The role of autoantibodies in the pathogenesis of multiple sclerosis (MS)

The role of autoantibodies in the pathogenesis of multiple sclerosis (MS) and additional demyelinating diseases is controversial, in part because widely used western blotting and ELISA methods either do not permit the detection of conformation-sensitive antibodies or do not distinguish them from conformation-independent antibodies. is definitely a more prominent target antigen in ADEM than MS. The part of autoantibodies in the pathogenesis of human being demyelinating diseases of the central nervous system (CNS) is an important, unresolved issue. In animal models, autoantibodies that recognize epitopes on the surface of myelin or myelin-producing oligodendrocytes can enhance demyelination1,2. A monoclonal antibody (8C18C5) against myelin oligodendrocyte glycoprotein (MOG) induces severe demyelination in mice and rats with slight experimental autoimmune encephalomyelitis (EAE) but does not induce disease in healthy animals because the antibody cannot gain access to the CNS parenchyma1,2. MOG is definitely a minor component of Torin 1 myelin but is definitely localized within the outer surface of the multilamellar myelin structure and is therefore accessible to antibodies, whereas more abundant antigens such as myelin basic protein are inaccessible in undamaged myelin1. In the marmoset primate model of EAE, immunization with MOG induces a chronic demyelinating disease with pathological features reminiscent of MS (ref. 3). In mouse models, however, severe demyelination is definitely observed in the absence of antibodies and B cells4, indicating that autoantibodies are not required for demyelination in all varieties. These elegant studies in animal models have shown the demyelinating potential of autoantibodies to myelin surface proteins, but their part in the pathogenesis of human being inflammatory demyelinating diseases such as MS and acute disseminated encephalomyelitis (ADEM) is definitely far less particular. MOG has been extensively studied like a potential target antigen for autoantibodies in MS (refs. 5C8), but the presence and involvement of such autoantibodies is definitely controversial. Although oligoclonal IgG is definitely often found in the cerebrospinal fluid (CSF) of individuals with MS (ref. 9), the specificities of these CRF (human, rat) Acetate locally produced antibodies and their part in disease progression are not known. A substantial fraction of individuals with neuromyelitis optica, a variant of MS in which the optic nerves and spinal cord are primarily affected, were recently shown to have autoantibodies against the aquaporin-4 water channel localized on astrocyte foot processes in the blood-brain barrier10. Unlike MS, ADEM typically has a rapidly progressive medical demonstration that includes encephalopathy11. The disease program is usually self limiting, although inside a minority of instances relapses may occur. The pathogenic relationship between MS and ADEM is definitely unclear, and it remains to be identified Torin 1 whether ADEM and MS are related in the spectrum of demyelinating diseases or whether they are entirely separate entities. Approximately 1 of 400 recipients of a CNS-derived rabies vaccine contaminated with myelin fundamental protein12 developed encephalomyelitis, the event of which was strongly correlated with the presence of serum autoantibodies to myelin fundamental protein13. It is important to distinguish vaccine-related forms of ADEM, which are the direct result of immunization with myelin proteins, from most ADEM instances, which often adhere to an illness14,15. In some cases, Torin 1 no obvious antecedent history of illness or vaccination is present. The evidence for an autoimmune process is definitely less conclusive for postinfectious forms of ADEM than vaccine-related instances. Although a moderate proliferative T-cell response to myelin fundamental protein has been observed in some individuals with postinfectious forms of ADEM (refs. 16C18), the analysis is still primarily based within the exclusion of CNS illness or other causes of acute demyelination. The presence of autoantibodies to MOG or additional myelin surface antigens has not been investigated in ADEM. Considerable studies in EAE models have shown that only antibodies that identify folded MOG protein are pathogenic, whereas antibodies that solely bind to.