Materiały źródłowe

• #1 Neuromyelitis optica spectrum disorders: from pathophysiology to therapeutic strategies | Journal of Neuroinflammation | Full Text

  https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-021-02249-1

  Neuromyelitis optica (NMO) is a chronic inflammatory autoimmune disease of the central nervous system (CNS) characterized by acute optic neuritis (ON) and transverse myelitis (TM). NMO is caused by a pathogenic serum IgG antibody against the water channel aquoporin 4 (AQP4) in the majority of patients. AQP4-antibody (AQP4-ab) presence is highly specific, and differentiates NMO from multiple sclerosis. It binds to AQP4 channels on astrocytes, triggering activation of the classical complement cascade, causing granulocyte, eosinophil, and lymphocyte infiltration, culminating in injury first to astrocyte, then oligodendrocytes followed by demyelination and neuronal loss. […] The discovery of selective AQP4-ab binding to AQP4 changed our understanding of NMOSD pathogenesis. What had been considered a primarily demyelinating disease is now categorized as an autoimmune astrocytopathy. AQP4 is a bi-directional, osmosis-driven water channel, found at highest concentration in perivascular and peripheral astrocyte endfeet, as well as in ependymal cell membranes.

• #2 Neuromyelitis optica spectrum disorders: from pathophysiology to therapeutic strategies – PubMed

  https://pubmed.ncbi.nlm.nih.gov/34530847/

  Neuromyelitis optica (NMO) is a chronic inflammatory autoimmune disease of the central nervous system (CNS) characterized by acute optic neuritis (ON) and transverse myelitis (TM). NMO is caused by a pathogenic serum IgG antibody against the water channel aquoporin 4 (AQP4) in the majority of patients. AQP4-antibody (AQP4-ab) presence is highly specific, and differentiates NMO from multiple sclerosis. It binds to AQP4 channels on astrocytes, triggering activation of the classical complement cascade, causing granulocyte, eosinophil, and lymphocyte infiltration, culminating in injury first to astrocyte, then oligodendrocytes followed by demyelination and neuronal loss. […] Pathophysiologic mechanisms and therapeutic targets for approved and experimental treatment options in NMOSD. AQP4-specific B cells differentiate in the periphery to plasma cells capable of producing anti-AQP4 antibodies (1), which penetrate the CNS and are deposited mainly on the feet of astrocytes. Specific T cells interact with B cells or dendritic cells, and in the presence of IL-6, IL-23, and TGF- differentiate into Th17 cells. These in turn penetrate the CNS, facilitate the passage of AQP4-ab into the CNS via opening the blood brain barrier (BBB), and contribute to the recruitment of neutrophils (2). This inflammatory environment activates complement through C1q which binds to anti-AQP4-ab, induces C5 cleavage into activated fractions C5a and C5b, causing astrocyte injury through complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC). When C1q binds to conformational Fc determinants on IgG or IgM antibody-antigen complexes, it produces cellular injury by formation of the pore-like membrane attack complex (MAC) (3). In addition to MAC formation, complement activation produces factors C3a and C5a, which together with VEGF increase vascular permeability and provide a chemotactic gradient, resulting in recruitment of neutrophils, eosinophils, basophils, mast cells, NK cells and macrophages (4). These cells produce complement-independent damage of astrocytes through ADCC or degranulation involving Fc receptors. Mechanisms described above may also generate cytotoxicity in neighboring cells including oligodendrocytes and neurons through bystander effects (5).

• #3 Neuromyelitis Optica – EyeWiki

  https://eyewiki.org/Neuromyelitis_Optica

  Neuromyelitis optica, (previously referred to as Devic disease) and now termed neuromyelitis optica spectrum disorders (NMOSD), is an inflammatory, antibody-mediated, immunologic disease of the central nervous system that causes demyelination of the optic nerve and spinal cord. […] The precise etiology of NMOSD remains to be completely defined. In the past there was debate as to whether NMO represented a variant of multiple sclerosis (MS), recent evidence however suggests that NMOSD has a completely different pathogenesis, pathology, mechanism of disease, presentation, course, treatment, and prognosis than MS. […] NMOSD is primarily an astrocytopathy. It involves demyelination and inflammation of multiple spinal cord segments and the optic nerves. NMOSD produces significant axonal loss associated with perivascular lymphocytic infiltration and vascular proliferation.

• #4 Molecular Pathogenesis of Neuromyelitis Optica

  https://www.mdpi.com/1422-0067/13/10/12970

  Aquaporins are water channels present on cell membranes. Of 13 different aquaporins, AQP4 is the predominant type found in mammalian brain. The AQP4 gene is located on chromosome 18. The gene product is a bidirectional, osmosis driven water channel mainly expressed on the foot processes of astrocytes and on ependymal cells in the CNS. It is also expressed in many other organs such as the kidneys, and the gastrointestinal and respiratory tracts. In the CNS AQP4 is preferentially expressed in the retina, optic nerve, hypothalamus, cerebellum, periventricular and periaqueductal regions, and the spinal cord, and low levels are observed in the cerebral cortex. AQP4 forms as a tetramer and each AQP4 monomer has two splicing isoforms identified as M1 and M23. M1 (32 kDa) is 22 amino acids longer than M23 (30 kDa) which is spliced in a shorter formation at the N-terminus. M23 is the predominant isoform in the CNS. AQP4 tetramers are arranged in groups in the form of orthogonal arrays of particles (OAP) on the cell membrane. The size and conformation of these arrays is determined by the relative amount of M23 versus M1 present in the tetramers. AQP4 OAPs have been likened to rafts. The M1 isoform limits the size of OAPs but M23 facilitates formation of larger aggregates. Post translationally, palmitic acid binds with N-terminal cysteines of M1 and inhibits orthogonal array formation. AQP4 is associated with the glutamate transporter, excitatory amino acid transporter 2 (EAAT2). In AQP4-transfected cells, EAAT2 is internalised during AQP4 endocytosis, a process that has not been observed in primary astrocyte cultures or in vivo experiments.

