An update on the contribution of the MHC to AS susceptibility

Abstract

The 40-year-old association of HLA-B27 with ankylosing spondylitis is one of the best examples of disease association with a hereditary marker. Genomewide association and family studies suggest that other important major histocompatibility complex (MHC) influences are operative in ankylosing spondylitis (AS) susceptibility. HLA-B27 positive hepatitis C individuals are immunologically more efficient in combating viral infections such as HIV-1, hepatitis C, and influenza and less efficient in combating against certain bacteria (and perhaps other organisms) capable of surviving intracellularly. A recent representative population survey of the frequency of HLA-B27 in the USA found a lower frequency of HLA-B27 in older US adults, perhaps reflecting this. Other HLA class I and class II alleles have been implicated in AS susceptibility, the most consistent being HLA-B*40/B60 (B*40:01) but also B14, B15, A*0201, DRB1*04:04, and certain DPA1 and DPB1 alleles. Non-HLA MHC alleles have also been implicated, although many such studies have been inconsistent, likely due to power issues related to the low number of HLA-B27-negative AS patients examined. The best evidence is for major histocompatibility complex class I chain-related gene A (MICA) whose recognition by intestinal epithelial T cells expressing different V-delta-1 gamma/delta TCR further implicates the gut in AS pathogenesis. The HLA class I and class II and other non-HLA allelic associations underscore the importance of T cells in AS pathogenesis.

Fig. 1

A Map of Prehistoric Human Migrations with Locations of HLA-B27 Subtypes Superimposed. More Common Alleles Are Indication in Larger Fonts

Fig. 2

AS susceptibility associations in the MHC locus conditioning on HLA-B*27 tagSNP rs116488202 and further conditioning on HLA-A*02:01 tagSNP rs2394250. The 85-kb gap between positions 32,465 kb and 32,550 kb corresponds to an assembly correction between NCBI human genome build 36 and 37 (the 85-kb gap between positions 32,465 kb and 32,550 kb corresponds to an assembly correction between NCBI human genome build 36 and 37; adapted from reference [3])

Fig. 3

The organization of the MHC, with loci implicated in AS susceptibility indicated by black arrows