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autoaggressive T cells from the repertoire. In the periHLA association with disease: phery, certain TCR specificities may be deleted by still a mechanistic mystery! the presentation of superantigens on MHC class II molecules, further modifying the circulating TCR HLA molecules have been suspected to play a role in repertoire. the pathogenesis of autoimmune disease since Brewerton Despite a quarter of a century of investigation, mechet al. [1] recognized that HLA-B27 was associated with anisms of HLA involvement in autoimmune disease the rheumatic disease ankylosing spondylitis in 1973. remain speculative. This is largely due to the difficulty This was followed by the description of associations of isolating the effect of a particular HLA molecule on between several class II MHC molecules and autothe disease studied. This problem has emerged in epiimmune diseases, including rheumatoid arthritis (RA), demiological, genetic and immunological approaches to insulin-dependent diabetes (IDDM ) and multiple sclerthe study of these diseases. osis (reviewed by Nepom and Ehrlich [2]). While this review focuses primarily on the association of HLA with HLA is only one piece of the puzzle autoimmune disease, there is good evidence that HLA molecules also influence host defence against foreign HLA-associated autoimmune diseases are complex, arising as a result of the interaction of environmental pathogens [3, 4], allergic responses and anti-tumour immunity [5]. influences with a polygenic background of susceptibility. In some cases, HLA appears to exert a large influence A variety of hypotheses have been advanced, based on current understanding of the biology of HLA on the susceptibility to disease and in other diseases it is a relatively small component. molecules, to explain the HLA association with disease [6 ]. Crystallographic studies have demonstrated that Neighbours tend to travel together MHC molecules bind peptide fragments in their binding cleft and present them to specific T-cell receptors (TCRs) The HLA complex encodes multiple HLA molecules [7–9]; in general, class I MHC molecules present and a number of other immunologically active molecules intracellular peptides to CD8+ T cells, while class II [10]. Loci in close proximity exhibit linkage disequilibmolecules present peptides from extracellular proteins rium and HLA-DR and -DQ alleles, for example, are to CD4+ T cells. The remarkable polymorphism of usually inherited together. The demonstration of an MHC molecules dictates the specificity of peptide bindassociation between a disease and a particular locus ing and, in turn, influences the processes of thymic may reflect an effect of either the locus studied, an selection and peripheral T-cell activation. The most adjacent genetic locus or a combination. popular hypothesis for HLA association with disease is HLA functions in concert with the rest of the that certain HLA molecules present a ‘pathogenic’ pepimmunological orchestra tide or peptides, and thereby elicit a deleterious immune response from specific T cells. Alternatively, disease susThe influence of a particular HLA molecule on immune ceptibility could be determined by variations in TCR responses will be modified by the ‘landscape’ of the repertoire. For example, during thymic selection, certain other HLA molecules among which it is expressed. Each HLA molecules (or HLA-derived peptides presented by HLA molecule expressed modifies the TCR repertoire a second HLA molecule) may fail to delete potentially selected in the thymus and, in the periphery, may compete with other HLA molecules for peptide presentation. In addition, fragments of HLA molecules are Submitted 25 February 1999; revised version accepted 4 March 1999. themselves presented in the peptide-binding groove of Correspondence to: G. Sønderstrup, D345 Fairchild Building, other HLA molecules [11]. HLA molecules also interact Department of Microbiology and Immunology, Stanford, CA 94305, USA. with an array of immunological components involved

Isolating the molecular suspect: HLA transgenic mice in the study of human autoimmune disease