Genetic Complexity and Expression of Human Class II Histocompatibility Antigens

Abstract

The genes encoding nearly all of the serologically defined class II antigens of the major histocompatibility complex have been isolated. Three class II loci have been studied in great detail. The DR region contains a single alpha gene and 3 beta chain genes, 1 of which is a pseudogene. The DR alpha chain gene has been linked to a DR beta gene which encodes a beta protein which contains the serological determinant MT3. A second cosmid cluster contains 2 beta genes, 1 of which encodes the DR4 allospecificity. The identification of these genes has been made by the comparison of amino terminal sequences of DR molecules obtained from a DR4 cell line and the deduced protein sequences of the beta 1 exons from cosmid and phage clones. A conserved element including the promoter and signal sequence is found at the 5' end of each of the 3 DR beta genes. Additionally, this element occurs three more times in the DR region, raising the question of whether additional beta chain genes might be found. The DQ region contains 2 pairs of genes, 1 of which encodes the DQ antigen. The 2nd pair of genes, called DX alpha and beta, appears to be capable of expressing a DQ-related product, although, to date, there is no evidence for its expression. The DP region also contains 2 pairs of genes. One pair encodes the DP antigen while the 2nd alpha-beta pair is shown to be composed of pseudogenes. The location of polymorphic regions in these genes and aspects of their relationship to the serology, evolution, and function of the class II MHC are discussed. The control of expression of class II genes by gamma-interferon has been examined. The promoters of class II genes are characterized by two conserved sequences common to all alpha and beta chain genes as well as by conserved sequences specific for either alpha or beta chain genes. In addition to studies of expression by DNA-mediated gene transformation, a system for the gene transfer of MHC antigens utilizing transmissible retrovirus vectors is described. Retrovirus vectors have been used to transmit DR alpha, DR beta, and the invariant chain (gamma) sequences to recipient cells with resultant expression of these proteins.

Individuals with IgA deficiency and common variable immunodeficiency share polymorphisms of major histocompatibility complex class III genes.

“…In search of a shared genetic basis for CVID and IgA-D, we have turned our attention to the major histocompatibility complex (MHC) of genes for two main reasons. First, this region of chromosome 6 encodes a variety of molecules involved in antigen presentation and T-cell/B-cell interactions (15). Second, studies of individuals with IgA-D have revealed a relatively high incidence of certain HLA haplotypes (16,17) and MHC supratypes, the most consistent feature of which is the presence of null alleles of the gene encoding the A isotype of complement component C4 (C4A) (14).…”

Asp57-negative HLA DQβ chain and DQA1*0501 allele are essential for the onset of DQw2-positive and DQw2-negative coeliac disease

“…These molecules interact with antigen peptide fragments and with the T cell receptor [1,2], and their essential role in the immune response together with their great polymorphism explain the association of certain allelic variants with the susceptibility to certain immune disorders [3].…”

Biology of the human histocompatibility leukocyte antigen (HLA) system and a hypothesis regarding the generation of autoimmune diseases.

“…The class II region of the human MHC is at least twice as large as that of the mouse, based on recombination frequency (8) (b) Linkage of a disease to DP would be a special case, since DP genes have little or no linkage disequilibrium with DQ and DR genes. At least one "hot spot" for recombination occurs between DP-DX and DQ-DR (see below).…”