Implication of structural class II gene polymorphism for the concept of serologic specificities

Area of Science:

• Immunogenetics
• Molecular Biology
• Human Leukocyte Antigen (HLA) system

Background:

• The Human Leukocyte Antigen (HLA) D region plays a crucial role in immune regulation and transplantation. Serological methods have established HLA-D region determinants, but their genetic underpinnings require deeper investigation. Understanding the genetic basis of HLA polymorphisms is essential for elucidating immune responses and disease associations.
• Genetic polymorphisms within the HLA-D region, specifically involving DR and DQ loci, are known to influence immune system function. Established serological reagents detect these determinants, but the precise genetic variations and their correlations are not fully understood.

Purpose of the Study:

• To investigate the relationship between genetic polymorphisms and established HLA-D region determinants using DNA-DNA hybridization.
• To re-evaluate the genetic basis of conventional DR specificities considering the variable number of DR beta genes.
• To explore the genetic basis of DR and DQ antigen combinations and their role in mixed lymphocyte reaction (MLR) stimulating determinants and disease associations.

Main Methods:

• DNA-DNA hybridization techniques were employed to analyze genetic polymorphisms.
• Restriction Fragment Length Polymorphisms (RFLPs) were detected using DR beta and DQ alpha/beta probes.
• Serological reagents were used to define established HLA-D region determinants for comparison with genetic findings.

Main Results:

• Supertypic determinants DRw52 and DRw53 are closely associated with a specific RFLP detected by a DR beta probe, potentially encoded by a distinct beta gene.
• DQw1 shows association with DQ alpha chain polymorphism, while DQw2 and DQw3 correlate with DQ beta probe RFLPs.
• Variable numbers of DR beta genes across different DR haplotypes (1-4) were observed, leading to a re-evaluation of DR specificity genetics. Distinct banding patterns were identified for DR1, DR2, and DR4, while DR3, DR5, DRw6, and DRw8 showed combinations of bands.
• Polymorphisms in DQ genes, in linkage disequilibrium with DR but without serological counterparts, were identified.
• The study suggests that differences between DR3 and DRw6 may stem from DQ beta gene variability and potentially lower DR locus product expression in DRw6 cells.
• The genetic basis for 'DR blanks' was discussed, linking them to unorthodox DR/DQ determinant combinations and low expression of known DR determinants.

Conclusions:

• The genetic basis for conventional DR specificities is complex, involving a variable number of DR beta genes and potentially DQ polymorphisms.
• The combination of DR and DQ locus-encoded determinants likely forms the basis for mixed lymphocyte reaction (MLR) stimulating determinants.
• Understanding these genetic variations is crucial for elucidating HLA and disease associations, particularly in cases of DR blanks and varying antigen expression levels.