• #5 Neuromyelitis Optica Spectrum Disorder: From Basic Research to Clinical Perspectives

  https://www.mdpi.com/1422-0067/23/14/7908

  AQP4 contributes to the stabilization of extracellular osmolality during neuronal activity. Moreover, it maintains glutamate homeostasis and energy balance as well as buffers the metabolic load in the BBB. The pathological features of NMOSD include activated complement with extensive vasculocentric immune complex deposition, the loss of AQP4 expression in astrocytes, neutrophil/macrophage/microglial infiltration and eosinophil degranulation, myelin loss, and thickened hyalinization blood. The two major AQP4 isoforms, M1 and M23, exhibit locational and maturational differences in the ratio of M1 to M23 proteins along the astrocytic membrane, which possibly determines the pathogenicity and a different anatomical distribution in the CNS and at different stages of CNS maturation in pediatric and adult patients. The proportion of the largest AQP4 aggregate is the highest in the optic nerve followed by the spinal cord; this is relevant to why NMO selectively targets the CNS tissue and spares non-CNS AQP4-expressing tissues. The M1 protein is completely internalized, but M23 resists internalization and activates the complement more efficiently than M1 when bound by the antigen. The relative components of AQP4 isoforms are tissue-specific, with an approximate 3:1 ratio of AQP4-M23 to AQP4-M1 in rat brain. Formation of supramolecular structures, called orthogonal arrays of particles (OAPs), by AQP4 is essential in NMOSD pathogenesis and enhances complement-dependent cytotoxicity (CDC) by the pathogenic AQP4-IgG. It remains unclear if the OAP composition varies in pediatric and adult patients or whether OAP differences may cause different phenotypes.

• #6 Neuromyelitis optica spectrum disorder – Wikipedia

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

  Neuromyelitis optica spectrum disorders (NMOSD) are a spectrum of autoimmune diseases characterized by acute inflammation of the optic nerve (optic neuritis, ON) and the spinal cord (myelitis). […] In more than 80% of NMO cases, the cause is immunoglobulin G autoantibodies to aquaporin 4 (anti-AQP4), the most abundant water channel protein in the central nervous system. […] NMOSD is caused by an autoimmune attack on the nervous system. In more than 80% of cases, IgG autoantibodies against aquaporin-4 (anti-AQP4+) are the cause, and in 10-40% of the remaining cases, IgG antibodies against MOG are the cause. […] NMOSD is usually caused by autoantibodies targeting aquaporin 4 (AQP4), a channel protein in the cell membrane that allows water to pass through the membrane. […] NMOSD selectively affects the optic nerve, spinal cord, and brain stem. This selectivity can be explained by the increased amount of AQP4 in these structures, and, furthermore, by the increased amount of AQP4 aggregates in the optic nerve and spinal cord. […] The inflammatory lesions in NMO have been classified as type II lesions (complement-mediated demyelination), but they differ from MS pattern II lesions in their prominent perivascular distribution.

• #7 Molecular Pathogenesis of Neuromyelitis Optica

  https://www.mdpi.com/1422-0067/13/10/12970

  NMO IgG has high specificity (99%) and moderate sensitivity ranging from 56% to 73% for NMO. It has been observed that the sensitivity of the autoantibody is higher in relapsing cases of NMO. The autoantibody in the blood of NMO patients is predominantly the IgG1 isotype (98% of cases), which can potently activate the complement system. IgG2, IgG3 and IgG4 also occur in a lower proportion of cases. NMO IgG binds to the third extracellular loop of AQP4 and the generation of conformational epitopes during OAP formation results in preferential binding with the M23 isoform. One study has suggested that NMO IgG has considerably lower affinity for the AQP4 protein when compared with the epitope presented by OAPs. NMO IgG does not cross the blood brain barrier (BBB) in normal subjects but it can cross the placenta. It has been demonstrated that NMO IgG is synthesised outside of the CNS. Persistent intrathecal synthesis of oligoclonal IgG, the most stable laboratory feature of MS, was absent in a study of 89 seropositive patients with NMO spectrum disorder, although transient intrathecal production was occasionally observed during acute relapses. CSF from 20 NMO patients showed lower titres of NMO IgG in CSF than in serum (with a ratio of 1:500) in keeping with extrathecal synthesis of the autoantibody. A further seven cases of NMO with low CSF antibody index of NMO IgG (AQP4 IgG/Total IgG) have since been reported. In order to cause disease in the CNS, the extrathecally produced autoantibody requires disruption of the BBB. NMO IgG is occasionally restricted to the CSF and AQP4 specific B cells have been identified in the CSF of one patient with NMO. In some patients, NMO IgG is produced by a subset of CD20 negative B cells that resembled early plasma cells.

• #8 Neuromyelitis optica pathogenesis and aquaporin 4 | Journal of Neuroinflammation | Full Text

  https://jneuroinflammation.biomedcentral.com/articles/10.1186/1742-2094-5-22

  Neuromyelitis optica (NMO) is a severe, debilitating human disease that predominantly features immunopathology in the optic nerves and the spinal cord. An IgG1 autoantibody (NMO-IgG) that binds aquaporin 4 (AQP4) has been identified in the sera of a significant number of NMO patients, as well as in patients with two related neurologic conditions, bilateral optic neuritis (ON), and longitudinal extensive transverse myelitis (LETM), that are generally considered to lie within the NMO spectrum of diseases. NMO-IgG is not the only autoantibody found in NMO patient sera, but the correlation of pathology in central nervous system (CNS) with tissues that normally express high levels of AQP4 suggests NMO-IgG might be pathogenic. If this is the case, it is important to identify and understand the mechanism(s) whereby an immune response is induced against AQP4. This review focuses on open questions about the „events” that need to be understood to determine if AQP4 and NMO-IgG are involved in the pathogenesis of NMO.

• #9 Neuromyelitis optica spectrum disorders: from pathophysiology to therapeutic strategies | Journal of Neuroinflammation | Full Text

  https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-021-02249-1

  Binding of AQP4-ab to astrocyte AQP4 channels triggers classical complement cascade activation, followed by granulocyte, eosinophil, and lymphocyte infiltration, culminating in injury first to astrocytes, then oligodendrocytes, demyelination, neuronal loss, and neurodegeneration. […] Clinical observations also support the hypothesis that AQP4-ab cause NMOSD and are highly specific. They can be detected in sera of most patients, and levels of both AQP4-ab and AQP4-abproducing plasmablasts correlate with disease activity. […] Growing evidence indicates AQP4-ab are synthetized peripherally, rather than intrathecally, subsequently entering the CNS through a disrupted BBB. […] The pathogenic role of AQP4-ab highlights the importance of B cells and plasma cells in NMOSD. […] AQP4-ab in NMO serum are IgG1, a subclass of mature IgG that requires help from T cells, indicating that AQP4-specific CD4+ T cells participate in the genesis of this adaptive humoral response.

