Morvan syndrome and related disorders associated with CASPR2 antibodies
Jan. 18, 2022
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In the last years, evidence for a critical involvement of a humoral immune response against myelin oligodendrocyte glycoprotein (MOG) in a subgroup of inflammatory demyelinating CNS diseases arose. Antibodies are present in monophasic and recurrent non-multiple sclerosis diseases with a predominance in acute disseminated encephalomyelitis (ADEM) and optic neuritis. Therefore, the term MOG antibody-associated spectrum diseases (MOGAD) was introduced. This article discusses the spectrum of MOG antibody-associated diseases, the implementation of MOG antibodies in clinical routine, and immunopathogenetic findings.
• Critical involvement of a humoral immune response against myelin oligodendrocyte glycoprotein exists in a subgroup of inflammatory demyelinating CNS diseases.
• Antibodies are predominately present in monophasic or recurrent non-multiple sclerosis-acquired demyelinating inflammatory CNS diseases.
• Although MOG antibodies were first described in pediatric patients, they are also found in a subgroup of adult patients.
• The clinical phenotype associated with MOG antibodies is age-dependent, with ADEM in children and an opticospinal presentation in older children and adults.
• MOG antibodies are associated with a distinct neuropathology.
Apart from multiple sclerosis as the most common inflammatory demyelinating central nervous system disease, other rare entities, such as neuromyelitis optica spectrum diseases or ADEM, must be considered as differential diagnosis in patients with a first demyelinating event. As early treatment initiation is recommended in multiple sclerosis, diagnosis at disease onset is important for patient management and treatment stratification. Despite typical clinical features and paraclinical markers (MRI and cerebrospinal fluid), diagnosis is often challenging. Therefore, there is a need for reliable biological markers for diagnostic and prognostic purposes. In inflammatory demyelinating CNS diseases, it is suggested that an autoimmune reaction finally leading to the cascade of inflammation, demyelination, and axonal loss initiates the development of the disease. Due to diagnostic role of autoantibodies in other autoimmune diseases and evidence for crucial involvement of B cells and antibodies in multiple sclerosis pathogenesis, an international research focus has been directed to antibodies against CNS antigens. A breakthrough was the detection of aquaporin-4 (AQP-4) antibodies in neuromyelitis optica spectrum disorder (26). Knowledge of immunopathogenesis and the diagnostic management changed, and now antibodies against AQP-4 are well integrated in the clinical diagnostic procedures. However, there is still a lack of biological markers for the identification of multiple sclerosis subtypes, AQP-4-negative neuromyelitis optica spectrum disorder cases, ADEM, and other atypical CNS demyelinating diseases.
Numerous potential antigen targets were studied. The most promising results came from studies using cell-based assays expressing full-length, conformationally correct folded myelin oligodendrocyte glycoprotein, which is a protein exclusively present in the CNS at the outermost surface of myelin sheaths and oligodendrocyte membranes. MOG, a protein of 245 amino acids, exposed an immunoglobulin domain in the extracellular space and, therefore, seems to be a potential target structure for an autoimmune reaction against myelin. The exact biological role of MOG remains unclear. It is well-known that in experimental autoimmune encephalomyelitis, MOG is a dominant antigen structure after immunization with CNS tissue homogenates (25). Furthermore, in animal models, antibodies against MOG can enhance demyelination and inflammation. Monoclonal MOG antibodies can cause demyelination in the presence of complement, can induce relapses, and are crucial for myelin phagocytosis of macrophages (32).
Although the role of MOG is well established in animal models, its relevance in human diseases was less clear. Numerous studies addressed the diagnostic, prognostic, and pathogenic relevance of MOG antibodies in multiple sclerosis and other CNS demyelinating diseases with controversial results. One problem was that many of the initial studies analyzed antibodies against recombinant linear or refolded human MOG expressed in E. coli using different test mechanisms, such as enzyme-linked immunosorbent assay (ELISA) or western blot. These assays recognized MOG lacking the correct membrane topology and glycosylation (32).
However, antibodies against MOG and their role in CNS demyelinating diseases were still of interest, and a breakthrough succeeded with the development of assay-detecting antibodies against conformational MOG. First evidence once again came from animal models: only antibodies against conformational correct MOG can mediate demyelination, pathogenic antibodies were directed against correct glycosylated MOG, and antibodies against native MOG correlate with disease severity (29; 31).
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