the primary cause of damage in MS. The specific elements that start this inflammation are still unknown. Studies have suggested that genetic, environmental and infectious agents may be among the factors influencing the development of MS. […] The innate immune response is initiated by microbial products that activate specific receptors, mainly toll-like receptors (TLRs) in an antigen nonspecific manner. […] The adaptive response is initiated by the presentation of a specific antigen to T lymphocytes by antigen presenting cells (APCs).

• #9

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5241505/

  Pathogen-associated molecules simultaneously bind to toll-like receptors on APCs and production of specific cytokines that include interleukin (IL)-12, IL-23 and IL-4 begins that these cytokines induce CD4+ T cell differentiation into Th1, Th2, or Th17 phenotypes which have ability to release special cytokines. […] B lymphocytes and their cytokines are other factors in the pathogenesis of MS. […] Many studies have shown that in addition to the above-mentioned cells, CD8+ T cells (or cytotoxic T cells) can be found in MS lesions. […] In addition to CNS inflammation, the myelin repair process due to oligodendrocyte death is also impaired. […] Fas ligand (FasL) is produced by lymphocyte cells. […] Environmental factors, including exposure to viral and bacterial agents such as Epstein Barr virus (EBV), human herpes virus type 6, and mycoplasma pneumonia, in addition to smoking, vitamin deficiency, diet, and exposure to UV radiation are associated with the onset of MS. […] A genetic predisposition may be involved in MS. […] The precise cause of MS is unknown. Nonetheless, genetic predispositions combined with environmental influences play an important role in the pathogenesis of this disease.

• #10 Immunopathogenesis of Multiple Sclerosis

  https://practicalneurology.com/diseases-diagnoses/ms-immune-disorders/immunopathogenesis-of-multiple-sclerosis/30127/

  Much of the information on immune mechanisms that mediate injury to the CNS in MS comes from studies using the animal model of MS, experimental autoimmune encephalomyelitis (EAE). The classic model of T-cell mediated pathogenesis starts with T-lymphocyte activation in the systemic immune compartment, presumably by an inciting environmental factor, such as a virus. Development of immunity against the agent results in autoimmunity because of shared homology between viral antigens and proteins of the CNS. Thought to be the main culprits of immune mediated injury, T cells cross the blood-brain barrier (BBB), they are reactivated by antigen-presenting cells (APCs) expressing major histocompatibility class (MHC) II molecules. In the CNS these cells include microglia, macrophages, and B-cells. Studies in EAE have further identified the specificities of the CD4 cells. The pro-inflammatory CD4 cells belong to the Th1 or the Th17 subtypes, whereas the anti-inflammatory CD4 T cells belong to the Th2 subtype.

• #11 Multiple Sclerosis: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/1146199-overview

  Multiple sclerosis is an inflammatory, demyelinating disease of the CNS. In pathologic specimens, the demyelinating lesions of MS, called plaques, appear as indurated areas hence the term sclerosis. […] Examination of the demyelinating lesions in the spinal cord and brain of patients with MS shows myelin loss, destruction of oligodendrocytes, and reactive astrogliosis, often with relative sparing of the axon cylinder. In some MS patients, however, the axon is also aggressively destroyed. […] The mechanism of demyelination in multiple sclerosis may be activation of myelin-reactive T cells in the periphery, which then express adhesion molecules, allowing their entry through the blood-brain barrier (BBB). T cells are activated following antigen presentation by antigen-presenting cells such as macrophages and microglia, or B cells. Perivascular T cells can secrete proinflammatory cytokines, including interferon gamma and tumor necrosis factor alpha. Antibodies against myelin also may be generated in the periphery or intrathecally. Ongoing inflammation leads to epitope spread and recruitment of other inflammatory cells (ie, bystander activation). The T cell receptor recognizes antigen in the context of human leukocyte antigen molecule presentation and also requires a second event (ie, co-stimulatory signal via the B7-CD28 pathway) for T cell activation to occur. Activated microglia may release free radicals, nitric oxide, and proteases that may contribute to tissue damage.

• #12 Immunopathogenesis of Multiple Sclerosis

  https://practicalneurology.com/diseases-diagnoses/ms-immune-disorders/immunopathogenesis-of-multiple-sclerosis/30127/

  Much of the information on immune mechanisms that mediate injury to the CNS in MS comes from studies using the animal model of MS, experimental autoimmune encephalomyelitis (EAE). The classic model of T-cell mediated pathogenesis starts with T-lymphocyte activation in the systemic immune compartment, presumably by an inciting environmental factor, such as a virus. Development of immunity against the agent results in autoimmunity because of shared homology between viral antigens and proteins of the CNS. Thought to be the main culprits of immune mediated injury, T cells cross the blood-brain barrier (BBB), they are reactivated by antigen-presenting cells (APCs) expressing major histocompatibility class (MHC) II molecules. In the CNS these cells include microglia, macrophages, and B-cells. Studies in EAE have further identified the specificities of the CD4 cells. The pro-inflammatory CD4 cells belong to the Th1 or the Th17 subtypes, whereas the anti-inflammatory CD4 T cells belong to the Th2 subtype.

• #13 Multiple Sclerosis: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/1146199-overview

  Molecular studies of white matter plaque tissue have shown that interleukin (IL)-12, a potent promoter of inflammation, is expressed at high levels in lesions that form early in MS. B7-1, a molecule required to stimulate lymphocytes to release proinflammatory cytokines, is also expressed at high levels in early MS plaques. Evidence exists of elevated frequencies of activated myelin-reactive T-cell clones in the circulation of patients with relapsing-remitting MS and higher IL-12 production in immune cells of patients with progressive MS. […] Decreased function of T-lymphocytes with a regulatory role (Tregs) has been implicated in MS. These Tregs are CD4+ CD25+ T cells that can be identified by their expression of a transcription factor known as Foxp3. […] Conversely, the cytokine IL-23 has been shown to drive cells to commit to a pathogenic phenotype in autoimmune diseases, including MS. These pathogenic CD4+ T cells act reciprocally to counteract Treg function and can be identified by their high expression of the proinflammatory cytokine IL-17; they are therefore referred to as TH 17 cells.

• #14 Multiple Sclerosis: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/1146199-overview

  Molecular studies of white matter plaque tissue have shown that interleukin (IL)-12, a potent promoter of inflammation, is expressed at high levels in lesions that form early in MS. B7-1, a molecule required to stimulate lymphocytes to release proinflammatory cytokines, is also expressed at high levels in early MS plaques. Evidence exists of elevated frequencies of activated myelin-reactive T-cell clones in the circulation of patients with relapsing-remitting MS and higher IL-12 production in immune cells of patients with progressive MS. […] Decreased function of T-lymphocytes with a regulatory role (Tregs) has been implicated in MS. These Tregs are CD4+ CD25+ T cells that can be identified by their expression of a transcription factor known as Foxp3. […] Conversely, the cytokine IL-23 has been shown to drive cells to commit to a pathogenic phenotype in autoimmune diseases, including MS. These pathogenic CD4+ T cells act reciprocally to counteract Treg function and can be identified by their high expression of the proinflammatory cytokine IL-17; they are therefore referred to as TH 17 cells.

• #15 Immunopathogenesis of Multiple Sclerosis

  https://practicalneurology.com/articles/2019-feb/immunopathogenesis-of-multiple-sclerosis

  Thought to be the main culprits of immune mediated injury, T cells cross the blood-brain barrier (BBB), they are reactivated by antigen-presenting cells (APCs) expressing major histocompatibility class (MHC) II molecules. […] Studies in EAE have further identified the specificities of the CD4 cells. […] The pro-inflammatory CD4 cells belong to the Th1 or the Th17 subtypes, whereas the anti-inflammatory CD4 T cells belong to the Th2 subtype. […] These phenotypes are defined by the lymphokines they secrete. […] Well-designed clinical trials with negative results still have provided information about pathogenesis. […] It was not until the unexpected success of rituximab, an antibody to CD20, that it became clear that B cells also played a significant role in the pathogenesis of MS. […] How B cells contribute to the pathogenesis of MS is largely unknown, however abundant evidence supports their role.

• #16 Multiple Sclerosis: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/1146199-overview

  Molecular studies of white matter plaque tissue have shown that interleukin (IL)-12, a potent promoter of inflammation, is expressed at high levels in lesions that form early in MS. B7-1, a molecule required to stimulate lymphocytes to release proinflammatory cytokines, is also expressed at high levels in early MS plaques. Evidence exists of elevated frequencies of activated myelin-reactive T-cell clones in the circulation of patients with relapsing-remitting MS and higher IL-12 production in immune cells of patients with progressive MS. […] Decreased function of T-lymphocytes with a regulatory role (Tregs) has been implicated in MS. These Tregs are CD4+ CD25+ T cells that can be identified by their expression of a transcription factor known as Foxp3. […] Conversely, the cytokine IL-23 has been shown to drive cells to commit to a pathogenic phenotype in autoimmune diseases, including MS. These pathogenic CD4+ T cells act reciprocally to counteract Treg function and can be identified by their high expression of the proinflammatory cytokine IL-17; they are therefore referred to as TH 17 cells.

