Etiology A Genetic

Epidemiologic studies provided early, albeit indirect, evidence of a genetic susceptibility toward developing MS. Studies of monozygotic twins illustrated a 2530% lifetime risk of developing the disease if one sibling is effected. Dizygotic twins have a risk similar to that of their nontwin siblings (2-5%), which is higher than that for the normal population. Additional studies have shown that the risk is higher in full siblings rather than half-siblings. Siblings of individuals with MS raised in separate homes retain a higher risk of developing the disease. First-degree, adoptive, nonbiologic relatives do not have an increased risk compared to the general population; thus, genetic rather than environmental factors are more likely to explain familial clustering of disease. In the early 1970s, an association between the risk of developing MS and the major histocompatibility complex (MHC) on chromosome 6, which encodes immune response genes, was recognized. The MHC class I and class II molecules are glycoproteins located on a cell surface that present antigen to antigen-specific T cells. An individual's ability to react to an antigen is determined by the MHC region. CD8 + T cells interact with MHC class I molecules on the surface of all nucleated cells in humans; those molecules are known as human leukocyte antigens (HLA)-A, -B, or -C. Class II molecules are present on only some cells, including monocytes, macrophages, endothelial cells, and microglial cells. These antigens are described as HLA-DP, -DQ, and-DR. Although there may be a weak association with HLA-A3, multiple studies have shown an increased occurrence of HLA-DR2 haplotypes associated with MS. Most individuals with MS do not have this HLA-DR haplotype; thus, it is not essential or sufficient to cause the disease. It is also possible that an unidentified gene close to the HLA gene is the susceptibility locus. Recent genetic studies indicate that multiple unlinked genes may influence the risk for developing MS. Each gene may add to the risk. Different genes may influence susceptibility in some individuals and not others. A screen of the entire genome for regions related to risk of MS with anonymous genetic markers identified a susceptibility loci in the MHC region.

One model for MS in animals is experimental allergic encephalomyelitis (EAE). In this animal model, the susceptibility to developing demyelination is based on genetic risk. Specific chromosomes and segments have been identified in the animal model that increase the risk. The model suggests that initial events that occur in the disease may be mediated by different genetic factors than those that cause later progression of the disease.

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