• #10 Neuromyelitis Optica, Part 2: Pathogenesis | Multiple Sclerosis Discovery Forum

  http://www.msdiscovery.org/news/news_synthesis/8147-neuromyelitis-optica-part-2-pathogenesis

  Still, it seems clear that it takes two things for NMO lesions to form: something that opens the BBB, such as a CNS-specific CD4+ T-cell response, and entry of the aquaporin-4 antibody into the CNS. This dual-hit model explains why patients with the antibody often don’t come down with NMO for years: That only happens once something opens the BBB. Apparently, the antibodies alone don’t do the job, they need some sort of second hit, and we think it’s the T cells. […] Once the aquaporin-4 antibody enters the CNS, it binds to its target, the water channels on the astrocytes. Some studies suggest that this gets a part of the immune system involved called the complement system, a group of proteins that get activated once they bind to antibody-coated cells. This eventually leads to the formation of a membrane attack complex that punches holes in the antibody-coated cells (in this case the astrocytes). As a result, the astrocytes die.

• #11 Neuromyelitis optica spectrum disorders: from pathophysiology to therapeutic strategies | Journal of Neuroinflammation | Full Text

  https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-021-02249-1

  AQP4-ab binds to extracellular epitopes of AQP4 present on the astrocyte plasma membrane. This triggers astrocyte injury through complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC). […] Studies in experimental animal models as well as in human NMOSD lesions show polymorphonuclear leukocytes (PMNs) as the key determinants of BBB permeability and NMOSD lesion formation.

• #12 Neuromyelitis Optica Spectrum Disorder: Up-to-Date Advance Researches for a Novel Therapeutic Target

  https://www.journal-dtt.org/journal/view.html?pn=mostread&uid=47&vmd=Full&

  Previous studies have shown that approximately 70-80% of NMO patient serum was detected with AQP4 autoantibodies. This antibody type is IgG1, and the pathology of aquaporin-4 IgG is shown in Fig. 1. This mechanism is B and helper T cell-mediated, which divides into a plasma cell. AQP4-IgG is initially produced here and crosses the blood-brain barrier, binding to AQP4 in the astrocyte end-feet. This causes complement activation, and the classical complement cascade begins. […] AQP4-IgG binding AQP4 is caused by a classical complement cascade that activates two cytotoxicity types: antibody-dependent cellular cytotoxicity (ADCC), which also involves complement-dependent cytotoxicity (CDC). […] In NMOSD, C1q binding to the Fc region of AQP4-IgG initiates activation of the classical complement pathway, amplifying the inflammatory reaction by producing proinflammatory (C3a, C4a, and C5a), and this cascade culminates in the generation of the membrane attack complex (MAC), which inserts into the target cell membrane, forming pores that compromise membrane integrity, ultimately resulting in target cell lysis and prompting the infiltration and activation of monocytes, neutrophils, and eosinophils (such as inflammatory cells).

• #13 Neuromyelitis Optica Spectrum Disorder: From Basic Research to Clinical Perspectives

  https://www.mdpi.com/1422-0067/23/14/7908

  Complement-dependent cytotoxicity (CDC), complement-dependent cellular cytotoxicity (CDCC), and antibody-dependent cellular cytotoxicity (ADCC) are responsible for astrocyte injury in NMOSD. ADCC seems to play a main role in facilitating macrophage and natural killer (NK) cell activation after binding to the CH3 region of IgG antibodies via the effector cells’ Fc receptors in the outer zone of developing lesions (penumbra). In CDC, antibody binding to a target antigen triggers the classic complement pathway and results in the formation of the membrane attack complex (MAC). In CDCC, another protein, C3b, is expressed during the complement cascade activation and interacts with NK cells and macrophages to facilitate cell lysis. […] The activation of the complement cascade in patients with NMOSD was reported to increase membrane permeability and promote the influx of serum AQP4-IgG antibodies, which further amplified the inflammatory reaction at the BBB of the CNS. Basic research demonstrated that AQP4 antibodies trigger the complement system and lead to MAC formation via the CDC pathway, which results in astrocyte damage and secondary neuronal injury. C1q-targeted monoclonal antibodies were demonstrated to effectively inhibit AQP4-IgG-mediated CDC, which interfered with MAC, and also IgG-mediated CDCC, which influenced the formation of the Cb3–Cb3R complex on macrophage and NK cells in an in vivo study. Eculizumab is a humanized monoclonal antibody that inhibits terminal C5 complement protein cleavage into the C5a (inducing proinflammatory activity) and C5b fragments (inducing the MAC formation).

• #14

  https://link.springer.com/article/10.1007/s40265-018-1039-7

  Sera from neuromyelitis optica patients disrupt the bloodbrain barrier. […] Increased cerebrospinal fluid metalloproteinase-2 and interleukin-6 are associated with albumin quotient in neuromyelitis optica: their possible role on bloodbrain barrier disruption. […] Autocrine MMP-2/9 secretion increases the BBB permeability in neuromyelitis optica. […] Neutrophil protease inhibition reduces neuromyelitis optica-immunoglobulin G-induced damage in mouse brain. […] Neutrophil elastase-induced elastin degradation mediates macrophage influx and lung injury in 60% O2-exposed neonatal rats. […] Neutrophil elastase inhibitors for the treatment of (cardio)pulmonary diseases: Into clinical testing with pre-adaptive pharmacophores. […] Eosinophil pathogenicity mechanisms and therapeutics in neuromyelitis optica.

• #15 Molecular Pathogenesis of Neuromyelitis Optica

  https://www.mdpi.com/1422-0067/13/10/12970

  Systemic production of autoantibody with disease limited to the CNS implicates the presence of orchestrating T helper cells as well as a cascade of cytokines in the periphery and within the CNS. B cells are also attracted to the CNS by chemokines secreted at sites of inflammation. A study involving 31 NMO patients found various Th2 related cytokines such as IL-1 receptor antagonist, IL-5, IL-10 and IL-13; and the Th17 related cytokines IL-6, IL-8 and granulocyte colony stimulating factor to be elevated in the CSF. However, the signature Th2 cytokine, IL-4, and Th17 cytokine, IL-17, were not detected in the CSF. Other studies have shown increased levels of IL-17 in the CSF of NMO patients. Therefore, Th17 cells may have an intermittent role in the CNS inflammation that characterises NMO. Chitinases, hydrolases secreted by the innate immune cells that play a role in Th2 as well as Th1 related inflammatory processes, are also increased in the CSF of NMO patients. In response to IL-13 monocytes obtained from NMO patients secrete chitinases that increase in vitro chemotaxis of eosinophils, macrophages and T cells across the BBB by promoting the secretion of various cytokines IL-8, RANTES (CCL5), MCP1 (CCL2), and eotaxins by monocytes. Eosinophils and macrophages are abundant in NMO lesions. CSF levels of CXCL13, a potent chemo-attractant for B cells, are elevated and correlate with disease severity. As indicated previously, anti-AQP4 B cells have been detected in the CSF of NMO patients. CXCL13 is secreted by sensitised T helper cells and antigen presenting cells (APC). B-cell activating factor (BAFF) is increased in the CSF but not serum of NMO patients. BAFF, secreted by innate immune cells, APC and activated astrocytes, increases the survival and maturation of B cells through NF-κB. Thus, BAFF can perpetuate the auto-reactive B cell population in the CNS. It is interesting to note that treatment with both β-interferon and glatiramer acetate was found to increase levels of BAFF in the serum of MS patients. This may account for the apparent worsening of NMO with β-interferon. Despite similar changes in BAFF occurring with glatiramer acetate the same concerns regarding its use in NMO have not been raised.

