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HLA class II polymorphism in Aka Pygmies and Bantu Congolese and a reassessment of HLA-DRB1 African diversity.

HLA-DRB1, -DQB1 and -DPB1 polymorphisms were investigated in two African populations, the Basse Lobaye Aka Pygmies of the Central African Republic, and a Bantu-speaking group from the Democratic Republic of Congo Kinshasa. Allelic and haplotypic frequency distributions reveal marked differences between the two populations in spite of their geographical proximity: the Aka exhibit high frequencies for several alleles, especially at the DPB1 locus (0.695 for DPB1*0402), probably due to rapid genetic drift, while the Bantu distributions are more even. Genetic distances computed from DRB1 allelic frequencies among 21 populations from North and sub-Saharan Africa were applied to a multidimensional scaling analysis. African populations genetic structure is significantly shaped by linguistic differentiation, as confirmed by an analysis of molecular variance. However, selective neutrality tests indicate that many African populations exhibit an excess of heterozygotes for DRB1, which is likely to explain the genetic similarity observed between some North African and Bantu populations. Overall, this study shows that natural selection must be taken into account when interpreting the patterns of HLA diversity, but that this effect is probably minor in relation to the stochastic events of human population differentiations.

Adult↗

Evidence that HLA class II disparity is required for the induction of renal allograft enhancement by donor-specific blood transfusions in man.

We studied 46 living-related primary renal allograft recipients between June 1980 and Jan 1988 to determine if enhancement of allograft survival by donor specific transfusions requires a major histocompatibility complex mismatch between the blood/kidney donor and the recipient. Recipients were matched for a single HLA haplotype, but differed at various HLA loci on the unshared haplotype. DST (200 ml) was administered either 3 times at two-week intervals pretransplant (n = 17), or once 3-4 weeks pretransplant, together with oral azathioprine (1 mg/kg/day/28 days) (n = 29). Patients were followed for at least 1 year and all clinical rejection episodes were confirmed histologically. Enhanced graft survival by DST was defined as a rejection-free posttransplant course. Incompatibility for class II determinants on the unshared haplotype of donor had a beneficial effect. A significantly greater proportion of recipients had stable, rejection-free, allograft function if incompatible for the DR locus (80% vs. 44%, P = 0.012), for class II public determinants (100% vs. 58%, P = 0.013), or for at least one of the class II gene products (DR, DQ, class II public) (81% vs. 40%, P = 0.006). Graft loss occurred in 7 of 46 (15%); 6 of the 7 recipients were HLA class II-compatible with their blood/kidney donor. Mismatches for HLA class I private or public determinants and other factors known to affect graft outcome did not influence the results. We conclude that enhanced kidney allograft survival by DST may be predicated by factors within the MHC--specifically class II disparity. These observations also suggest that better HLA matching at the class II locus may account for the apparent "disappearance" of the transfusion effect in cadaver renal transplants in the cyclosporine era.

Blood Transfusion↗

HLA class II genotyping in chronic hepatitis B infection.

OBJECTIVES: To analyze the role of HLA genotypes in persistence of chronic hepatitis B in Western India. METHODS: HLA genotyping for class II-DR was done in 26 subjects having chronic hepatitis B infection (HBsAg positive) and in 100 healthy controls. Statistics were done using Halden's modification of Woolf's formula. RESULT: Significant association of chronic hepatitis B infection was found for class II-DR antigens DRB1*15XX (57.6 vs. 25%) and DRB1*11XX (23 vs. 4%). DRB1*13XX (0 vs. 19%) was negatively associated with chronic hepatitis B infection. CONCLUSION: HLA phenotype, which varies with different regions, is one of the factors in persistence of hepatitis B infection. Our study supports negative association of DRB1*13XX to persistence of HBV. Also there may be role of DRB1*11XX and DRB1*15XX in persistence of HBV and development of chronic HBV hepatitis.

Adult↗

HLA class II antigens: structure, function, and expression in immunodeficiencies, autoimmune diseases, and allograft rejection.

The major histocompatibility complex (MHC) genes, coding for the histocompatibility leukocyte antigens (HLAs) are located on the short arm of chromosome 6. The HLA gene products are involved in many immune responses. Class I and class II molecules are composed of two subunits. Class I antigens are expressed on all cell types except red blood cells; class II molecules have a more limited distribution and are found only on certain cell types. A review of our current knowledge of the genes coding for these molecules, their biochemical analysis, and the current investigation into the three-dimensional structure of the glycoproteins will allow us to understand better how this complex system, which has been preserved in animal species throughout the evolutionary process, operates. The biologic significance of HLA class I and class II molecules in the development of an efficient immune system that permits our survival in the sea of microorganisms in which we are immersed is illustrated by the severe and lethal infections that occur when these antigens are absent. Important and interesting variations in class II antigen expression are also observed in certain autoimmune diseases. Furthermore, the role of these antigens in the allogeneic reaction of graft rejection has now been clearly identified. It has become increasingly apparent how important it is to understand the antigenic variation between organs, or even between cells within an organ, and to be able to identify the circumstances that are associated with modulation of antigen expression.

Autoimmune Diseases↗

Clusters of HLA class II beta restriction fragments describe allelic series.

Eighty-eight HLA haplotypes have been investigated for the presence or absence of 52 restriction fragments generated by four restriction enzymes (EcoRI, EcoRV, HindIII, BamHI), and detected by a DQ beta cDNA probe. Correlation analysis showed several sets of positively associated fragments forming 11 clusters. They constitute three different allelic series. The first coincides with DR alleles, the second with DQ alleles, and within the third, one cluster coincides with DRw53 (MT). As shown by comparative hybridization, most fragments belonging to the DR- as well as the DQ-related series correspond to DQ beta genes. In contrast, the MT-related series corresponds to DR beta genes. The evolutionary significance of these restriction fragment clusters is discussed.

Alleles↗

Differential expression of HLA-class II antigens in the human thymus. Relative paucity of HLA-DQ antigens in the thymic medulla.

By using well-characterized monoclonal antibodies, HU-20, HOK7(1E4) and HU-18, which specifically recognize either common epitopes of HLA-DR molecules (HU-20, HOK7) or HLA-DQw3 molecules (HU-18), it was demonstrated that there were different distributions of these antigens in human thymus. In the cortex, both DR and DQ antigens were strongly expressed on thymic epithelial cells (TEC). The double stainings revealed simultaneous expression of both antigens on TEC. On the other hand, in the medulla, DQ antigens had more limited expression than DR antigens, the latter antigens being demonstrated in the confluent pattern. The double staining method could show small numbers of dual-positive cells in the medulla, which looked like TEC, indicating that at least some medullary TEC were also DR+,DQ+, although the presence of small numbers of DR-,DQ-, as well as DR+,DQ- TEC in the medulla cannot be excluded. The preponderance of DR over DQ antigen in the medulla was consistently found--from a ten week embryo to a two-year-old child--and could be attributed to very weak or no expression of DQ antigens on dendritic cells/macrophages. The distribution pattern of these antigens within the thymus may have correlations with the intrathymic development of T cells through the unique functions of each antigen.

Adolescent↗