Molecular variants of the HLA-B27 antigen in healthy individuals and patients with spondylarthropathies.

Despite major advances in genetic and structural studies of the HLA-B27 antigen, the underlying mechanism responsible for the remarkable association between this antigen and spondylarthropathies remains unknown. At a molecular level, the use of B27M1 and B27M2 monoclonal antibodies has permitted the identification of distinct allospecific epitopes on the B27 molecule. One of these epitopes, B27M2, is polymorphic and has allowed us to define B27 variants: B27M2[+], B27M2[-], and B27M2[int]. The heterogeneity of the B27 antigen correlates well with biochemical and cytotoxic evidence of genetic heterogeneity. These variants exhibit ethnic variation and also appear to correlate, in preliminary studies, with disease susceptibility, especially among Orientals. HLA gene probing is potentially an even more precise tool than monoclonal antibodies for the study of MHC-related disease susceptibilities. Initial work in our laboratory has resulted in the production of probes with specificity for HLA-B locus genes and current efforts are directed toward the derivation of B27 allele-specific probes. It seems likely that, when such probes are applied to B27-positive individuals, complexity in addition to the B27M2 variants will be revealed. Yet to be defined is the mechanism behind the association between B27 and AS. Is the association causal for disease, or is B27 indeed just a marker for other pathogenic factors somehow linked to it? Available evidence points to both causal and linked roles for B27 in ankylosing spondylitis. Products of both HLA and non-HLA gene families may interact with infectious disease pathogens in susceptible individuals to produce a disorder which may not be specific in its association with any one pathogenic factor.