• #17 Multiple Sclerosis: Pathogenesis and Treatment

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3151595/

  Regulatory T cells (T reg) are another CD4+ T cell type involved in the pathogenesis of MS. […] Besides the involvement of CD4+ T cells in MS pathogenesis, studies have shown that CD8+ T cells are present in MS lesions and may have regulatory function in the progression of disease. […] In addition to T cells, B cells and their products are involved in the pathogenesis of MS. […] Genetic factors influence MS pathogenesis susceptibility. […] Environmental factors, such as exposure to infectious agents as well as sunlight exposure/vitamin D are felt to account for changing risk of MS when a person migrates from one risk area to another before age 15 years old.

• #18 Immunopathogenesis of Multiple Sclerosis

  https://practicalneurology.com/articles/2019-feb/immunopathogenesis-of-multiple-sclerosis

  Lymphokines are toxic to myelin as well as oligodendrocytes, especially TNF-. […] Axonal injury can occur directly by CD8+-cytotoxic lymphocytes because Class 1 antigens are expressed on axons especially at the nodes of Ranvier. […] Primary axonal injury by T cells may be an important mechanism of axonal injury not secondary to demyelination. […] Resident CNS cells including activated microglia and astrocytes have been implicated in active demyelinating and neuronal-axonal injury through the release of toxic mediators including nitric oxide (NO), oxygen radicals, and glutamate release further driving progressive disease. […] Mitochondrial abnormalities also play a role in the pathogenesis of progression.

• #19 Immunopathogenesis of Multiple Sclerosis

  https://practicalneurology.com/diseases-diagnoses/ms-immune-disorders/immunopathogenesis-of-multiple-sclerosis/30127/

  It was not until the unexpected success of rituximab, an antibody to CD20, that it became clear that B cells also played a significant role in the pathogenesis of MS. How B cells contribute to the pathogenesis of MS is largely unknown, however abundant evidence supports their role. Histopathological studies have shown the presence of ectopic B-cell follicles containing germinal centers in the cerebral meninges of patients with MS. These follicles have been implicated in pathogenesis of cerebral cortical plaques. Shared B-cell clones also have been identified both in the CNS as well as draining cervical lymph nodes (LNs). […] The BBB is composed of the tight junctions between the post capillary endothelial cells, the astrocyte foot processes, and the extracellular matrix (ECM). All immune cells that traffic to the brain first interact with the postcapillary venular endothelium where cells are attached via interaction of very late antigen-4 (VLA-4; 41 integrin) molecules on the mononuclear cells with vascular cell adhesion protein 1 (VCAM1). Cells are then internalized by the endothelium and extruded to the nonluminal perivenular space where they come in contact with the ECM. Breakdown of ECM is commensurate with breakdown of the BBB. Inflammation occurs as immune cells cross into the CNS across a leaky BBB.

• #20 Impact of B cells to the pathophysiology of multiple sclerosis | Journal of Neuroinflammation | Full Text

  https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-019-1517-1

  Multiple sclerosis (MS) is a chronic autoimmune disorder that affects the central nervous system and compromises the health and well-being of millions of people worldwide. B cells have been linked to MS and its progression. This review aimed to determine the role of B cells in MS development. […] B cells play key roles in immune system functioning and MS. The findings of this review illustrate the complex nature of B cell actions, their effects on the autoimmune system, and the method by which they contribute to MS pathogenesis. […] Previous research implicates biological, genetic, and environmental factors in MS pathogenesis. This review suggests that B cells contribute to MS development and advancement by influencing and regulating autoimmune processes such as T cell production and APC activity.

• #21 Immunopathogenesis of Multiple Sclerosis

  https://practicalneurology.com/diseases-diagnoses/ms-immune-disorders/immunopathogenesis-of-multiple-sclerosis/30127/

  It was not until the unexpected success of rituximab, an antibody to CD20, that it became clear that B cells also played a significant role in the pathogenesis of MS. How B cells contribute to the pathogenesis of MS is largely unknown, however abundant evidence supports their role. Histopathological studies have shown the presence of ectopic B-cell follicles containing germinal centers in the cerebral meninges of patients with MS. These follicles have been implicated in pathogenesis of cerebral cortical plaques. Shared B-cell clones also have been identified both in the CNS as well as draining cervical lymph nodes (LNs). […] The BBB is composed of the tight junctions between the post capillary endothelial cells, the astrocyte foot processes, and the extracellular matrix (ECM). All immune cells that traffic to the brain first interact with the postcapillary venular endothelium where cells are attached via interaction of very late antigen-4 (VLA-4; 41 integrin) molecules on the mononuclear cells with vascular cell adhesion protein 1 (VCAM1). Cells are then internalized by the endothelium and extruded to the nonluminal perivenular space where they come in contact with the ECM. Breakdown of ECM is commensurate with breakdown of the BBB. Inflammation occurs as immune cells cross into the CNS across a leaky BBB.

• #22 Impact of B cells to the pathophysiology of multiple sclerosis | Journal of Neuroinflammation | Full Text

  https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-019-1517-1

  A large amount of research and evidence implicates different bodily molecules and components, such as B cells, in MS pathogenesis. […] Research indicates that B cells affect MS development and progression by targeting autoantigens. […] Studies have revealed that oligoclonal immunoglobulin (Ig) persists in the cerebrospinal fluid (CSF) in approximately 90% of patients, further supporting the idea that B cells contribute to MS pathogenesis. […] Evidence from histological studies shows that Ig colocalization and deposition in areas of CNS demyelination are central to MS development. […] B cells usually act as a source of antibody-generating plasma cells to contribute to MS development and progression. […] The existence of the B1 cells in the body has been inversely correlated with disease progression.

• #23 Impact of B cells to the pathophysiology of multiple sclerosis | Journal of Neuroinflammation | Full Text

  https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-019-1517-1

  A large amount of research and evidence implicates different bodily molecules and components, such as B cells, in MS pathogenesis. […] Research indicates that B cells affect MS development and progression by targeting autoantigens. […] Studies have revealed that oligoclonal immunoglobulin (Ig) persists in the cerebrospinal fluid (CSF) in approximately 90% of patients, further supporting the idea that B cells contribute to MS pathogenesis. […] Evidence from histological studies shows that Ig colocalization and deposition in areas of CNS demyelination are central to MS development. […] B cells usually act as a source of antibody-generating plasma cells to contribute to MS development and progression. […] The existence of the B1 cells in the body has been inversely correlated with disease progression.

• #24 Immunopathogenesis of Multiple Sclerosis

  https://practicalneurology.com/diseases-diagnoses/ms-immune-disorders/immunopathogenesis-of-multiple-sclerosis/30127/

  It was not until the unexpected success of rituximab, an antibody to CD20, that it became clear that B cells also played a significant role in the pathogenesis of MS. How B cells contribute to the pathogenesis of MS is largely unknown, however abundant evidence supports their role. Histopathological studies have shown the presence of ectopic B-cell follicles containing germinal centers in the cerebral meninges of patients with MS. These follicles have been implicated in pathogenesis of cerebral cortical plaques. Shared B-cell clones also have been identified both in the CNS as well as draining cervical lymph nodes (LNs). […] The BBB is composed of the tight junctions between the post capillary endothelial cells, the astrocyte foot processes, and the extracellular matrix (ECM). All immune cells that traffic to the brain first interact with the postcapillary venular endothelium where cells are attached via interaction of very late antigen-4 (VLA-4; 41 integrin) molecules on the mononuclear cells with vascular cell adhesion protein 1 (VCAM1). Cells are then internalized by the endothelium and extruded to the nonluminal perivenular space where they come in contact with the ECM. Breakdown of ECM is commensurate with breakdown of the BBB. Inflammation occurs as immune cells cross into the CNS across a leaky BBB.

• #25

  https://link.springer.com/article/10.1007/BF00687954

  The pathogenesis of multiple sclerosis remains a dilemma despite many years of study. Evidence for an infective agent is lacking: much doubt remains regarding the pathogenetis significance, if any, of the many reported alterations of the immune system. […] There is strong evidence to support the idea that the alteration of the blood-brain barrier is an obligatory step in the development of the plaque. […] The available data lead to the following hypothesis: multiple sclerosis is a disease which requires the following factors for the production of demyelinating lesions of the central nervous system: (1) a genetically determined susceptibility, (2) an environmental, probably viral, probably immune-mediated initiatory event producing a symptomless systemic illness, (3) a subsequent alteration of the blood-brain barrier resulting from diverse mechanisms including trauma or a second, immune-mediated event, (4) a myelinoclastic plaque-forming mechanism which is operative only in the central nervous system.

• #26 Immunopathogenesis of Multiple Sclerosis

  https://practicalneurology.com/diseases-diagnoses/ms-immune-disorders/immunopathogenesis-of-multiple-sclerosis/30127/

  It was not until the unexpected success of rituximab, an antibody to CD20, that it became clear that B cells also played a significant role in the pathogenesis of MS. How B cells contribute to the pathogenesis of MS is largely unknown, however abundant evidence supports their role. Histopathological studies have shown the presence of ectopic B-cell follicles containing germinal centers in the cerebral meninges of patients with MS. These follicles have been implicated in pathogenesis of cerebral cortical plaques. Shared B-cell clones also have been identified both in the CNS as well as draining cervical lymph nodes (LNs). […] The BBB is composed of the tight junctions between the post capillary endothelial cells, the astrocyte foot processes, and the extracellular matrix (ECM). All immune cells that traffic to the brain first interact with the postcapillary venular endothelium where cells are attached via interaction of very late antigen-4 (VLA-4; 41 integrin) molecules on the mononuclear cells with vascular cell adhesion protein 1 (VCAM1). Cells are then internalized by the endothelium and extruded to the nonluminal perivenular space where they come in contact with the ECM. Breakdown of ECM is commensurate with breakdown of the BBB. Inflammation occurs as immune cells cross into the CNS across a leaky BBB.