• #16 Molecular Pathogenesis of Neuromyelitis Optica

  https://www.mdpi.com/1422-0067/13/10/12970

  IL-6 is elevated not only in the CSF but also in the serum of patients with NMO, particularly in patients with more severe disease. This proinflammatory cytokine, which can also be secreted by activated astrocytes, increases the survival of NMO IgG producing B cells and the production of antibody. In ex vivo experiments in murine spinal cord, IL-6 increased the induced NMO-like lesions. In a study of 18 NMO patients, IL-9, a T cell growth factor, was elevated in the serum but, not the CSF. IL-6 is involved in the development of IL-17-secreting CD4+ T cells (Th17). Th17 cells have been implicated in many autoimmune disorders such as rheumatoid arthritis, psoriasis, MS and inflammatory bowel disease. Th17 cells and their principal product, IL-17, are found to be increased in serum from patients with NMO, and some studies have also shown elevated IL-17 in the CSF, suggesting the involvement of Th17 cells and IL-17 in the pathogenesis of the disease. IL-17 is seen to mediate inflammation in the brain of EAE mice by promoting microglial activation. Th17 cells may dictate the autoimmune milieu that facilitates the pathogenesis of NMO. A subset of B cells (CD27highCD38highCD180− with low CD20 and CD19−), which may be producing anti-AQP4 antibody, appear to be activated. Further implicating a role for humoral immunity in NMO, CD27+ memory B cell levels rise in association with relapses. There is some evidence that cellular autoimmunity is also initiated as CD4+ T cells against AQP4 are detectable in the blood of patients with NMO.

• #17 ENSPRYNG® (satralizumab) Mechanism of Action (MOA) | Neuromyelitis Optica Spectrum Disorder (NMOSD)

  https://www.enspryng-hcp.com/about-nmosd/how-it-works.html

  ENSPRYNG (satralizumab-mwge) targets IL-6, which has been implicated in neuromyelitis optica spectrum disorder (NMOSD)1,3,12 […] Recent research has led to a better understanding of the pathogenesis of NMOSD, including the pivotal role IL-6 plays in driving the inflammatory response2,10 […] The autoimmune cascade is active in the periphery, where IL-6 promotes T-cell-mediated inflammation by promoting the maturation of T cells into Th17 cells. IL-6 stimulates the differentiation of B cells to plasmablasts, promotes their survival, and enhances AQP4-IgG antibody secretion2,10-12 […] In addition, IL-6 increases blood-brain barrier permeability, allowing penetration of AQP4-IgG antibodies and proinflammatory cells into the central nervous system2,10-12 […] This leads to even more IL-6 production by astrocytes and further damage2,10-12

• #18 Molecular Pathogenesis of Neuromyelitis Optica

  https://www.mdpi.com/1422-0067/13/10/12970

  Anti-AQP4 antibody has been reported in some studies to cause internalisation of AQP4. However, internalisation of AQP4, a process that could paradoxically protect astrocytes from immune mediated cytotoxicity, is unlikely to be the principal pathogenic mechanism in NMO. As noted previously the absence of AQP4 function does not result in neurological disorder in AQP4 knockout mice. Additionally, little or no internalisation of antibody-AQP4 complex is observed in primary astrocyte culture or in vivo, emphasising the limited applicability of AQP4-transfected cells when modelling human disease. It has also been shown that astrocytes do not suffer any osmotic injury as NMO IgG does not disturb the function of AQP4. […] Perivascular glial fibrillary acid protein (GFAP) positive astrocytes are consistently lost in NMO lesions in contrast with MS, where lesional GFAP is usually upregulated. CSF levels of GFAP are markedly elevated during relapses of NMO but not MS. GFAP is a cytoskeletal protein that plays a role in astrocyte motility and structure. It is highly expressed by reactive astrocytes.

• #19 Neuromyelitis optica and myelin oligodendrocyte glycoprotein – Huang – Annals of Eye Science

  https://aes.amegroups.org/article/view/4317/html

  MOG-IgG binds to the extracellular domains of MOGs, which can cause temporary reversible damage to the myelin and axons. […] The changes may affect the structure of the nodes of Ranvier and impact potential firing of the nerves. […] The exact effect of MOG-IgG in vivo is unknown. […] Studies indicate that MOG-IgG binding may cause conformational changes that directly impair the myelin structure, and that there is a lack of complement activation. […] In NMO, binding of AQP4 antibodies to the astrocytic foot processes is believed to damage astrocytes causing release of astrocytic proteins into the CSF, including GFAP. […] The presence of elevated GFAP levels in the CSF suggests an NMO relapse rather than MS.

• #20 Molecular Mechanism of Neuromyelitis Optica Spectrum Disorders | Encyclopedia MDPI

  https://encyclopedia.pub/entry/43566

  The binding of AQP4-IgG to AQP4 induces endocytosis, which results in the loss or internalization of the excitatory amino acid transporter 2 (EAAT2). The internalization of glutamate receptors reduces the astrocytic enzyme glutamate synthase activity, causing glutamate accumulation. […] The binding of AQP4-IgG causes endocytosis of AQP4 and reduces water transport across the plasma membrane. […] The binding of AQP4-IgG to AQP4 induces endocytosis, which results in the loss or internalization of the excitatory amino acid transporter 2 (EAAT2). […] The complement cascade is activated by binding AQP4-IgG onto AQP4, which recruits the complement factors and forms the membrane attack complex formation that attacks the astrocytes, oligodendrocytes, and neurons, leading to demyelination and neuronal cell death. […] The studies on gut microbiota and NMOSD explain the correlation between gut dysbiosis and NMOSD by signifying the abundance of pathogenic bacteria and reduction in commensal organisms, which cause abnormal metabolism and metabolic signals in the pathogenesis of autoimmune diseases such as NMOSD.

