In other examples of strong genetic predisposition, anti-LGI1 encephalitis shows a strong HLA association with the DRB1 *07:01 allele, which is carried by 90% of patients vs.
An off-center binding topology (as has been demonstrated with a T cell clone isolated from a MS patient), may permit autoreactive T cell clones to escape negative thymic selection but still cause disease ( 10). For example, the HLA-peptide T cell receptor binding geometry may play a crucial role in disease causation ( 9). Such variations play an important role in the differences between individuals in their immune response to auto-antigens, and is the basis for the strong association between specific MHC alleles and predisposition to autoimmune disease (as in myasthenia gravis or multiple sclerosis). The MHC locus is also the most polymorphic in the human genome, with a differential ability to bind and efficiently present peptides. MHCII molecules on antigen presenting cells capture peptides and present them to T cells. The MHC locus makes a greater contribution to risk of autoimmune disease than any other loci. Also higher incidence in females of most autoimmune diseases, points to the importance of still poorly understood X chromosome factors in genetic susceptibility ( 7), although effects of sex hormones on immune responses may also play an important role ( 8). In multiple sclerosis (MS), concordance in monozygotic twins of about 25% compared to ~5% in dizygotic twins ( 3) and in myasthenia gravis (MG) concordance of ~35% in monozygotic twins compared to ~5% in dizygotic twins ( 4), suggests the contribution of genetic factors to disease causation. Neuroinflammatory disorders due to other causes such as cerebral degeneration or nervous system involvement secondary to systemic autoimmune disorders such as systemic lupus erythematosus are not included in this discussion.
These include central nervous system demyelinating disorders such as multiple sclerosis and neuromyelitis optica, paraneoplastic, and other autoimmune encephalomyelitis and autoimmune inflammatory myositis and demyelinating neuropathies. In this article autoimmune disorders of the central and peripheral nervous system are discussed, including disorders where an auto-antigen has yet to be defined. Abnormal immune responses against self can result in more than 80 autoimmune diseases ( 2) including about 30 autoimmune disorders of the nervous system. However, in an estimated 4.5% of individuals the immune system attacks the very individual it is designed to protect ( 1). The immune system has evolved to have the extraordinary ability to protect us from a vast multitude of infectious agents.
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