The genetic basis for the association of the 8.1 ancestral haplotype (A1, B8, DR3) with multiple immunopathological diseases

An individual's major histocompatibility complex (MHC) ancestral haplotype (AH) is the dearest single determinant of susceptibility to MHC associated immunopathological disease, as it defines the alleles carried at all loci i n the MHC. However, the direct effects of any of the 150-200 genes that con stitute the MHC are difficult to determine since recombination only occurs at defined hotspots. This review concerns the 8.1 AH (HLA-AI, C7, B8, C4AQ0 , C4B1, DR3, DQ2), which is carried by most Caucasians with HLA-B8. It is a ssociated with accelerated human immunodeficiency virus (HIV) disease, and susceptibility to insulin-dependent diabetes mellitus (IDDM), systemic lupu s erythematosus, dermatitis herpetiformis, common variable immunodeficiency and IgA deficiency myasthenia gravis and several other conditions. We have mapped susceptibility genes for HN, IDDM and myasthenia gravis to the cent ral MHC between HLA-B and the tumour necrosis factor or complement genes. H ere we consider which of the remaining 8.1-associated diseases are more clo sely associated with HLA-DR3 and/or DQ2. Several candidate genes in the cen tral MHC have the potential to modulate immune or inflammatory responses in an antigen-independent manner, as is seen in studies of cultured cells fro m healthy carriers of the 8.1 AH. Hence these genes may act as a common co- factor in the diverse immunopathological conditions associated with the 8.1 AH.