A case can be made for contributions of several and, most likely, many different genes in auto-immunity, although the strongest contribution appears to be from the MHC. Where other genes have been identified, they are also generally implicated in immune recognition. In SLE for example, genes specifying antigen clearance, tolerance induction or hormonal status are all involved.
The levels of variation in these other contributory genes tend to be minor in comparison to HLA. Like MHC genes, the variant alleles are common in the population and do not result in marked deleterious effects expected of a 'mutant' allele. Phenotypic effects invoked by these minor variants are generally subtle and uncovering them demands a panoply of approaches, to obtain and compare data from genetic mapping and phenotyping in both humans and mice. For example, a role for the immunomodulatory co-receptor CTLA-4 has been long suspected from functional considerations as well as genetic data but its mechanism has been elusive. A study recently uncovered effects of DNA sequences distal to the main body of the gene that resulted in altered levels of splice variants that could make soluble molecules, which antagonise binding of the membrane-associated form to its ligand (Ueda etal, 2003).
The effects of other loci are not necessarily simply additive. Recent studies have searched for the involvement of KIR molecules in MHC-associated disease since, like HLA, these genes are highly polymorphic and they interact with MHC class I molecules as ligands (Trowsdale, 2001). KIR genes are encoded on chromosome 19 and are inherited independently of the MHC. This coupling of two sets of polymorphic receptors in immune recognition has suggested studies of combinations of interacting HLA and KIR alleles. Subtle epistatic effects have been noted in common disorders (Martin et al., 2002a; 2002b). Not unexpectedly, some of the most marked effects have been in transplantation, where combinations of NK cells which have already been highly selected in a host are juxtaposed with target tissues from another individual (Parham and McQueen, 2003). The most dramatic effects so far suggest that these normally deleterious responses could be harnessed by selected mis-matching to provide a beneficial graft versus leukemia response (Karre, 2002).
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