Implication of Structural Class II Gene Polymorphism for the Concept of Serologic Specificities

Abstract

We have used DNA-DNA hybridization methods to study the relationship of genetic polymorphisms to the established HLA-D region determinants as detected with serological reagents. The supertypic determinants DRw52 and 53 are closely associated with a particular RFLP detected with the DR beta probe, but are seemingly encoded by a distinct beta gene compared to the "conventional" DR antigens. DQw1 is closely associated with a DQ alpha chain polymorphism, whereas the DQw2 and 3 specificities have correlations to RFLP using the DQ beta probe. Additional DQ polymorphism, in linkage disequilibrium with DR but yet without a serological counterpart is also described. Considering the finding that there exist a varying number of DR beta genes in different DR haplotypes (Böhme et al. 1985), from 1 in DRw8 to 3 (or 4) in DR4- and DR7-positive cells, we have made a tentative re-evaluation of the genetic basis for the conventional DR specificities. The combination of cell surface antigens encoded by DR and DQ loci are believed to form the basis for MLC stimulating determinants. We have speculated that a combination of determinants encoded by distinct DR beta genes and in certain instances additional DQ polymorphism is responsible for the DR types. Thus, only a limited variability is observed after DNA-DNA hybridization using DR beta probes. Only DR1-, 2- and 4-positive cells have distinct bands not detected in any other haplotypes, whereas DR3, 5, w6, and w8 can be characterized by a combination of bands, which is the result of hybridization with several DR beta genes. Furthermore, we have suggested that the difference between the DR3 and DRw6 specificities is due to variability with regard to 1 DQ beta gene, and have also made the assumption that DRw6 cells may express a lower concentration of DR locus encoded products compared to DR3-positive cells (Haziot et al. 1985). In addition, we have discussed the genetic basis for so-called DR blanks, implying that an unorthodox combination of DR and DQ determinants forms the basis for difficulties in assigning DR types to such cells in some cases and that "blanks" can be associated with low expression at the cell surface of well-known DR determinants. The use of cDNA and genomic probes for distinct class II genes to elucidate the mechanisms of HLA and disease association has been documented and discussed.