• #27 Immunopathogenesis of Multiple Sclerosis

  https://practicalneurology.com/diseases-diagnoses/ms-immune-disorders/immunopathogenesis-of-multiple-sclerosis/30127/

  Although BBB breach is generally attributed to T-cell-mediated mechanisms, recent studies in NMO identify mechanisms of BBB disruption that are not cell mediated. Pathologic studies suggest that complement activation by antibodies can be the initiating event in MS before any T cells are identified at the site of injury. […] Demyelination is the hallmark of MS but the mechanisms of injury remain poorly understood. Much of the myelin injury results from antibody production, complement activation, and the subsequent removal of myelin by activated macrophages. Lymphokines are toxic to myelin as well as oligodendrocytes, especially TNF-. Focal demyelination occurs not only in white matter but also in gray matter of the cerebral cortex and the deep gray nuclei. […] In clinical practice, conventional MRI readily detects focal demyelination as increased T2/fluid-attenuated inversion recovery (FLAIR) signal in lesions; in contrast, axonal injury is only seen late in the process, when black holes emerge on T1 imaging. Brain atrophy, which is accelerated in MS, is a reflection of cortical neuron loss and white matter axon and myelin loss.

• #28 Immunopathogenesis of Multiple Sclerosis

  https://practicalneurology.com/diseases-diagnoses/ms-immune-disorders/immunopathogenesis-of-multiple-sclerosis/30127/

  Although BBB breach is generally attributed to T-cell-mediated mechanisms, recent studies in NMO identify mechanisms of BBB disruption that are not cell mediated. Pathologic studies suggest that complement activation by antibodies can be the initiating event in MS before any T cells are identified at the site of injury. […] Demyelination is the hallmark of MS but the mechanisms of injury remain poorly understood. Much of the myelin injury results from antibody production, complement activation, and the subsequent removal of myelin by activated macrophages. Lymphokines are toxic to myelin as well as oligodendrocytes, especially TNF-. Focal demyelination occurs not only in white matter but also in gray matter of the cerebral cortex and the deep gray nuclei. […] In clinical practice, conventional MRI readily detects focal demyelination as increased T2/fluid-attenuated inversion recovery (FLAIR) signal in lesions; in contrast, axonal injury is only seen late in the process, when black holes emerge on T1 imaging. Brain atrophy, which is accelerated in MS, is a reflection of cortical neuron loss and white matter axon and myelin loss.

• #29 The Pathologic Foundations of Multiple Sclerosis: Current Considerations

  https://www.ajmc.com/view/the-pathologic-foundations-of-multiple-sclerosis-current-considerations

  An active lesion is a focal area of myelin loss that has been infiltrated with variable inflammatory components, myelin degradation products, scarring (gliosis), and relative axonal preservation. The inflammation that is seen in acute lesions changes over time and decreases with the age of the patient and the duration of the disease. Early in the disease course, these focal lesions are primarily located in the WM, and as the disease progresses, widespread demyelination with axonal loss results in profound tissue atrophy in the brain and spinal cord. […] The exact mechanism of direct injury to oligodendrocytes and axons is not completely understood, but it likely includes cluster of differentiation (CD) 4+ and CD8+ T-cell activity, B-cell activity, antibody production, activated microglia and macrophages, and indirect effects of proinflammatory cytokines, such as interleukin-17, tumor necrosis factor alpha, and nitric oxide. Results from recent studies have substantially broadened the view on the pathogenesis of MS. Although early concepts focused predominantly on T-cell interactions as key mediators in inflammatory damage within the CNS, emerging evidence suggests that B cells and other immune cells play a comparably important role.

• #30 Immunopathogenesis of Multiple Sclerosis

  https://practicalneurology.com/diseases-diagnoses/ms-immune-disorders/immunopathogenesis-of-multiple-sclerosis/30127/

  Although BBB breach is generally attributed to T-cell-mediated mechanisms, recent studies in NMO identify mechanisms of BBB disruption that are not cell mediated. Pathologic studies suggest that complement activation by antibodies can be the initiating event in MS before any T cells are identified at the site of injury. […] Demyelination is the hallmark of MS but the mechanisms of injury remain poorly understood. Much of the myelin injury results from antibody production, complement activation, and the subsequent removal of myelin by activated macrophages. Lymphokines are toxic to myelin as well as oligodendrocytes, especially TNF-. Focal demyelination occurs not only in white matter but also in gray matter of the cerebral cortex and the deep gray nuclei. […] In clinical practice, conventional MRI readily detects focal demyelination as increased T2/fluid-attenuated inversion recovery (FLAIR) signal in lesions; in contrast, axonal injury is only seen late in the process, when black holes emerge on T1 imaging. Brain atrophy, which is accelerated in MS, is a reflection of cortical neuron loss and white matter axon and myelin loss.

• #31 Immunopathogenesis of Multiple Sclerosis

  https://practicalneurology.com/diseases-diagnoses/ms-immune-disorders/immunopathogenesis-of-multiple-sclerosis/30127/

  Although BBB breach is generally attributed to T-cell-mediated mechanisms, recent studies in NMO identify mechanisms of BBB disruption that are not cell mediated. Pathologic studies suggest that complement activation by antibodies can be the initiating event in MS before any T cells are identified at the site of injury. […] Demyelination is the hallmark of MS but the mechanisms of injury remain poorly understood. Much of the myelin injury results from antibody production, complement activation, and the subsequent removal of myelin by activated macrophages. Lymphokines are toxic to myelin as well as oligodendrocytes, especially TNF-. Focal demyelination occurs not only in white matter but also in gray matter of the cerebral cortex and the deep gray nuclei. […] In clinical practice, conventional MRI readily detects focal demyelination as increased T2/fluid-attenuated inversion recovery (FLAIR) signal in lesions; in contrast, axonal injury is only seen late in the process, when black holes emerge on T1 imaging. Brain atrophy, which is accelerated in MS, is a reflection of cortical neuron loss and white matter axon and myelin loss.

• #32 Multiple Sclerosis: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/1146199-overview

  Multiple sclerosis is an inflammatory, demyelinating disease of the CNS. In pathologic specimens, the demyelinating lesions of MS, called plaques, appear as indurated areas hence the term sclerosis. […] Examination of the demyelinating lesions in the spinal cord and brain of patients with MS shows myelin loss, destruction of oligodendrocytes, and reactive astrogliosis, often with relative sparing of the axon cylinder. In some MS patients, however, the axon is also aggressively destroyed. […] The mechanism of demyelination in multiple sclerosis may be activation of myelin-reactive T cells in the periphery, which then express adhesion molecules, allowing their entry through the blood-brain barrier (BBB). T cells are activated following antigen presentation by antigen-presenting cells such as macrophages and microglia, or B cells. Perivascular T cells can secrete proinflammatory cytokines, including interferon gamma and tumor necrosis factor alpha. Antibodies against myelin also may be generated in the periphery or intrathecally. Ongoing inflammation leads to epitope spread and recruitment of other inflammatory cells (ie, bystander activation). The T cell receptor recognizes antigen in the context of human leukocyte antigen molecule presentation and also requires a second event (ie, co-stimulatory signal via the B7-CD28 pathway) for T cell activation to occur. Activated microglia may release free radicals, nitric oxide, and proteases that may contribute to tissue damage.

• #33 The Pathologic Foundations of Multiple Sclerosis: Current Considerations

  https://www.ajmc.com/view/the-pathologic-foundations-of-multiple-sclerosis-current-considerations

  An active lesion is a focal area of myelin loss that has been infiltrated with variable inflammatory components, myelin degradation products, scarring (gliosis), and relative axonal preservation. The inflammation that is seen in acute lesions changes over time and decreases with the age of the patient and the duration of the disease. Early in the disease course, these focal lesions are primarily located in the WM, and as the disease progresses, widespread demyelination with axonal loss results in profound tissue atrophy in the brain and spinal cord. […] The exact mechanism of direct injury to oligodendrocytes and axons is not completely understood, but it likely includes cluster of differentiation (CD) 4+ and CD8+ T-cell activity, B-cell activity, antibody production, activated microglia and macrophages, and indirect effects of proinflammatory cytokines, such as interleukin-17, tumor necrosis factor alpha, and nitric oxide. Results from recent studies have substantially broadened the view on the pathogenesis of MS. Although early concepts focused predominantly on T-cell interactions as key mediators in inflammatory damage within the CNS, emerging evidence suggests that B cells and other immune cells play a comparably important role.

