TCR gene polymorphisms and autoimmune disease

Autoimmunity may result from abnormal regulation within the immune system. As the T cell is the principal regulator of the immune system and its normal function depends on immune recognition or self/non-self discrimination, abnormalities of the idiotypic T-cell receptor (TCR) may be one cause of autoimmune disease. The TCR is a clonally distributed, cell-surface heterodimer which binds peptide antigen when complexed with HLA molecules. In order to recognize the variety of antigens it may possibly encounter, the TCR, by necessity, is a diverse structure. As with immunoglobulin, it is the variable domain of the TCR which interacts with antigen and exhibits the greatest amount of amino acid variability. The underlying genetic basis for this structural diversity is similar to that described for immunoglobulin, with TCR diversity relying on the somatic recombination, in a randomly imprecise manner, of smaller gene segments to form a functional gene. There are a large number of gene segments to choose from (particularly the TCRAV, TCRAJ and TCRBV gene segments) and some of these also exhibit allelic variation. Finally, polymorphisms in non-coding regions of TCR genes, leading to biased recombination or expression, are also beginning to be recognized. All these factors contribute to the polymorphic nature of the TCR, in terms of both structure and repertoire formation. It follows that inherited abnormalities in either coding or regulatory regions of TCR genes may predispose to aberrant T-cell function and autoimmune disease. This review will outline the genomic organization of the TCR genes, the genetic mechanisms responsible for the generation of diversity, and the results of investigations into the association between germline polymorphisms and autoimmune disease.