• #21

  https://link.springer.com/article/10.1007/s40265-018-1039-7

  Aquaporin-4-binding autoantibodies in patients with neuromyelitis optica impair glutamate transport by down-regulating EAAT2. […] Molecular outcomes of neuromyelitis optica (NMO)-IgG binding to aquaporin-4 in astrocytes. […] Aquaporin-4 deficiency down-regulates glutamate uptake and GLT-1 expression in astrocytes. […] Neuromyelitis optica IgG stimulates an immunological response in rat astrocyte cultures. […] A role for humoral mechanisms in the pathogenesis of Devics neuromyelitis optica. […] Loss of aquaporin 4 in lesions of neuromyelitis optica: distinction from multiple sclerosis. […] Oligodendrocytes are damaged by neuromyelitis optica immunoglobulin G via astrocyte injury. […] Cytotoxic effect of neuromyelitis optica antibody (NMO-IgG) to astrocytes: an in vitro study. […] Functional consequences of neuromyelitis optica-IgG astrocyte interactions on bloodbrain barrier permeability and granulocyte recruitment.

• #22 Neuromyelitis Optica Spectrum Disorder: Up-to-Date Advance Researches for a Novel Therapeutic Target

  https://www.journal-dtt.org/journal/view.html?pn=mostread&uid=47&vmd=Full&

  AQP4-IgG activated astrocytes therefore induce prominent microglia activation. This results in the activated pro-inflammatory cytokine as well as including TNF-A, IL-1beta, and IL-6. Subsequently, NMO is characterized pathologically by significant astrocyte injuries, initiating secondary responses, such as demyelination, oligodendrocyte, and neuronal loss.

• #23

  https://www.jci.org/articles/view/138804

  The role of the classical complement pathway in NMO pathogenesis is well established. […] The importance of the complement pathway in NMO is underscored by the recent approval of the C5 inhibitor, eculizumab (Soliris), in treatment of AQP4-seropositive NMO. […] The work by Chen et al. highlights 2 features of AQP4 antibody and complement-mediated NMO pathogenesis. […] Now, showing that astrocytic C3 production activates microglia emphasizes a bidirectional relationship between these 2 cells in CNS inflammation. […] Microglia may be a target for NMO therapy. […] The report by Chen, et al. now draws attention to the potential cooperation of astrocytes and microglia in NMO.

• #24 Neuromyelitis Optica, Part 2: Pathogenesis | Multiple Sclerosis Discovery Forum

  http://www.msdiscovery.org/news/news_synthesis/8147-neuromyelitis-optica-part-2-pathogenesis

  The binding of the aquaporin-4 antibody also induces antibody-dependent cellular cytotoxicity (ADCC), which attracts immune cells that further damage the tissue. […] Once the astrocytes are affected, other cells that depend on them are likely affected as well: the oligodendrocytes, which depend on the astrocytes in their energy supply, and the nerve cells, which are damaged once the astrocytes don’t remove excessive nerve-cell-stimulating neurotransmitters anymore. Once the astrocytes die, oligodendrocytes and nerve cells eventually die as well, and without the oligodendrocytes, the myelin sheath around the nerve fibers disappears.

• #25 Molecular Pathogenesis of Neuromyelitis Optica

  https://www.mdpi.com/1422-0067/13/10/12970

  Disruption of the BBB is required for NMO IgG to enter the CNS. Serum from NMO patients can cause breakdown of the BBB by an unknown mechanism. However, autoantibodies against cultured human brain microvascular endothelial cells were detected in 10 out of 14 seropositive NMO patients. These autoantibodies, which are distinct from anti-AQP4, were observed to reduce the expression of the tight junction proteins, that constitute the BBB, possibly through the autocrine secretion of vascular endothelial growth factor. The BBB is further disrupted by injury to astrocytic foot processes sustained in the disease process. […] Oligodendrocyte damage appears to follow immune mediated astrocyte injury and these cells are not affected in AQP4 null mice when exposed to NMO IgG and complement factors. Glutamate induced excitotoxicity is one potential mechanism of oligodendrocyte injury. Glutamate is removed by excitatory amino acid transporter 2 (EAAT2) present on astrocytes in association with AQP4. In AQP4 transfected cells, the glutamate transporter is internalised with antibody-AQP4 complex, implicating glutamate excitotoxicity in NMO. However, studies utilising primary astrocyte cultures as a substrate and in vivo studies have failed to demonstrate significant AQP4 complex or glutamate transporter internalisation. Recent work has suggested that NMO IgG bound to the M23 isoform of AQP4 increases resistance to internalisation but does cause internalisation of the M1 isoform. AQP4 has been observed in autopsy studies to be lost both in MS and NMO lesions. This may be due to loss of astrocytes rather than internalisation. Loss of AQP4 in EAE models has been observed to be neuroprotective, but it is likely that this effect is mediated by its water channelling action, which is not affected by NMO IgG binding. Thus, loss of AQP4 in NMO, either by internalisation or astrocyte loss, is one of the markers of the disease but may not be a primary pathogenic process. Whilst it is possible that the inflammatory process primarily targeting astrocytes causes bystander injury to nearby oligodendrocytes, widespread loss of oligodendrocytes is reported in early NMO lesions in the absence of a significant macrophage infiltrate. The immunoglobulin predominantly seen in lesions of NMO patients in one study was of IgM type but as noted earlier it is only detected in the blood of 10% of patients. A possible explanation for this is intrathecal synthesis by local B-cells undergoing class switching. However, another study also showed IgG along with IgM in lesions of NMO patients thus supporting the role of IgG as a pathogenic antibody.

• #26 Neuromyelitis optica spectrum disorder | Radiology Reference Article | Radiopaedia.org

  https://radiopaedia.org/articles/neuromyelitis-optica-spectrum-disorder?lang=us

  Neuromyelitis optica spectrum disorder (NMOSD) is a severe demyelinating diseases, which in seropositive cases, is caused by an autoantibody to the aquaporin-4 (AQP4) water channel. […] In approximately 70% (sensitivity of 70-90%; specificity of 90%) of patients with established NMOSD, a specific immunoglobulin can be isolated (anti-AQP4-IgG) which targets a transmembrane water channel (aquaporin-4) present on astrocyte foot processes abutting the limiting membrane. […] This accounts for some of the predilection for the circumventricular organs (e.g. periaqueductal grey matter) which are particularly rich in aquaporin-4. […] Early in the disease, demyelinating regions will demonstrate similar findings to multiple sclerosis, such as macrophage/microglia activation and axonal damage. Additionally, however, and relatively specific for NMOSD, these regions will also demonstrate extensive eosinophilic infiltration, perivascular deposition of immunoglobulins (especially IgM) and local activation of the complement cascade. […] Another differentiating feature is that axonal damage precedes demyelination in NMOSD. […] Generally, the condition is sporadic, although some overlap in immunogenic features between certain viruses and aquaporin-4 water channel have been identified.