• #34 The Pathologic Foundations of Multiple Sclerosis: Current Considerations

  https://www.ajmc.com/view/the-pathologic-foundations-of-multiple-sclerosis-current-considerations

  An active lesion is a focal area of myelin loss that has been infiltrated with variable inflammatory components, myelin degradation products, scarring (gliosis), and relative axonal preservation. The inflammation that is seen in acute lesions changes over time and decreases with the age of the patient and the duration of the disease. Early in the disease course, these focal lesions are primarily located in the WM, and as the disease progresses, widespread demyelination with axonal loss results in profound tissue atrophy in the brain and spinal cord. […] The exact mechanism of direct injury to oligodendrocytes and axons is not completely understood, but it likely includes cluster of differentiation (CD) 4+ and CD8+ T-cell activity, B-cell activity, antibody production, activated microglia and macrophages, and indirect effects of proinflammatory cytokines, such as interleukin-17, tumor necrosis factor alpha, and nitric oxide. Results from recent studies have substantially broadened the view on the pathogenesis of MS. Although early concepts focused predominantly on T-cell interactions as key mediators in inflammatory damage within the CNS, emerging evidence suggests that B cells and other immune cells play a comparably important role.

• #35 The Pathologic Foundations of Multiple Sclerosis: Current Considerations

  https://www.ajmc.com/view/the-pathologic-foundations-of-multiple-sclerosis-current-considerations

  Historically, the initiation of the inflammatory cascade has been attributed to CD4+ major histocompatibility complex (MHC) class II restricted T cells; however, the CD8+ MHC class I restricted T-cell populations actually show dominant clonal expansion in MS lesions. Lymphocytes enter the CNS and trigger an inflammatory cascade, leading to the release of cytokines and chemokines. Some exert proinflammatory effects that cause direct injury to neurons and oligodendrocytes and some apply antiinflammatory effects that limit injury. Additionally, B cells may contribute to CNS damage through the secretion of myelin-reactive antibodies, which, after binding to tissue surfaces, promote injury to neuronal structures. […] Initial tissue injury in the CNS is also associated with the recruitment of other immune mediators, including microglia, macrophages, and astrocytes, and may exert deleterious effects and protective effects on myelin and axons. Macrophages, when activated, secrete proinflammatory mediators such as nitric oxide, cytokines, glutamate, and reactive oxygen species. Conversely, for axonal growth and remyelination to take place, macrophages/microglia phagocytosis of myelin debris is required. Astrocytes release proinflammatory mediators while also contributing to cell homeostatic functions, such as maintaining the BBB. The dual mechanisms and the role of many of these inflammatory components in MS have not been fully elucidated.

• #36 The Pathologic Foundations of Multiple Sclerosis: Current Considerations

  https://www.ajmc.com/view/the-pathologic-foundations-of-multiple-sclerosis-current-considerations

  Historically, the initiation of the inflammatory cascade has been attributed to CD4+ major histocompatibility complex (MHC) class II restricted T cells; however, the CD8+ MHC class I restricted T-cell populations actually show dominant clonal expansion in MS lesions. Lymphocytes enter the CNS and trigger an inflammatory cascade, leading to the release of cytokines and chemokines. Some exert proinflammatory effects that cause direct injury to neurons and oligodendrocytes and some apply antiinflammatory effects that limit injury. Additionally, B cells may contribute to CNS damage through the secretion of myelin-reactive antibodies, which, after binding to tissue surfaces, promote injury to neuronal structures. […] Initial tissue injury in the CNS is also associated with the recruitment of other immune mediators, including microglia, macrophages, and astrocytes, and may exert deleterious effects and protective effects on myelin and axons. Macrophages, when activated, secrete proinflammatory mediators such as nitric oxide, cytokines, glutamate, and reactive oxygen species. Conversely, for axonal growth and remyelination to take place, macrophages/microglia phagocytosis of myelin debris is required. Astrocytes release proinflammatory mediators while also contributing to cell homeostatic functions, such as maintaining the BBB. The dual mechanisms and the role of many of these inflammatory components in MS have not been fully elucidated.

• #37 The role of astrocytes in multiple sclerosis pathogenesis | Neurología (English Edition)

  https://www.elsevier.es/en-revista-neurologia-english-edition–495-articulo-the-role-astrocytes-in-multiple-S2173580820301218

  Furthermore, astrocytes can modulate BBB permeability through cytokine production. The combination of cytokines produced by astrocytes depends on their interactions with other cells and the stimuli received from other cytokines. […] Astrocytes play a major role in MS pathogenesis since they are actively involved in CNS inflammation and also limit inflammation through several mechanisms, including: 1) expression of TLRs, which enable astrocytes to act as immune cells; 2) expression of MHC class I and II molecules, as well as co-stimulatory molecules, which allows astrocytes to serve as professional APCs; 3) regulation of BBB permeability; and 4) production of IL-12, IL-23, and IL-27, which regulate the expression of Th1 and Th17 inflammatory profiles in the CNS.

• #38 The Pathologic Foundations of Multiple Sclerosis: Current Considerations

  https://www.ajmc.com/view/the-pathologic-foundations-of-multiple-sclerosis-current-considerations

  Historically, the initiation of the inflammatory cascade has been attributed to CD4+ major histocompatibility complex (MHC) class II restricted T cells; however, the CD8+ MHC class I restricted T-cell populations actually show dominant clonal expansion in MS lesions. Lymphocytes enter the CNS and trigger an inflammatory cascade, leading to the release of cytokines and chemokines. Some exert proinflammatory effects that cause direct injury to neurons and oligodendrocytes and some apply antiinflammatory effects that limit injury. Additionally, B cells may contribute to CNS damage through the secretion of myelin-reactive antibodies, which, after binding to tissue surfaces, promote injury to neuronal structures. […] Initial tissue injury in the CNS is also associated with the recruitment of other immune mediators, including microglia, macrophages, and astrocytes, and may exert deleterious effects and protective effects on myelin and axons. Macrophages, when activated, secrete proinflammatory mediators such as nitric oxide, cytokines, glutamate, and reactive oxygen species. Conversely, for axonal growth and remyelination to take place, macrophages/microglia phagocytosis of myelin debris is required. Astrocytes release proinflammatory mediators while also contributing to cell homeostatic functions, such as maintaining the BBB. The dual mechanisms and the role of many of these inflammatory components in MS have not been fully elucidated.

• #39 The role of astrocytes in multiple sclerosis pathogenesis | Neurología (English Edition)

  https://www.elsevier.es/en-revista-neurologia-english-edition–495-articulo-the-role-astrocytes-in-multiple-S2173580820301218

  Astrocytes are the most abundant type of glial cells in the CNS and play a dual role in MS pathogenesis: firstly, they contribute to disease progression, acting as CNS immune cells and secreting chemokines that promote immune cell migration from the peripheral blood to the CNS; and secondly, they promote the migration, proliferation, and differentiation of oligodendrocyte precursor cells, favouring remyelination. […] The available evidence suggests that the role of astrocytes should be reevaluated, as these cells not only provide support and contribute to maintaining homeostasis, but also play a major role in the pathogenesis of CNS autoimmune diseases, particularly MS. […] Astrocytes present close contact with the basal lamina of the BBB, since their processes line blood vessel walls.

• #40 The Pathologic Foundations of Multiple Sclerosis: Current Considerations

  https://www.ajmc.com/view/the-pathologic-foundations-of-multiple-sclerosis-current-considerations

  MS lesions evolve differently during early disease phases compared with chronic disease phases. Acute active lesions that are characteristic of early or relapsing disease are infiltrated by macrophages that contain myelin debris. In progressive disease, chronic lesions develop and consist of completely demyelinated axons and a substantial loss of oligodendrocytes, rendering them vulnerable to inflammatory mediators. Microphages and microglia diminish over time while astrocytes produce glial fibers to fill the demyelinated lesion, which leaves a glial scar (plaque). […] Inflammation, the hallmark of MS pathology, is present, but its severity decreases with advanced age and disease duration. Furthermore, dense aggregates of inflammatory cells, which may be facilitated by B cells, organize within the CNS in structures and resemble features of lymph follicles. These compartmentalized structures, called tertiary lymphoid organs, continue to contribute to the inflammatory neuronal axonal and synaptic destruction in the cerebral cortex of patients with MS even after T-cell and B-cell inflammation has diminished. Inflammation may be trapped in part behind a closed or repaired BBB as perivascular inflammatory infiltrates are sometimes identified in chronic lesions. Continued axonal damage and neurodegeneration that occurs after the decrease in the inflammatory response implies that other mechanisms, such as mitochondrial failure, play an important role in perpetuating neuronal damage in advanced disease.

