Illustration of the four different types of glial cells found in the central nervous system: ependymal cells, astrocytes, microglial cells, and oligodendrocytes Anti-AQP4+ variants 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. AQP4 monomers form tetramers, and the tetramers aggregate. AQP4 is found in astrocytes, which are the basis for the glymphatic system. Thus, NMOSD involving AQP4-IgG can be considered an astrocytopathy or autoimmune astrocytic channelopathy, since the astrocytes are semi-selectively destroyed. The astrocytes surround the blood–brain barrier (BBB), a system responsible for preventing substances in the blood from entering the brain. For antibodies from the blood to reach astrocytes in the central nervous system (CNS), they must cross the BBB, the mechanism of which is not completely known. Some reports point to the metalloproteinase-2 and interleukin-6 as culprits responsible for the BBB failure. There is broad consensus that AQP4/NMO-IgG initially enters the brain via BBB-deficient sites such as the area postrema, where there is access to cerebrospinal fluid (CSP). In any case, anti-AQP4 is produced mainly intrathecally. Within astrocytes, AQP4 is primarily found in astrocytic foot processes that abut blood vessels and the linings of the brain (meninges). NMOSD brain lesions, as seen under a microscopic, show IgG, Immunoglobulin M (IgM), inflammatory cells, and complement deposits around blood vessels. AQP4-IgG is a member of the IgG1 immunoglobulin family, which is an activator of the complement system, which seems to play an integral part in the autoimmune response. There is a loss of astrocytes, and sometimes also a loss of neurons and oligodendrocytes. Loss of cells other than astrocytes is a consequence of collateral inflammatory damage or astroctye dysfunction. NMOSD selectively affects the<unk> 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<unk> nerve and spinal cord. The increased BBB permeability at the area postrema helps explain involvement there. AQP4 is present in tissues outside the central nervous system (e.g. the kidneys), but these tissues aren't affected in NMOSD, at least in part because of the presence of autoimmune downregulators outside of the central nervous system. In NMOSD, areas of brain tissue that appear normal in conventional magnetic resonance imaging (MRI) can show damage in diffusion tensor imaging (DTI), although less so compared to multiple sclerosis (MS). Most research into the pathology of NMO has focused on the spinal cord. The damage can range from inflammatory demyelination to necrotic damage of the white and grey matters. 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. Therefore, the pattern of inflammation is often quite distinct from that seen in MS. AQP4-IgG levels are coarsely correlated with NMOSD disease activity, those levels generally increasing before relapse and declining during remission, with higher levels being correlated to more severe disease manifestation. NMO-IgG-negative cases are less understood. It seems that astrocytes are spared in these cases. Anti-MOG+ variants The second most frequent autoantibody in NMO is MOG-IgG, which targets myelin oligodendrocyte glycoprotein (MOG). MOG is an integral membrane glycoprotein found on the surface of oligodendrocytes and the outermost surface of myelin sheaths. Its function is not entirely known. MOG-IgG is produced outside the central nervous system (CNS) despite MOG existing only in the CNS (with the BBB separating the two), leading to the hypothesis that MOG drained via cerebral spinal fluid into lymph nodes causes autoimmune reaction formation. MOG-IgG-positive NMOSD brain lesions, as seen under a microscopic, show demyelination with preservation of oligodendrocytes and axons, presence of inflammatory cells, and IgG and complement deposits. MOG-IgG levels coarsely correlate with disease severity, with levels being higher during active disease, and higher levels being associated with more severe disease manifestation. Antibodies against MOG are considered mostly absent in similar diseases, such as MS. Therefore, it can be said that anti-MOG diseases are grouped within AQP4-IgG-negative NMOSD. Together with anti-AQP4 disease, anti-MOG diseases form the wider part of the NMO<unk> . The NMO cases are classified in four classes, according to the presence or absence of any of these two main auto-antibodies. The clinical course and the response to therapy is different for various diseases classed within these groups, showing a better prognosis for those in the NMO-Ab(−)/MOG-Ab(−) group, and a worse prognosis for those in the NMO-Ab(+)/MOG-Ab(+) group. The MOG-related NMO can be radiologically identified by the conus involvement. Myelin-oligodendrocyte glycoprotein antibody–positive patients were more likely to have conus involvement on spinal magnetic resonance imaging.
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