Molecular analysis of a functional subtype of HLA-B27. A possible evolutionary pathway for HLA-B27 polymorphism

The structure of a new HLA-B27 subtype antigen B27.4(B27D), distinguishable from the HLA-B27.1, B27.2, and B27.3 subtypes by cytolytic T lymphocytes and isoelectric focusing, has been established by comparative peptide mapping and sequence analysis. HLA-B27.4 differs from the main B27.1 subtype in the same two changes of aspartate-77 to serine-77 and valine-152 to glutamate-152, which distinguish the B27.1 and B27.3 subtypes. In addition, there are two other amino acid changes of histidine-114 to aspartate-114 and of aspartate-116 to tyrosine-116, which are unique to B27.4. The close structural relationship between B27.3 and B27.4 explains the similarity of these two subtypes in terms of T cell recognition. The presence of the two single amino acid differences between B27.3 and B27.4 within a span of three residues in the linear sequence provides a new example, suggesting that gene conversion-like mechanisms play a major role in the diversification of HLA-B27. A comparison of the structure of HLA-B27.4 with those of B27.1, B27.2, and B27.3 in the context of their ethnic distribution suggests that the diversification of the HLA-B27 antigens is an ongoing process that has continued after the separation of the major ethnic groups. A tentative evolutionary model for HLA-B27 polymorphism is proposed.