• #41 The Pathologic Foundations of Multiple Sclerosis: Current Considerations

  https://www.ajmc.com/view/the-pathologic-foundations-of-multiple-sclerosis-current-considerations

  MS lesions evolve differently during early disease phases compared with chronic disease phases. Acute active lesions that are characteristic of early or relapsing disease are infiltrated by macrophages that contain myelin debris. In progressive disease, chronic lesions develop and consist of completely demyelinated axons and a substantial loss of oligodendrocytes, rendering them vulnerable to inflammatory mediators. Microphages and microglia diminish over time while astrocytes produce glial fibers to fill the demyelinated lesion, which leaves a glial scar (plaque). […] Inflammation, the hallmark of MS pathology, is present, but its severity decreases with advanced age and disease duration. Furthermore, dense aggregates of inflammatory cells, which may be facilitated by B cells, organize within the CNS in structures and resemble features of lymph follicles. These compartmentalized structures, called tertiary lymphoid organs, continue to contribute to the inflammatory neuronal axonal and synaptic destruction in the cerebral cortex of patients with MS even after T-cell and B-cell inflammation has diminished. Inflammation may be trapped in part behind a closed or repaired BBB as perivascular inflammatory infiltrates are sometimes identified in chronic lesions. Continued axonal damage and neurodegeneration that occurs after the decrease in the inflammatory response implies that other mechanisms, such as mitochondrial failure, play an important role in perpetuating neuronal damage in advanced disease.

• #42 The Pathologic Foundations of Multiple Sclerosis: Current Considerations

  https://www.ajmc.com/view/the-pathologic-foundations-of-multiple-sclerosis-current-considerations

  MS lesions evolve differently during early disease phases compared with chronic disease phases. Acute active lesions that are characteristic of early or relapsing disease are infiltrated by macrophages that contain myelin debris. In progressive disease, chronic lesions develop and consist of completely demyelinated axons and a substantial loss of oligodendrocytes, rendering them vulnerable to inflammatory mediators. Microphages and microglia diminish over time while astrocytes produce glial fibers to fill the demyelinated lesion, which leaves a glial scar (plaque). […] Inflammation, the hallmark of MS pathology, is present, but its severity decreases with advanced age and disease duration. Furthermore, dense aggregates of inflammatory cells, which may be facilitated by B cells, organize within the CNS in structures and resemble features of lymph follicles. These compartmentalized structures, called tertiary lymphoid organs, continue to contribute to the inflammatory neuronal axonal and synaptic destruction in the cerebral cortex of patients with MS even after T-cell and B-cell inflammation has diminished. Inflammation may be trapped in part behind a closed or repaired BBB as perivascular inflammatory infiltrates are sometimes identified in chronic lesions. Continued axonal damage and neurodegeneration that occurs after the decrease in the inflammatory response implies that other mechanisms, such as mitochondrial failure, play an important role in perpetuating neuronal damage in advanced disease.

• #43 Progressive multiple sclerosis: pathology and pathogenesis | Nature Reviews Neurology

  https://www.nature.com/articles/nrneurol.2012.168

  Oxidative stress seems to be mainly driven by inflammation and oxidative burst in microglia; however, its effects might be amplified in patients with progressive MS by age-dependent iron accumulation in the brain and by mitochondrial gene deletions, triggered by the chronic inflammatory process. […] Multiple mechanisms contribute to neurodegeneration in progressive MS, including exhaustion of functional compensation, lack of trophic support, chronic microglial activation and altered expression of ion channels in demyelinated axons. […] Mitochondrial injury induced by oxidative stress might underlie the pathological features of MS lesions, such as oligodendrocyte apoptosis, demyelination, destruction of thin-calibre axons, and lack of remyelination. […] Age-related iron accumulation in the human brain and release of iron in lesioned tissue might amplify oxidative damage, particularly in progressive MS. […] Treatment of progressive MS is hindered by the presence of inflammation 'trapped’ behind the blood-brain barrier, and might require a combination of anti-inflammatory and neuroprotective strategies.

• #44 Progressive multiple sclerosis: pathology and pathogenesis | Nature Reviews Neurology

  https://www.nature.com/articles/nrneurol.2012.168

  Oxidative stress seems to be mainly driven by inflammation and oxidative burst in microglia; however, its effects might be amplified in patients with progressive MS by age-dependent iron accumulation in the brain and by mitochondrial gene deletions, triggered by the chronic inflammatory process. […] Multiple mechanisms contribute to neurodegeneration in progressive MS, including exhaustion of functional compensation, lack of trophic support, chronic microglial activation and altered expression of ion channels in demyelinated axons. […] Mitochondrial injury induced by oxidative stress might underlie the pathological features of MS lesions, such as oligodendrocyte apoptosis, demyelination, destruction of thin-calibre axons, and lack of remyelination. […] Age-related iron accumulation in the human brain and release of iron in lesioned tissue might amplify oxidative damage, particularly in progressive MS. […] Treatment of progressive MS is hindered by the presence of inflammation 'trapped’ behind the blood-brain barrier, and might require a combination of anti-inflammatory and neuroprotective strategies.

• #45 Immunopathogenesis of Multiple Sclerosis

  https://practicalneurology.com/diseases-diagnoses/ms-immune-disorders/immunopathogenesis-of-multiple-sclerosis/30127/

  Mitochondrial abnormalities also play a role in the pathogenesis of progression. Early oxidative injuries to mitochondrial DNA accumulate over time, similar to the phenomenon observed in aging. When mitochondria with defective DNA predominate in a neuron, oxidative phosphorylation is impaired resulting in a state of virtual hypoxia that impairs neuron function. Neurons with defective mitochondria undergo apoptosis. Over time, neuron attrition leads to accelerated brain atrophy, a hallmark of progression.

• #46 Progressive multiple sclerosis: pathology and pathogenesis | Nature Reviews Neurology

  https://www.nature.com/articles/nrneurol.2012.168

  Oxidative stress seems to be mainly driven by inflammation and oxidative burst in microglia; however, its effects might be amplified in patients with progressive MS by age-dependent iron accumulation in the brain and by mitochondrial gene deletions, triggered by the chronic inflammatory process. […] Multiple mechanisms contribute to neurodegeneration in progressive MS, including exhaustion of functional compensation, lack of trophic support, chronic microglial activation and altered expression of ion channels in demyelinated axons. […] Mitochondrial injury induced by oxidative stress might underlie the pathological features of MS lesions, such as oligodendrocyte apoptosis, demyelination, destruction of thin-calibre axons, and lack of remyelination. […] Age-related iron accumulation in the human brain and release of iron in lesioned tissue might amplify oxidative damage, particularly in progressive MS. […] Treatment of progressive MS is hindered by the presence of inflammation 'trapped’ behind the blood-brain barrier, and might require a combination of anti-inflammatory and neuroprotective strategies.

• #47 Progressive multiple sclerosis: pathology and pathogenesis | Nature Reviews Neurology

  https://www.nature.com/articles/nrneurol.2012.168

  Oxidative stress seems to be mainly driven by inflammation and oxidative burst in microglia; however, its effects might be amplified in patients with progressive MS by age-dependent iron accumulation in the brain and by mitochondrial gene deletions, triggered by the chronic inflammatory process. […] Multiple mechanisms contribute to neurodegeneration in progressive MS, including exhaustion of functional compensation, lack of trophic support, chronic microglial activation and altered expression of ion channels in demyelinated axons. […] Mitochondrial injury induced by oxidative stress might underlie the pathological features of MS lesions, such as oligodendrocyte apoptosis, demyelination, destruction of thin-calibre axons, and lack of remyelination. […] Age-related iron accumulation in the human brain and release of iron in lesioned tissue might amplify oxidative damage, particularly in progressive MS. […] Treatment of progressive MS is hindered by the presence of inflammation 'trapped’ behind the blood-brain barrier, and might require a combination of anti-inflammatory and neuroprotective strategies.

• #48 Immunopathogenesis of Multiple Sclerosis

  https://practicalneurology.com/diseases-diagnoses/ms-immune-disorders/immunopathogenesis-of-multiple-sclerosis/30127/

  Mitochondrial abnormalities also play a role in the pathogenesis of progression. Early oxidative injuries to mitochondrial DNA accumulate over time, similar to the phenomenon observed in aging. When mitochondria with defective DNA predominate in a neuron, oxidative phosphorylation is impaired resulting in a state of virtual hypoxia that impairs neuron function. Neurons with defective mitochondria undergo apoptosis. Over time, neuron attrition leads to accelerated brain atrophy, a hallmark of progression.

• #49

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5241505/

  Multiple sclerosis (MS) is a chronic inflammatory disease characterized by central nervous system (CNS) lesions that can lead to severe physical or cognitive disability as well as neurological defects. […] Although the etiology and pathogenesis of MS remains unclear, the present documents illustrate that the cause of MS is multifactorial and include genetic predisposition together with environmental factors such as exposure to infectious agents, vitamin deficiencies, and smoking. […] Inflammation of the white and gray matter tissues in the CNS due to focal immune cell infiltration and their cytokines are the incipient cause of damage in MS. […] Many studies have suggested T helper (Th) cell (also known as CD4+ T cells) intervention and adaptive immune responses which initiated by interaction between antigen presenting cells (APCs) with T lymphocytes play an important role in the initiation and progression of MS.