• #27 Neuromyelitis optica spectrum disorder (NMOSD): Clinical features and diagnosis – UpToDate

  https://www.uptodate.com/contents/neuromyelitis-optica-spectrum-disorder-nmosd-clinical-features-and-diagnosis

  Neuromyelitis optica spectrum disorder (NMOSD; previously known as Devic disease or neuromyelitis optica [NMO]) is an inflammatory disorder of the central nervous system characterized by severe, immune-mediated demyelination and axonal damage predominantly targeting optic nerves and the spinal cord. […] However, the discovery of a disease-specific serum NMO-immunoglobulin G (IgG) antibody that selectively binds aquaporin-4 (AQP4) has led to increased understanding that NMOSD is distinct from classic relapsing-remitting multiple sclerosis with respect to pathogenesis, imaging features, biomarkers, neuropathology, and treatment. […] Neuropathology – In NMOSD, florid demyelination and inflammation involve multiple spinal cord segments and the optic nerves with associated astrocyte death, axonal loss, perivascular lymphocytic infiltration, and vascular proliferation. Unlike multiple sclerosis, necrosis and cavitation typically involve both gray and white matter. The neuropathologic features of NMOSD at autopsy are those of a much more severe necrotic lesion of the cord rather than incomplete demyelination. This may result from the distribution of aquaporin-4 (AQP4) receptors, which predominate in astrocytes rather than oligodendrocytes.

• #28 Neuromyelitis optica spectrum disorder | MedLink Neurology

  https://www.medlink.com/articles/neuromyelitis-optica-spectrum-disorders

  Lesions in neuromyelitis optica spectrum disorder show perivascular and parenchymal leukocyte infiltration, deposition of IgG, IgM, and complement, loss of GFAP and AQP4 staining, hemorrhagic exudation, edema, capillary proliferation, vascular fibrosis, hyalinization, tissue necrosis, and cavitation. […] Both white and gray matter are affected. Lesions are more similar to necrotizing vasculitis than to the predominantly demyelinating lesions of multiple sclerosis or acute disseminated encephalomyelitis.

• #29 SciELO Brazil – Devic’s neuromyelitis optica: a critical review Devic’s neuromyelitis optica: a critical review

  https://www.scielo.br/j/anp/a/sxQzPdxvpDVnTszzKzHjHSv/?lang=en

  It was suggested that classical Devic’s NMO and conventional MS represent two extremes of a spectrum of the same condition. […] The pattern of tissue inflammation in early demyelinating active NMO with a unique perivascular pattern supported a role for humoral autoimmunity in the pathogenesis of the disease. […] The abnormalities of the perivascular region with macrophage infiltrate and massive deposition of complement and immunoglobulin associated with the prominent vascular hyalinization definitely led the authors to suggest the perivascular space as the primary target site of the pathogenic process. […] The structural and immunopathological features of NMO were compared with cases of MS, acute demyelinating encephalomyelitis (ADEM) and acute spinal cord infarction. […] In NMO, there are a pronounced perivascular deposition of immunoglobulin and complement, eosinophilic infiltration and prominent vascular fibrosis and hyalinization within the lesions.

• #30 Molecular Pathogenesis of Neuromyelitis Optica

  https://www.mdpi.com/1422-0067/13/10/12970

  A genetic predisposing factor is likely in NMO, as the disease is relatively more prevalent in non-Caucasian populations, as compared to MS which is more common in Europeans. However, the stand alone prevalence of NMO (not relative to MS) has not been systematically determined in any large population. Further clues favouring a genetic predisposition derive from familial NMO cases. While such cases have been described for many years, only a small proportion (3%) of cases have a positive family history, predominantly those with Asian or Latino descent. In the most comprehensive familial study to date (12 families, 25 affected individuals), the pattern of inheritance was thought to be complex. The human leukocyte antigen (HLA) associations of NMO are contrasted with MS. NMO IgG positivity has been found to be associated with HLA-DRB1*03 (DR3) in French and Brazilian populations and HLA-DPB1*0501 in Japanese and Chinese populations. Notably, these HLA haplotypes are also associated with other humoral autoimmune disorders such as systemic lupus erythematosus (SLE) and Graves’ disease. Indeed, NMO often coexists with other autoimmune conditions such as SLE and Sjögren syndrome and these disorders are also more common in family members of patients with NMO. Recent diagnostic criteria for NMO have tended to exclude SLE and Sjögren syndrome as not being compatible with a diagnosis of NMO.

• #31 A whole-genome sequence study identifies genetic risk factors for neuromyelitis optica | Nature Communications

  https://www.nature.com/articles/s41467-018-04332-3

  Neuromyelitis optica (NMO) is a rare autoimmune disease that affects the optic nerve and spinal cord. Most NMO patients (70%) are seropositive for circulating autoantibodies against aquaporin 4 (NMO-IgG+). […] We identify two independent signals in the major histocompatibility complex (MHC) region associated with NMO-IgG+, one of which may be explained by structural variation in the complement component 4 genes. […] Our results suggest that genetic variants in the MHC region contribute to the etiology of NMO-IgG+ and that NMO-IgG+ is genetically more similar to SLE than MS. […] To elucidate genetic factors driving NMO risk and to clarify the genetic architecture of this disease, we analyzed up to 6.8 million single-nucleotide polymorphisms (SNPs) and performed copy number variation (CNV) analysis on 215 cases and 1244 controls of European ancestry.

• #32 A whole-genome sequence study identifies genetic risk factors for neuromyelitis optica | Nature Communications

  https://www.nature.com/articles/s41467-018-04332-3

  In this study, we find two independent significant genetic signals in the major histocompatibility complex (MHC) region associated with NMO. […] We also provide initial evidence that suggest NMO-IgG+ is genetically more similar to systemic lupus erythematosus (SLE) than to MS. […] A significant association was identified in the NMO-IgG+ group (OR=6.21, P=1.0109) for reduced copy number in the region annotated by a complex structural site on the location of complement component 4 (C4). […] Thus, the cumulative evidence suggests that C4 deletions may be the functional driver of the association with NMO-IgG+. […] The association of the same C4 deletions in SLE and NMO-IgG+ and the genetic link observed in the Mendelian Randomization study between SLE and NMO-IgG+ suggest a potential common strategy for therapeutic targeting of autoantibody production.

