SUSCEPTIBILITY LOCUS FOR IGA DEFICIENCY AND COMMON VARIABLE IMMUNODEFICIENCY IN THE HLA-DR3, HLA-B8, HLA-A1 HAPLOTYPES

Background: A common genetic basis for IgA deficiency (IgAD) and commo n variable immunodeficiency (CVID) is suggested by their occurrence in members of the same family and the similarity of the underlying B cel l differentiation defects. An association between IgAD/CVID and HLA al leles DR3, B8, and Al has also been documented. In a search for the ge ne(s) in the major histocompatibility complex (MHC) that predispose to IgAD/CVID, we analyzed the extended MHC haplotypes present in a large family with 8 affected members. Materials and Methods: We examined th e CVID proband, 72 immediate relatives, and 21 spouses; and determined their serum immunoglobulin concentrations. The MHC haplotype analysis of individual family members employed 21 allelic DNA and protein mark ers, including seven newly available micsrosatellite markers. Results: Forty-one (56%) of the 73 relatives by common descent were heterozygo us and nine (12%) were homozygous for a fragment or the entire extende d MHC haplotype designated haplotype 1 that included HLA-DR3, -C4A-0, -B8, and -Al. The remarkable prevalence of haplotype 1 was due in part to marital introduction into the family of 11 different copies of the haplotype, eight sharing 20 identical genotype markers between HLA-DR 3 and HLA-B8, and three that contained fragments of haplotype 1. Concl usion: Crossover events within the MHC indicated a susceptibility locu s for IgAD/CVID between the class III markers D821/D823 and HLA-Bg, a region populated by 21 genes that include tumor necrosis factor alpha and lymphotoxins alpha and beta. Inheritance of at least this fragment of haplotype 1 appears to be necessary for the development of IgAD/CV ID in this family.