• #50 Immunopathogenesis of Multiple Sclerosis

  https://practicalneurology.com/diseases-diagnoses/ms-immune-disorders/immunopathogenesis-of-multiple-sclerosis/30127/

  Disruption of immune tolerance, inflammation, and blood-brain barrier breach lead to demyelination and axonal injury. Of presumed autoimmune origin, multiple sclerosis (MS) is a chronic acquired inflammatory disorder of the central nervous system (CNS). Although the etiology and pathogenesis remain largely unknown, MS is recognized as a consequence of complex host genetic and environmental factors resulting in immune-mediated CNS injury. The immune system mediates much of the early injury and accounts for mechanisms underlying clinical relapses. In contrast, mechanisms of progression are less understood and may share similarities with other neurodegenerative disorders. […] The initial events leading to disruption of immune tolerance are unknown. Genome-wide association studies have identified more than 200 genes linked to MS. The HLA-DRB1*1501 allele has the strongest genetic association. In a susceptible individual, exposure to environmental factors at a critical age predisposes the person to MS. A specific pathogen may play a role, and exposure to Epstein-Barr virus has been implicated due to the higher incidence of infectious mononucleosis in patients with MS compared with the general population. Other factors implicated include vitamin D deficiency, smoking, and obesity. Recently, a pivotal role has been attributed to the gut microbiome as a site for immunotolerance disruption.

• #51 Immunopathogenesis of Multiple Sclerosis

  https://practicalneurology.com/articles/2019-feb/immunopathogenesis-of-multiple-sclerosis

  Disruption of immune tolerance, inflammation, and blood-brain barrier breach lead to demyelination and axonal injury. […] Of presumed autoimmune origin, multiple sclerosis (MS) is a chronic acquired inflammatory disorder of the central nervous system (CNS). […] Although the etiology and pathogenesis remain largely unknown, MS is recognized as a consequence of complex host genetic and environmental factors resulting in immune-mediated CNS injury. […] The immune system mediates much of the early injury and accounts for mechanisms underlying clinical relapses. […] In contrast, mechanisms of progression are less understood and may share similarities with other neurodegenerative disorders. […] The initial events leading to disruption of immune tolerance are unknown. […] Genome-wide association studies have identified more than 200 genes linked to MS.

• #52 The Causal Cascade to Multiple Sclerosis: A Model for MS Pathogenesis | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0004565

  MS pathogenesis seems to involve both genetic susceptibility and environmental risk factors. […] A mathematical Model for MS pathogenesis is developed, incorporating these environmental and genetic factors into a causal scheme that can explain some of the recent changes in MS-epidemiology (e.g., increasing disease prevalence, a changing sex-ratio, and regional variations in monozygotic twin concordance rates). […] This Model suggests that genetic susceptibility is overwhelmingly the most important determinant of MS pathogenesis. Indeed, over 99% of individuals seem genetically incapable of developing MS, regardless of what environmental exposures they experience. […] Consequently, that there must be important environmental or epigenetic factors involved in MS pathogenesis. […] The potential importance of this Model for MS pathogenesis is that, if correct, a therapeutic strategy, designed to interrupt one or more of these sequential factors, has the potential to markedly reduce or eliminate disease prevalence in the future.

• #53 Immunopathogenesis of Multiple Sclerosis

  https://practicalneurology.com/diseases-diagnoses/ms-immune-disorders/immunopathogenesis-of-multiple-sclerosis/30127/

  Disruption of immune tolerance, inflammation, and blood-brain barrier breach lead to demyelination and axonal injury. Of presumed autoimmune origin, multiple sclerosis (MS) is a chronic acquired inflammatory disorder of the central nervous system (CNS). Although the etiology and pathogenesis remain largely unknown, MS is recognized as a consequence of complex host genetic and environmental factors resulting in immune-mediated CNS injury. The immune system mediates much of the early injury and accounts for mechanisms underlying clinical relapses. In contrast, mechanisms of progression are less understood and may share similarities with other neurodegenerative disorders. […] The initial events leading to disruption of immune tolerance are unknown. Genome-wide association studies have identified more than 200 genes linked to MS. The HLA-DRB1*1501 allele has the strongest genetic association. In a susceptible individual, exposure to environmental factors at a critical age predisposes the person to MS. A specific pathogen may play a role, and exposure to Epstein-Barr virus has been implicated due to the higher incidence of infectious mononucleosis in patients with MS compared with the general population. Other factors implicated include vitamin D deficiency, smoking, and obesity. Recently, a pivotal role has been attributed to the gut microbiome as a site for immunotolerance disruption.

• #54 Immunopathogenesis of Multiple Sclerosis

  https://practicalneurology.com/diseases-diagnoses/ms-immune-disorders/immunopathogenesis-of-multiple-sclerosis/30127/

  Disruption of immune tolerance, inflammation, and blood-brain barrier breach lead to demyelination and axonal injury. Of presumed autoimmune origin, multiple sclerosis (MS) is a chronic acquired inflammatory disorder of the central nervous system (CNS). Although the etiology and pathogenesis remain largely unknown, MS is recognized as a consequence of complex host genetic and environmental factors resulting in immune-mediated CNS injury. The immune system mediates much of the early injury and accounts for mechanisms underlying clinical relapses. In contrast, mechanisms of progression are less understood and may share similarities with other neurodegenerative disorders. […] The initial events leading to disruption of immune tolerance are unknown. Genome-wide association studies have identified more than 200 genes linked to MS. The HLA-DRB1*1501 allele has the strongest genetic association. In a susceptible individual, exposure to environmental factors at a critical age predisposes the person to MS. A specific pathogen may play a role, and exposure to Epstein-Barr virus has been implicated due to the higher incidence of infectious mononucleosis in patients with MS compared with the general population. Other factors implicated include vitamin D deficiency, smoking, and obesity. Recently, a pivotal role has been attributed to the gut microbiome as a site for immunotolerance disruption.

• #55 Immunopathogenesis of Multiple Sclerosis

  https://practicalneurology.com/articles/2019-feb/immunopathogenesis-of-multiple-sclerosis

  The HLA-DRB1*1501 allele has the strongest genetic association. […] In a susceptible individual, exposure to environmental factors at a critical age predisposes the person to MS. […] A specific pathogen may play a role, and exposure to Epstein-Barr virus has been implicated due to the higher incidence of infectious mononucleosis in patients with MS compared with the general population. […] Other factors implicated include vitamin D deficiency, smoking, and obesity. […] Recently, a pivotal role has been attributed to the gut microbiome as a site for immunotolerance disruption. […] The classic model of T-cell mediated pathogenesis starts with T-lymphocyte activation in the systemic immune compartment, presumably by an inciting environmental factor, such as a virus. […] Development of immunity against the agent results in autoimmunity because of shared homology between viral antigens and proteins of the CNS.

• #56

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5241505/

  Multiple sclerosis (MS) is a chronic inflammatory disease characterized by central nervous system (CNS) lesions that can lead to severe physical or cognitive disability as well as neurological defects. […] Although the etiology and pathogenesis of MS remains unclear, the present documents illustrate that the cause of MS is multifactorial and include genetic predisposition together with environmental factors such as exposure to infectious agents, vitamin deficiencies, and smoking. […] Inflammation of the white and gray matter tissues in the CNS due to focal immune cell infiltration and their cytokines are the incipient cause of damage in MS. […] Many studies have suggested T helper (Th) cell (also known as CD4+ T cells) intervention and adaptive immune responses which initiated by interaction between antigen presenting cells (APCs) with T lymphocytes play an important role in the initiation and progression of MS.

• #57 Multiple Sclerosis: Pathogenesis and Treatment

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3151595/

  Multiple sclerosis (MS) is a chronic inflammatory autoimmune demyelinating disease of the central nervous system. The main mechanism of injury appears to be inflammation and 8 agents are now FDA approved to help control MS. […] Inflammation of central nervous system is the primary cause of damage in MS. The specific elements that start this inflammation are still unknown. Studies have suggested that genetic, environmental and infectious agents may be among the factors influencing the development of MS. […] The innate immune response is initiated by microbial products that activate specific receptors, mainly toll-like receptors (TLRs) in an antigen nonspecific manner. […] The adaptive response is initiated by the presentation of a specific antigen to T lymphocytes by antigen presenting cells (APCs).

• #58 The Pathologic Foundations of Multiple Sclerosis: Current Considerations

  https://www.ajmc.com/view/the-pathologic-foundations-of-multiple-sclerosis-current-considerations

  Since the introduction of myelin immunohistochemistry, the knowledge of GM pathology that is associated with MS has greatly expanded. Additionally, new magnetic resonance imaging (MRI) methods have improved in vivo detection, although the majority of cortical lesions are still not seen by any MRI technique. The appearance of cortical GM and deep grey matter (DGM) neurodegeneration is an important early event in the pathogenesis of MS. Not only is GM pathology highly heterogeneous across patients, but cortical demyelination and neurodegeneration is extensive and manifests throughout all phases of relapsing-remitting disease. In studies of patients with CIS and RRMS, only GM atrophy was detected early in the disease course. Additionally, postmortem and clinical MRI studies found no correlation between cortical lesion volume and WM lesion volume. GM lesions were found to differ significantly from WM lesions and had less or absent immunoactivation. Thus, the GM demyelination and axonal degeneration may be caused by an independent, primary disease process that arises in the GM or a secondary disease process caused by damage to WM.