• #33 Molecular Pathogenesis of Neuromyelitis Optica

  https://www.mdpi.com/1422-0067/13/10/12970

  In one series the onset of neurological symptoms in almost 30% of NMO cases was preceded by a viral or bacterial infection (more cases associated with varicella zoster and mycobacterium tuberculosis) and vaccination against human papilloma virus has been reported to precede the onset of NMO in 4 teenage girls. Parainfectious NMO may have a different immunopathogenesis as the majority of these cases have a monophasic course. Rarely, a paraneoplastic association has also been described in NMO, especially with carcinoma of the breast and lung, and B cell-lymphoma. A recent study of the T cells derived from the blood of 15 NMO patients has supported molecular mimicry as a possible cause of autoimmunity in NMO. Homology between the immunogenic amino acids 66–75 of AQP4 and the surface protein ABC-TP of clostridia species especially Clostridium perfringens has been observed and ABC-TP was shown to cross react with anti-AQP4 T cells. Clostridium perfringens is a ubiquitous organism and can occur in human gut as a commensal. This study requires independent replication.

• #34 Research Interests | The Zamvil Laboratory

  https://neuroimmunol.ucsf.edu/research-interests

  Our group is currently studying T cell reactivity to AQP4, the primary autoantigen in NMO. We provided the first evidence that AQP4-specific T cells exist in NMO patients and that there is a higher frequency of AQP4-reactivity T cells in NMO patients than controls. […] In NMO, T cells specific for the immunodominant AQP4 determinant exhibit a Th17 bias, providing support for a Th17-mediated pathogenesis, and cross-react with a homologous amino acid sequence in a Clostridium perfringens ABC transporter, suggesting molecular mimicry. […] Recently, we discovered there is an overabundance of C. perfringens in the gut microbiome of NMO patients, further supporting the potential role of C. perfringens in NMO pathogenesis. […] We have identified the pathogenic T cell epitopes of AQP4 in mice and demonstrated that T cells targeting them can cause paralysis and opticospinal inflammation. […] Our findings indicate that the T cell repertoire to AQP4 is regulated strongly by negative selection, a possibility that we are investigating currently.

• #35 Fellows Forum Case Report: Neuromyelitis Optica – The Rheumatologist

  https://www.the-rheumatologist.org/article/fellows-forum-case-report-neuromyelitis-optica/?singlepage=1

  The presence of neutrophils or eosinophils greater than 5/uL argues in favor of NMOSD over MS. […] The lack of oligoclonal bands is supportive of the diagnosis because it is seen in less than 20% of patients with NMOSD; however, they can be transiently noted during an attack. […] In 2015, a revised international consensus criteria for the diagnosis of NMOSD proposed by the American Academy of Neurology included criteria using the results of testing for AQP4-IgG. […] NMOSD can be related to other autoimmune/rheumatologic conditions, as well. […] It is estimated that 30-50% of NMOSD patients have laboratory or clinical evidence of these diseases. […] Because some of these conditions, such as SLE, may cause visual loss, one should carefully evaluate patients to rule out the diagnostic possibilities, especially in those patients who are negative for AQP4-IgG.

• #36 Copresence of myasthenia gravis and neuromyelitis optica: a report of 2 cases | Neurología (English Edition)

  https://www.elsevier.es/en-revista-neurologia-english-edition–495-articulo-copresence-myasthenia-gravis-neuromyelitis-optica-S2173580820302686

  The pathogenesis of this association may be linked to CD4+ regulatory T cells, which are involved in immunologic self-tolerance and whose levels may decrease or be altered in both entities. […] In conclusion, we should be aware of the possible association between MG and NMO; correct diagnosis may have considerable implications for treatment and prognosis.

• #37 Molecular Pathogenesis of Neuromyelitis Optica

  https://www.mdpi.com/1422-0067/13/10/12970

  Great strides have been made in elucidating the molecular underpinnings of NMO, but aspects of the pathogenesis remain unknown and no currently proposed disease model is completely satisfactory. It seems likely that NMO is an autoimmune disease that develops in genetically susceptible individuals. There is already some evidence for specific HLA alleles and polymorphisms of the AQP4 gene being associated with NMO. Infection, vaccination, and neoplasm may trigger the disease process in some cases but a recognisable initiating event is lacking in most. In the schema presented, this trigger induces the release of inflammatory cytokines, including IL-6, and Th17 cells are stimulated. A subset of B-cells in the peripheral tissues is stimulated to produce anti-AQP4 IgG antibody. The BBB is made permeable to the autoantibody by either a systemic inflammatory response or a local pathological process in the CNS. Auto-reactive B cells may also enter the CNS and undergo class switching to produce IgM autoantibody. The antibody fixes complement on AQP4 expressing astrocytic foot processes. Stellate astrocytes are damaged by complement dependent cytotoxicity and complement dependent cellular cytotoxicity. Oligodendrocytes that are in close proximity to astrocyte foot processes are possibly affected through bystander inflammatory damage or, more likely, loss of trophic support from astrocytes. The resulting demyelination causes loss of saltatory conduction and conduction block, leading to neurological deficit. With continuing or repeated inflammation, substantial neuro-axonal loss ensues. The near absence of progressive forms of NMO (primary or secondary) suggests that neuro-axonal damage is the result of the acute inflammation, whether directly or indirectly, rather than as a result of a secondary degenerative process as appears to be the case in some forms of MS. Some CNS sites, such as cerebellum, express AQP4 abundantly but are not usually involved in NMO. Similarly, cerebral cortex expresses AQP4 but is not affected. This may be due to the specific local immune environment. Elucidation of such protective mechanisms will be helpful in identifying new therapeutic targets. The processes responsible for oligodendrocyte loss are also largely unknown and the mechanism of axonal injury in chronic lesions is also poorly understood. Important questions regarding the aetiopathogenesis of seronegative cases with NMO phenotypes remain. Do these cases have a different antigenic target (heterogeneity) or do they represent a milder form of the disease (forme fruste), or do they reflect technical problems with the currently available NMO IgG assays (false negatives)?

