The Role of Human Major Histocompatibility Complex (HLA) Genes in Disease

ABSTRACT

The human major histocompatibility complex (MHC), also designated the human leukocyte antigen (HLA) system, was initially characterized using maternal antisera that identified paternal transplantation antigens expressed in the offspring. HLA typing was originally developed to facilitate organ and tissue transplantation, particularly renal transplantation. The discovery that the ability of mice to make an immune response to synthetic polypeptides was linked to the murine MHC, designated H-2,1 and the earlier demonstration that susceptibility to Gross-virus-induced leukemogenesis was also linked to H-2,2 stimulated a search for direct or indirect effects of MHC genes on susceptibility to many different diseases.

INTRODUCTION

The human major histocompatibility complex (MHC), also designated the human leukocyte antigen (HLA) system, was initially characterized using maternal antisera that identified paternal transplantation antigens expressed in the offspring. HLA typing was originally developed to facilitate organ and tissue transplantation, particularly renal transplantation. The discovery that the ability of mice to make an immune response to synthetic polypeptides was linked to the murine MHC, designated H-2,¹ and the earlier demonstration that susceptibility to Gross-virus-induced leukemogenesis was also linked to H-2,² stimulated a search for direct or indirect effects of MHC genes on susceptibility to many different diseases.

This search was highly productive, and within a few years it was shown that susceptibility to a wide variety of diseases was preferentially increased in individuals of particular HLA genotypes. Associations between HLA and disease were initially reported for systemic lupus erythematosus (SLE),³ ankylosing spondylitis,⁴ multiple sclerosis (MS),⁵ and insulin-dependent diabetes mellitus (IDDM).⁶ In the ensuing 20 years, susceptibility to more and more diseases was shown to be determined in part by HLA genotype; linkage of HLA type with disease was demonstrated in family studies; and a bewildering array of new genes was described and characterized in the MHC. There are now more than 30 diseases associated with HLA genotype, and more than 35 to 50 expressed genes that map in the HLA region. This makes the task of determining with certainty which genes in the HLA region predispose to which diseases extremely complex. This task is further complicated by the fact that very little genetic recombination occurs over long stretches of the MHC, which in humans extends over 4000 kbs (4 Mbp). The lack of recombination results in the phenomenon of linkage disequilibrium, in which particular combinations of alleles of the various loci in the MHC remain linked together in the population as a haploid set or haplotype, and show very little recombination either in family or population studies. Thus, relatively weak associations between IDDM and HLA class I alleles, for example, HLA-B8 (i.e., HLA-B*0801), were later shown to be due to a much stronger association of this disease with the HLA class II allele HLA-DR3 (i.e., HLA-DRB1*0301), which is in linkage disequilibrium with HLA-B8 (HLA-B*0801). Because HLA-DR3 (HLA-DRB1*0301) is itself in linkage disequilibrium with other genes in ...