• #59 The Pathologic Foundations of Multiple Sclerosis: Current Considerations

  https://www.ajmc.com/view/the-pathologic-foundations-of-multiple-sclerosis-current-considerations

  Since the introduction of myelin immunohistochemistry, the knowledge of GM pathology that is associated with MS has greatly expanded. Additionally, new magnetic resonance imaging (MRI) methods have improved in vivo detection, although the majority of cortical lesions are still not seen by any MRI technique. The appearance of cortical GM and deep grey matter (DGM) neurodegeneration is an important early event in the pathogenesis of MS. Not only is GM pathology highly heterogeneous across patients, but cortical demyelination and neurodegeneration is extensive and manifests throughout all phases of relapsing-remitting disease. In studies of patients with CIS and RRMS, only GM atrophy was detected early in the disease course. Additionally, postmortem and clinical MRI studies found no correlation between cortical lesion volume and WM lesion volume. GM lesions were found to differ significantly from WM lesions and had less or absent immunoactivation. Thus, the GM demyelination and axonal degeneration may be caused by an independent, primary disease process that arises in the GM or a secondary disease process caused by damage to WM.

• #60 The Pathologic Foundations of Multiple Sclerosis: Current Considerations

  https://www.ajmc.com/view/the-pathologic-foundations-of-multiple-sclerosis-current-considerations

  In recent years GM has emerged as a focal point of MS research. GM neurodegeneration may be more relevant to understand MS disability than WM neurodegeneration. An early study of the relationship between whole brain volume and disability found that patients with MS had low total brain volume and GM volume. GM volume was associated with progressive clinical MS involvement and high expanded disability status scale (EDSS) score, which indicates that GM atrophy may be more relevant to clinical progression than WM atrophy. Studies evaluating WM lesion load have resulted in similar outcomes. […] Findings from a systematic review and meta-analysis of primary research that relates cognitive function to WM lesion burden identified a modest correlation of patients with MS from MRI measures of the total WM lesions and cognitive function. There has been no study of more than 100 patients with results demonstrating a strong correlation between WM lesions and cognitive function. In a longitudinal MRI study of patients with MS, there was no considerable difference in WM lesion volume at 3 years follow-up in patients who were clinically worsening than in those who were clinically stable. Cortical lesion volume at baseline and follow-up correlated with EDSS score at baseline and over time. WM injury may be independent of the GM pathologic events, and WM changes cannot currently be used to discern those patients with extensive GM disease in clinical practice or to predict long-term clinical outcomes.

• #61 Immunopathogenesis of Multiple Sclerosis

  https://practicalneurology.com/diseases-diagnoses/ms-immune-disorders/immunopathogenesis-of-multiple-sclerosis/30127/

  The molecular mechanisms mediating functional recovery are also poorly understood. Clinical recovery is seldom a consequence of remyelination, which occurs poorly in the CNS. If axons are spared, during recovery Na+ channels realign and occupy the demyelinated internode, which probably requires synthesis of new Na+ channels. […] Progressive MS is best defined as a decline in neurologic function in the absence of exacerbations. Although relapsing-remitting MS and both forms of progressive MS seem to lie on a clinical spectrum, there are clear differences in the predominant underlying mechanisms of relapsing vs progressive disease. Individuals with progressive disease tend to have fewer gadolinium-enhancing lesions, probably because immune-mediated injury is not the main mechanism of injury. Pathologically, abnormal proliferation of microglia occurs; and inflammatory cells, particularly T lymphocytes are few, especially where cortical lesions are evident. Resident CNS cells including activated microglia and astrocytes have been implicated in active demyelinating and neuronal-axonal injury through the release of toxic mediators including nitric oxide (NO), oxygen radicals, and glutamate release further driving progressive disease.

• #62 Immunopathogenesis of Multiple Sclerosis

  https://practicalneurology.com/diseases-diagnoses/ms-immune-disorders/immunopathogenesis-of-multiple-sclerosis/30127/

  The molecular mechanisms mediating functional recovery are also poorly understood. Clinical recovery is seldom a consequence of remyelination, which occurs poorly in the CNS. If axons are spared, during recovery Na+ channels realign and occupy the demyelinated internode, which probably requires synthesis of new Na+ channels. […] Progressive MS is best defined as a decline in neurologic function in the absence of exacerbations. Although relapsing-remitting MS and both forms of progressive MS seem to lie on a clinical spectrum, there are clear differences in the predominant underlying mechanisms of relapsing vs progressive disease. Individuals with progressive disease tend to have fewer gadolinium-enhancing lesions, probably because immune-mediated injury is not the main mechanism of injury. Pathologically, abnormal proliferation of microglia occurs; and inflammatory cells, particularly T lymphocytes are few, especially where cortical lesions are evident. Resident CNS cells including activated microglia and astrocytes have been implicated in active demyelinating and neuronal-axonal injury through the release of toxic mediators including nitric oxide (NO), oxygen radicals, and glutamate release further driving progressive disease.

• #63 Immunopathogenesis of Multiple Sclerosis

  https://practicalneurology.com/diseases-diagnoses/ms-immune-disorders/immunopathogenesis-of-multiple-sclerosis/30127/

  The molecular mechanisms mediating functional recovery are also poorly understood. Clinical recovery is seldom a consequence of remyelination, which occurs poorly in the CNS. If axons are spared, during recovery Na+ channels realign and occupy the demyelinated internode, which probably requires synthesis of new Na+ channels. […] Progressive MS is best defined as a decline in neurologic function in the absence of exacerbations. Although relapsing-remitting MS and both forms of progressive MS seem to lie on a clinical spectrum, there are clear differences in the predominant underlying mechanisms of relapsing vs progressive disease. Individuals with progressive disease tend to have fewer gadolinium-enhancing lesions, probably because immune-mediated injury is not the main mechanism of injury. Pathologically, abnormal proliferation of microglia occurs; and inflammatory cells, particularly T lymphocytes are few, especially where cortical lesions are evident. Resident CNS cells including activated microglia and astrocytes have been implicated in active demyelinating and neuronal-axonal injury through the release of toxic mediators including nitric oxide (NO), oxygen radicals, and glutamate release further driving progressive disease.

• #64 Immunopathogenesis of Multiple Sclerosis

  https://practicalneurology.com/articles/2019-feb/immunopathogenesis-of-multiple-sclerosis

  Lymphokines are toxic to myelin as well as oligodendrocytes, especially TNF-. […] Axonal injury can occur directly by CD8+-cytotoxic lymphocytes because Class 1 antigens are expressed on axons especially at the nodes of Ranvier. […] Primary axonal injury by T cells may be an important mechanism of axonal injury not secondary to demyelination. […] Resident CNS cells including activated microglia and astrocytes have been implicated in active demyelinating and neuronal-axonal injury through the release of toxic mediators including nitric oxide (NO), oxygen radicals, and glutamate release further driving progressive disease. […] Mitochondrial abnormalities also play a role in the pathogenesis of progression.

• #65 Progressive multiple sclerosis: pathology and pathogenesis | Nature Reviews Neurology

  https://www.nature.com/articles/nrneurol.2012.168

  Major progress has been made during the past three decades in understanding the inflammatory process and pathogenetic mechanisms in multiple sclerosis (MS). […] This Review summarizes studies on the pathology of progressive MS and discusses new data on the mechanisms underlying its pathogenesis. […] In progressive MS, as in relapsing-remitting MS, active tissue injury is associated with inflammation, but the inflammatory response in the progressive phase occurs at least partly behind the blood-brain barrier, which makes it more difficult to treat. […] The other mechanisms that drive disease in patients with primary or secondary progressive MS are currently unresolved, although oxidative stress resulting in mitochondrial injury might participate in the induction of demyelination and neurodegeneration in both the relapsing-remitting and progressive stages of MS.

• #66 Immunopathogenesis of Multiple Sclerosis

  https://practicalneurology.com/diseases-diagnoses/ms-immune-disorders/immunopathogenesis-of-multiple-sclerosis/30127/

  The molecular mechanisms mediating functional recovery are also poorly understood. Clinical recovery is seldom a consequence of remyelination, which occurs poorly in the CNS. If axons are spared, during recovery Na+ channels realign and occupy the demyelinated internode, which probably requires synthesis of new Na+ channels. […] Progressive MS is best defined as a decline in neurologic function in the absence of exacerbations. Although relapsing-remitting MS and both forms of progressive MS seem to lie on a clinical spectrum, there are clear differences in the predominant underlying mechanisms of relapsing vs progressive disease. Individuals with progressive disease tend to have fewer gadolinium-enhancing lesions, probably because immune-mediated injury is not the main mechanism of injury. Pathologically, abnormal proliferation of microglia occurs; and inflammatory cells, particularly T lymphocytes are few, especially where cortical lesions are evident. Resident CNS cells including activated microglia and astrocytes have been implicated in active demyelinating and neuronal-axonal injury through the release of toxic mediators including nitric oxide (NO), oxygen radicals, and glutamate release further driving progressive disease.

