Evolving views of the major histocompatibility complex

Abstract

The MHC has long been known to play a major role in the determination of genetic susceptibility to autoimmune disorders, and a large part of this is due to polymorphisms in the class II genes. However, there are at least some cases where the evidence is strong that non-class II genes of the MHC also play a role in the predisposition to autoimmunity. The identification of additional genes in this region that modify the propensity for autoimmune diseases could have important diagnostic and therapeutic implications. In recent years analyses of MHC encoded transcripts has shown that there are within the MHC more than 10 different structurally diverse families of genes whose patterns of expression indicate a specific role in the immune system. The number of different MHC genes functioning in the immune response and the extensive regions of linkage disequilibrium seen in some instances in the MHC make it particularly difficult to use positional genetic approaches to assign disease contributions to particular gene products. Short of understanding the regulation and function of each protein at a level such that the effect of amino acid or nucleotide sequence variations could be predicted, perhaps the best genetic approach is to look for sense changes in codons or variation in known promoter elements for each gene, and then test in large populations to see if there is any correlation with disease manifestations independent of their disequilibrium with the class II genes. This could be very difficult for a number of reasons, not least of which is the extensive degree of linkage disequilibrium and the consequent occurrence of extended haplotypes in this region.