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Multiple sclerosis: major histocompatibility complexity and antigen presentation

DOI: 10.1186/gm105

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Multiple sclerosis (MS) as a disease has been recognized for well over a century, but relatively little is understood about its cause. MS is a putative autoimmune disorder of the central nervous system, characterized by inflammatory demyelination, varying degrees of axonal pathology and progressive neurological dysfunction. Risk factors associated with the disease appear to exert effects many years before the clinical onset of MS, lending credence to the idea of a causal cascade in MS development. Genetic-epidemiological studies point unequivocally to large genetic and environmental influences on susceptibility [1]. An association between MS and alleles of the major histocompatibility complex (MHC) was found in the 1970s, notably involving the class II human leukocyte antigen HLA-DR2 [2]. This was later fine-mapped to the extended haplotype HLA-DRB5*0101-HLA-DRB1*1501-HLA-DQA1*0102-HLA-DQB1*0602 [3] (to briefly explain HLA nomenclature, the first two digits of an allele describe its serological antigen (called an allelotype) while the third and fourth digits are used to list the allele subtypes. Alleles with different numbers in these first four digits must differ by at least one non-synonymous nucleotide substitution). This extended haplotype confers a relative risk of approximately 3, but much larger effects are seen if haplotypic and diplotypic (both haplotypes in combination) information is taken into account, and the odds ratio for risk spanned by variation in the class II HLA region is thought to exceed 30.Genome-wide association studies have highlighted the fact that the HLA class II region exerts by far the strongest genetic effect on risk [4], but exactly how it alters the risk of developing MS is not yet fully understood. As HLA-DRB1 alleles have different structural capacities for antigen presentation depending on their amino acid sequence, the MS MHC association has been used to support the concept that disease pathogenesis is the result of an autoimmune


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