• #67

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5241505/

  Pathogen-associated molecules simultaneously bind to toll-like receptors on APCs and production of specific cytokines that include interleukin (IL)-12, IL-23 and IL-4 begins that these cytokines induce CD4+ T cell differentiation into Th1, Th2, or Th17 phenotypes which have ability to release special cytokines. […] B lymphocytes and their cytokines are other factors in the pathogenesis of MS. […] Many studies have shown that in addition to the above-mentioned cells, CD8+ T cells (or cytotoxic T cells) can be found in MS lesions. […] In addition to CNS inflammation, the myelin repair process due to oligodendrocyte death is also impaired. […] Fas ligand (FasL) is produced by lymphocyte cells. […] Environmental factors, including exposure to viral and bacterial agents such as Epstein Barr virus (EBV), human herpes virus type 6, and mycoplasma pneumonia, in addition to smoking, vitamin deficiency, diet, and exposure to UV radiation are associated with the onset of MS. […] A genetic predisposition may be involved in MS. […] The precise cause of MS is unknown. Nonetheless, genetic predispositions combined with environmental influences play an important role in the pathogenesis of this disease.

• #68 Immune-Mediated Disease and MS | National MS SocietyNational Multiple Sclerosis Society LogoNational Multiple Sclerosis Society LogoOpen search

  https://www.nationalmssociety.org/understanding-ms/what-is-ms/how-ms-affects-the-brain/immune-mediated-disease

  The abnormal immune system attack produces inflammation and: Damages or destroys myelin and oligodendrocytes (a process referred to as demyelination), Causes damage to the axons, Produces lesions or scars along the nerve, which can be detected on MRI, Slows or halts nerve conduction — producing the neurologic signs and symptoms of MS. […] In MS, the immune system primarily attacks the myelin sheath that surrounds the nerve fibers, also known as axons. This makes it harder for the CNS to replace the damaged myelin. All of this leads to a loss of myelin, or demyelination. Without the myelin insulation, the axons, or nerve fibers, also get damaged. They can even be completely severed. A disease that causes this process is called a demyelinating disease. […] The DMTs for MS work by various mechanisms, with different therapies having different mechanisms of action. These mechanisms include: Interfering with the activation of T cells, Reducing the inflammation and immune activity, Blocking the movement of immune system cells, Depleting the numbers of immune system cells, Limiting entry of immune cells into the CNS.

• #69 Immune-Mediated Disease and MS | National MS SocietyNational Multiple Sclerosis Society LogoNational Multiple Sclerosis Society LogoOpen search

  https://www.nationalmssociety.org/understanding-ms/what-is-ms/how-ms-affects-the-brain/immune-mediated-disease

  The abnormal immune system attack produces inflammation and: Damages or destroys myelin and oligodendrocytes (a process referred to as demyelination), Causes damage to the axons, Produces lesions or scars along the nerve, which can be detected on MRI, Slows or halts nerve conduction — producing the neurologic signs and symptoms of MS. […] In MS, the immune system primarily attacks the myelin sheath that surrounds the nerve fibers, also known as axons. This makes it harder for the CNS to replace the damaged myelin. All of this leads to a loss of myelin, or demyelination. Without the myelin insulation, the axons, or nerve fibers, also get damaged. They can even be completely severed. A disease that causes this process is called a demyelinating disease. […] The DMTs for MS work by various mechanisms, with different therapies having different mechanisms of action. These mechanisms include: Interfering with the activation of T cells, Reducing the inflammation and immune activity, Blocking the movement of immune system cells, Depleting the numbers of immune system cells, Limiting entry of immune cells into the CNS.

• #70 Progressive multiple sclerosis: pathology and pathogenesis | Nature Reviews Neurology

  https://www.nature.com/articles/nrneurol.2012.168

  Oxidative stress seems to be mainly driven by inflammation and oxidative burst in microglia; however, its effects might be amplified in patients with progressive MS by age-dependent iron accumulation in the brain and by mitochondrial gene deletions, triggered by the chronic inflammatory process. […] Multiple mechanisms contribute to neurodegeneration in progressive MS, including exhaustion of functional compensation, lack of trophic support, chronic microglial activation and altered expression of ion channels in demyelinated axons. […] Mitochondrial injury induced by oxidative stress might underlie the pathological features of MS lesions, such as oligodendrocyte apoptosis, demyelination, destruction of thin-calibre axons, and lack of remyelination. […] Age-related iron accumulation in the human brain and release of iron in lesioned tissue might amplify oxidative damage, particularly in progressive MS. […] Treatment of progressive MS is hindered by the presence of inflammation 'trapped’ behind the blood-brain barrier, and might require a combination of anti-inflammatory and neuroprotective strategies.

• #71 Immune-Mediated Disease and MS | National MS SocietyNational Multiple Sclerosis Society LogoNational Multiple Sclerosis Society LogoOpen search

  https://www.nationalmssociety.org/understanding-ms/what-is-ms/how-ms-affects-the-brain/immune-mediated-disease

  Researchers have developed disease-modifying therapies that target the parts of the immune response in MS that cause inflammation and damage. There are now many different DMTs available that help modify the MS disease process and prevent the demyelination that causes MS symptoms, disease progression and disability.

• #72 The Pathologic Foundations of Multiple Sclerosis: Current Considerations

  https://www.ajmc.com/view/the-pathologic-foundations-of-multiple-sclerosis-current-considerations

  Significant advances have been made in understanding the MS pathological processes and the treatment of disease. Although MRI has emerged as a useful diagnostic and monitoring tool, there is still a good deal to learn regarding MRI correlations and clinical disability. Current clinically useful MRIs have low sensitivity for the detection of cortical lesions and limited sensitivity, even in WM disease. Additionally, improved imaging techniques would allow for the visualization of early inflammatory cortical demyelination and provide a better understanding of the whole brain lesion load. The identification of a disease biomarker would allow for individualization of treatment and ultimately improve functional outcomes. […] An improved understanding of pathology coupled with refined imaging technologies could yield more effective interventions from targeted disease-modifying therapies, with the goal of providing neuroprotection and delaying disease and disability progression. Maintaining neurological reserve and a regular monitoring strategy can help promote brain preservation in MS. Because a larger brain volume has been associated with positive cognitive function, healthy lifestyle and recreational activities have the potential to protect against any dismal loss in brain volume to influence cognition.

• #73 The Pathologic Foundations of Multiple Sclerosis: Current Considerations

  https://www.ajmc.com/view/the-pathologic-foundations-of-multiple-sclerosis-current-considerations

  Significant advances have been made in understanding the MS pathological processes and the treatment of disease. Although MRI has emerged as a useful diagnostic and monitoring tool, there is still a good deal to learn regarding MRI correlations and clinical disability. Current clinically useful MRIs have low sensitivity for the detection of cortical lesions and limited sensitivity, even in WM disease. Additionally, improved imaging techniques would allow for the visualization of early inflammatory cortical demyelination and provide a better understanding of the whole brain lesion load. The identification of a disease biomarker would allow for individualization of treatment and ultimately improve functional outcomes. […] An improved understanding of pathology coupled with refined imaging technologies could yield more effective interventions from targeted disease-modifying therapies, with the goal of providing neuroprotection and delaying disease and disability progression. Maintaining neurological reserve and a regular monitoring strategy can help promote brain preservation in MS. Because a larger brain volume has been associated with positive cognitive function, healthy lifestyle and recreational activities have the potential to protect against any dismal loss in brain volume to influence cognition.

• #74 The Pathologic Foundations of Multiple Sclerosis: Current Considerations

  https://www.ajmc.com/view/the-pathologic-foundations-of-multiple-sclerosis-current-considerations

  Significant advances have been made in understanding the MS pathological processes and the treatment of disease. Although MRI has emerged as a useful diagnostic and monitoring tool, there is still a good deal to learn regarding MRI correlations and clinical disability. Current clinically useful MRIs have low sensitivity for the detection of cortical lesions and limited sensitivity, even in WM disease. Additionally, improved imaging techniques would allow for the visualization of early inflammatory cortical demyelination and provide a better understanding of the whole brain lesion load. The identification of a disease biomarker would allow for individualization of treatment and ultimately improve functional outcomes. […] An improved understanding of pathology coupled with refined imaging technologies could yield more effective interventions from targeted disease-modifying therapies, with the goal of providing neuroprotection and delaying disease and disability progression. Maintaining neurological reserve and a regular monitoring strategy can help promote brain preservation in MS. Because a larger brain volume has been associated with positive cognitive function, healthy lifestyle and recreational activities have the potential to protect against any dismal loss in brain volume to influence cognition.

• #75 The Pathologic Foundations of Multiple Sclerosis: Current Considerations

  https://www.ajmc.com/view/the-pathologic-foundations-of-multiple-sclerosis-current-considerations

  Significant advances have been made in understanding the MS pathological processes and the treatment of disease. Although MRI has emerged as a useful diagnostic and monitoring tool, there is still a good deal to learn regarding MRI correlations and clinical disability. Current clinically useful MRIs have low sensitivity for the detection of cortical lesions and limited sensitivity, even in WM disease. Additionally, improved imaging techniques would allow for the visualization of early inflammatory cortical demyelination and provide a better understanding of the whole brain lesion load. The identification of a disease biomarker would allow for individualization of treatment and ultimately improve functional outcomes. […] An improved understanding of pathology coupled with refined imaging technologies could yield more effective interventions from targeted disease-modifying therapies, with the goal of providing neuroprotection and delaying disease and disability progression. Maintaining neurological reserve and a regular monitoring strategy can help promote brain preservation in MS. Because a larger brain volume has been associated with positive cognitive function, healthy lifestyle and recreational activities have the potential to protect against any dismal loss in brain volume to influence cognition.

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