CHARACTERIZATION OF HLA-DMB

Abstract

Genes in the HLA Class II region encode molecules which play an important role in the humoral immune response. These molecules are glycoproteins that are found on the surface of activated T cells, B cells, and macrophages, and are involved in the presentation of antigens to helper T cells (CD4+). The class II molecules contain extracellular peptide binding domains which are the most polymorphic region of the molecule. The high degree of polymorphism in class II is functionally significant in that it allows presentation of a large variety of antigenic peptides to T cells, thereby initiating an immune response. Of all the genes located in the HLA class II region, the DR, DO, and DP gene products have been studied intensively in terms of their functional role in immune response and polymorphism. Recently a number of novel genes have been observed in this region. Two of these, DMA and DMB, have sequence homology to "classical" class II genes and also to class I genes. These genes are located between the DQ and DP loci and, like DP, DO, and DR, appear to encode a heterodimer. In this study the extent of polymorphism in the second and third exons of the DMA and DMB genes was determined using single-strand conformation polymorphism (SSCP) and sequence analysis. Five alleles of DMB were observed which were derived from one variant site in the second exon and four variant sites in the third exon of DMB. Frequencies of the alleles were determined using DNA from the Centre d'Etude du Polymorphisme Humain (CEPH) families. A recombinant chromosome was identified in one family, and the cross-over site was localized to the region between DMB and DQB. Finally, linkage disequilibrium between DMB and other HLA class II loci (DRB1, DPB1, DQA1, DQB1, and the TAP genes) was analyzed. Two of the more rare DMB alleles were found in association with certain other alleles, giving insight into a possible evolutionary scenario for DMB.