HLA the major genetic locus in autoimmunity

The first recognition of a role for a specific gene for determining autoimmune susceptibility came from the identification in 1973 that the vast majority of patients with ankylosing spondilitis, a disorder of axial joints, possessed HLA B-27 (Brewerton et al., 1973). This observation was made utilizing HLA antisera rather than DNA-based genetic methodology and has led to the transformation in our understanding of the genetics of autoimmunity and of the functional role of HLA antigens themselves. This initial report was shortly followed by similar observations in a range of other autoimmune diseases. In the case of diabetes, investigators identified a role for HLA B8 in the juvenile form of disease, distinguishing a subtype of diabetes, now known as Type 1 diabetes, from other more common adult forms of the disease (Cudworth and Woodrow, 1976). As the tools for typing HLA variants became better and incorporated both cellular and humoral reagents, it became clear that the exact nature of susceptibility within the MHC was extremely complex. The relationship between disease and HLA is covered elsewhere in this volume. The exploration of determinants of disease lying within the MHC has revealed the opportunities and challenges associated with studying regions of strong linkage disequilibrium and the problems associated with identifying precise genetic variants mediating disease when multiple loci within the same region may contribute to pathogenesis. These lessons have been relearned repeatedly in other regions of the genome associated with disease genes over the past 15 years. Importantly, allelic variants within the MHC can contribute both to susceptibility and to resistance to autoimmune disease, and alleles at these loci have also been demonstrated to confer resistance and susceptibility to a range of infectious pathogens (Segal and Hill, 2003) including major pathogens which drive significant selection in human populations such as HIV and malaria. This strongly suggests that the driving evolutionary pressure that has created and fixed such extensive polymorphism in the population has been exposure to infectious pathogens.

Molecular dissection at a DNA level of allelic variants within the MHC has ultimately delivered a better understanding of the precise alleles associated with some autoimmune diseases than was ever achieved using antisera. Notable among these are the role of trans-heterodimers in mediating celiac disease (Sollid, 2002), and the role of HLA-DR and DQ motifs in mediating susceptibility to Type 1 diabetes (Todd et al., 1987) and rheumatoid arthritis (Wordsworth et al., 1989).

Interestingly, comparisons using linear DNA sequence ultimately provide only part of the explanation of HLA disease susceptibility. Sequences of DNA confer their ultimate contribution to risk through protein structure and function and the definitive approach to understanding the contribution to disease susceptibility from multiple alleles lies in an understanding of the similarities and differences in three dimensions within, for example, the HLA and peptide binding groove. Systematic analysis of a range of HLA DQ crystal structures, for example, has revealed an important interplay between the volume of the P6 pocket and the specificity of the P9 pocket in determining protection from Type 1 diabetes, implying that an expanded peptide repertoire is important in producing such protection (Siebold et al., 2004).

It is humbling to recognize that, after 30 years of investigation, the precise nature of HLA-encoded susceptibility to many autoimmune diseases is still not fully refined and that the mechanism by which these alleles confer their susceptibility, in particular their interaction with environmental stimuli, has not yet been demonstrated with clarity in any single autoimmune disease. This indicates the challenge ahead in determining a precise role for less important genetic factors in these and other complex diseases.

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