Epidemiologic data strongly support a genetic predisposition to MS. Other putative autoimmune diseases such as SLE and rheumatoid arthritis are well documented to occur at a higher frequency within families of affected patients than in the general population (41). Twenty percent of patients with MS report a positive family history for MS (42,43). Approximately 30% of monozygotic twins are concordant when one of the twins has MS, while among other siblings the risk is 2% to 5%, and among half-siblings the risk is 1.1% to 1.4% (44). Among adopted siblings and the general U.S. and Canadian populations, the risk is 0.1% (45,46). The familial predisposition to MS has prompted investigations into immune-response genes to explain this enhanced susceptibility.
MHC-II molecules are expressed on the surface of antigen-presenting cells and present processed antigen to CD4+ T-cells (47). The CD4+ T-cell, in turn, is the primary mediator of the animal model for MS, EAE (48), and is strongly implicated in MS. A number of purported autoimmune diseases including rheumatoid arthritis (49), type 1 diabetes mellitus (50), and MS (51) are associated with specific MHC-II haplotypes. This suggests immune mechanisms in their pathophysiology. The MHC II DR2 (HLA DRB1*1501 and DRB1*1503) haplotype has been found to convey susceptibility to MS (51,52). In addition, a "dose effect" of HLA-DR2 haplotypes on both susceptibility and progression of MS has been documented. Patients with two copies of HLA-DR2 have an increased risk of developing MS and of having a more severe course compared with heterozygotes (53). Different HLA II genes appear to influence disease susceptibility in people of non-European descent (54).
Investigations of other immune system-related genes have yielded data in support of an environmental effect superimposed on the genetic predisposition for the immune dysfunction. Utz et al. examined T-cell receptor (TCR) gene usage in T-cells reactive with myelin basic protein (MBP) and tetanus toxoid from concordant and discordant monozygotic twins. They found that MS-affected twins' T-cells selected Va8 TCR after stimulation with MBP, whereas nonaffected discordant twins selected different TCRs (55). These and earlier studies (56) implicate the T-cell as a contributor to MS pathogenesis. In a follow-up study of five pairs of monozygotic twins (two discordant sets, two concordant sets, and one healthy set), Utz et al. (57) confirmed the over expression of Va8 in MBP-specific cells from MS patients, and examined the complementarity-determining region 3 (CDR3) of Va8-positive TCRs. The latter studies demonstrated a profound heterogeneity of CDR3 usage, which correlated with disease severity. The extensive heterogeneity was restricted to MS-affected subjects, and was limited to T-cells specific for MBP and not seen in cells specific for tetanus toxoid. The data were interpreted as being suggestive of a role for MBP-reactive T-cells in MS pathogenesis.
The theory of autoimmune disease postulates that loss of T-cell tolerance to self-antigens underlies the development of the autoimmune reaction. Dysfunction of the CTLA-4 receptor is one possible mediator of this lack of self-tolerance. Both CD28 and CTLA-4 are T-cell receptors for the costimulatory B7 molecules expressed on antigen presenting cells (APC). Most T-cells bear the CD28 receptor, which upon ligation contributes to T-cell activation with ensuing secretion of the pro-inflammatory cytokine IL-2 (58). T-cell activation induces expression of CTLA-4 (59). Ligation of CTLA-4 by B7 molecules, on the other hand, causes T-cell inactivation. Oliveira et al. (60) sought to determine whether the CTLA-4 receptor behaved differently in MS patients compared to controls. Blocking the CTLA-4:B7 interaction, following stimulation with MBP, led to increased proliferation and cytokine production by T-cells from healthy controls compared with MS patients. Thus, MS patient cells may have impaired sensitivity to the regulatory effects of CTLA-4. Polymorphisms of the CTLA-4 exon 1 have been associated with rheumatoid arthritis, Grave's disease, type 1 diabetes mellitus, and MS (61,62). Presence of the A allele of the CTLA-4 gene may convey a worse prognosis with regards to MS progression (63).
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