• #38 Molecular Pathogenesis of Neuromyelitis Optica

  https://www.mdpi.com/1422-0067/13/10/12970

  As the first autoimmune disease of the CNS for which a specific autoantibody and antigenic target have been identified NMO represents a significant opportunity to better understand and hopefully treat its more heterogeneous and complex cousin, MS. Very recent research has highlighted a novel potential therapeutic approach utilising small-molecule inhibitors to reduce AQP4 mediated astrocyte cytotoxicity by disrupting the interaction between NMO-IgG and M23-AQP4. These experiments demonstrate the very direct way in which a greater understanding of the pathogenesis of autoimmune diseases such as NMO can lead to new therapeutic interventions. The prominent role played by IL-6 in NMO has led to the suggestion that IL-6 receptor blockade may be an effective therapy. The development of fully humanised monoclonal antibodies against the B-cell antigens CD20 and CD19 raise exciting prospects for improved tolerability and potentially greater efficacy in the treatment of NMO.

• #39 Neuromyelitis Optica Spectrum Disorder: From Basic Research to Clinical Perspectives

  https://www.mdpi.com/1422-0067/23/14/7908

  The new evidence on NMOSD pathophysiology highlights promising treatment modalities as well as clinical studies. Restoring immune tolerance might provide an interesting treatment strategy in the future. Some success was achieved by using autologous hematopoietic stem cell transplantation, peptide-loaded tolerogenic dendritic cells, DNA vaccine encoding myelin basic protein, autoreactive T cell vaccination, and regulatory T cells. Further alternative targets for NMOSD treatments are the blood–brain barrier, the complement cascade, and B cells.

• #40 Molecular Pathogenesis of Neuromyelitis Optica

  https://www.mdpi.com/1422-0067/13/10/12970

  Rituximab has been found to be clinically effective in NMO and reduces the levels of anti-NMO IgG, but the antibody does not completely disappear. There may also be a BAFF related transient elevation in the anti-NMO titres observed 2 weeks after the first injection of rituximab. One possible explanation for this is that plasma cells, which do not express CD20 (the target of rituximab), may continue to produce antibody for a period of time, possibly at an increased rate due to the depletion of memory B cells and other modulatory B cells (regulatory B cells) which do carry CD20. Repeated rituximab therapy may reduce the level of NMO IgG after the depletion of memory B cells and natural death of short-lived plasmablasts/plasma cells. Long-lived plasma cells may continue to secrete autoantibody despite the treatment with rituximab. An alternative explanation is that it is purely through the modulatory effects of B cells on T cells that rituximab is having an effect, such that removal of memory B cells and activated B cells diminishes the proinflammatory milieu.

• #41 SciELO Brazil – Treatment of neuromyelitis optica: an evidence based review Treatment of neuromyelitis optica: an evidence based review

  https://www.scielo.br/j/anp/a/rdSpmcLbFzPkCPK4cMfmZsw/

  AQP-4 antibody, also known as NMO-IgG, an autoantibody exclusively detected in the sera of NMO, is directed against AQP-4, a water channel richly expressed on foot processes of astrocytes in the CNS. […] There is evidence that AQP-4 antibody titers are reduced in patients without relapses under immunosuppressant treatment. […] A possible explanation for the occurrence of relapses following initiation of rituximab in some NMO patients is the transient increase in AQP-4 antibody titers and of B cell activating factor levels, which is observed for two weeks following the initial infusion. […] Eculizumab is a humanized monoclonal IgG antibody that binds to complement protein C5, preventing cleavage into C5a and C5b. Eculizumab inhibits the subsequent formation of terminal complex C5b-9 or membrane attack complex.

• #42 ENSPRYNG® (satralizumab) Mechanism of Action (MOA) | Neuromyelitis Optica Spectrum Disorder (NMOSD)

  https://www.enspryng-hcp.com/about-nmosd/how-it-works.html

  Once in the brain, AQP4-IgG antibodies bind with AQP4 channels on astrocytes, triggering activation of the complement cascade leading to astrocyte injury, oligodendrocyte loss, demyelination, and neuronal loss. IL-6 also recruits neutrophils and eosinophils. This causes bystander damage and activates microglia which produce TNF-alpha and IL-1 beta, cytokines toxic to neurons and nearby cells2,10-12 […] IL-6 is therefore an important therapeutic target in the treatment of NMOSD2,10 […] While the precise mechanism by which ENSPRYNG exerts therapeutic effects in NMOSD is unknown, it is presumed to involve inhibition of IL-6-mediated signaling via binding through soluble and membrane-bound IL-6 receptors1 […] To summarize, by inhibiting IL-6 signaling, ENSPRYNG is thought to help decrease IL-6 mediated autoimmune T- and B-cell activation, as well as differentiation of B cells into AQP4-IgG-secreting plasmablasts1,10

• #43 ENSPRYNG® (satralizumab) Mechanism of Action (MOA) | Neuromyelitis Optica Spectrum Disorder (NMOSD)

  https://www.enspryng-hcp.com/about-nmosd/how-it-works.html

  In turn, this targets inflammation, blood-brain barrier permeability, and astrocyte injury all key drivers of NMOSD disease1,2,10 […] Four functions of Interleukin 6 (IL-6): AQP4-IgG production, T helper 17 (Th17) cells, Blood-brain barrier (BBB) permeability, and astrocyte injury and lesion propagation. […] By inhibiting IL-6 signaling, ENSPRYNG is thought to help decrease IL-6-mediated autoimmune T- and B-cell activation […] Differentiation of B cells into AQP4-IgG-secreting plasmablasts.

• #44 Optic neuritis: Differentiating MS from neuromyelitis optica

  https://www.ophthalmologytimes.com/view/optic-neuritis-differentiating-ms-from-neuromyelitis-optica

  The bottom line is that antibodies to aquaporin-4 are the pathogenesis of the periarterial inflammation in NMO compared with MS in which the extravasation of immunologically active cells emerge in perivenular location. […] Complement activation and increased levels of IL-6 also develop. […] Histopathologic studies have shown that NMO may produce ischemic damage, strokes in the spinal cord correlating very well with what can develop in the central retinal artery and its branches. […] NMO attacks can result in blindness, paralysis, and death from neurogenic respiratory failure. Incomplete recovery from attacks is the typical course that can result in cumulative disability. […] Three medications have received FDA approval for treating NMO: Uplizna (inebilizumab-cdon, Viela Bio) for B-cell depletion; Soliris (eculizumab, Alexion Pharmaceuticals Inc.) for complement inhibition; and Enspryng (satralizumab, Chugai Pharmaceutical) for antiIL-6 activity.

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