Molecular genetics and population studies of the KIR and HLA gene complexes

Division Of Basic Sciences - Nci

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Abstract

Human immunoglobulin G (IgG) molecules, IgG1, IgG2 and IgG3, exhibit substantial inter-individual variation in their constant heavy chain regions, as discovered by serological methods. This polymorphism is encoded by the IGHG1, IGHG2, and IGHG3 genes and may influence antibody function. We sequenced the coding fragments of these genes in 95 European Americans, 94 African Americans, and 94 Black South Africans. Striking differences were observed between the population groups, including extremely low amino acid sequence variation in IGHG1 among South Africans, and higher IGHG2 and IGHG3 diversity in individuals of African descent compared to individuals of European descent. Molecular definition of the loci illustrates a greater level of allelic polymorphism than previously described, including the presence of common IGHG2 and IGHG3 variants that were indistinguishable serologically. Comparison of our data with the 1000 Genome Project sequences indicates overall agreement between the datasets, although some inaccuracies in the1000 Genomes Project are likely. These data represent the most comprehensive analysis of IGHG polymorphisms across major populations, which can now be applied to deciphering their functional impact. HLA-E presents VL9 nonomers derived from signal peptides (SP) of classical HLA-I molecules and serves as a ligand for the inhibitory CD94/NKG2A and activating CD94/NKG2C receptors expressed on NK and T cells. We are investigating how HLA-I SP polymorphism can influence HLA-E peptide loading and interaction with their receptors. Of 16 common HLA-I SP variants, only six can be loaded on HLA-E and facilitate receptor recognition. We plan to expand our experiments to comprehensively characterize the impact of SP polymorphism on HLA-E function in regulating effector cell activity. We also found that SP polymorphism can influence cell surface expression levels of classical HLA-I, a regulatory mechanism in addition to the HLA allele-specific mRNA regulation previously characterized by our lab. Investigation of SP polymorphism influence on HLA-I function will serve as a basis for developing models to predict immune responses in human diseases based on HLA genotypes alone. A number of HLA class I (HLA-I) alleles, especially HLA-B alleles, are strongly associated with protection from or susceptibility to HIV disease progression. We considered that HLA genotype might influence the immune response against HIV antigens after vaccination against HIV. The Janssen vaccine phase 2 clinical trial studied the immune response to a mosaic antigen vaccine. Although there was no significant correlation of HLA alleles with overall response to all antigens combined as measured by either ELISA or ELISpot, there was a significant correlation of HLA-I alleles with differential ELISpot response to gag vs. env antigens that reflect the impact of the same alleles on control of HIV viral load in natural history cohorts. The Imbokodo vaccine trial in Africa was deemed a failure, but we hope to determine (again in collaboration with Janssen) whether the trial was actually successful in subjects carrying these protective HLA alleles. The products of the highly polymorphic HLA-I genes initiate the immune response by presenting antigenic peptides to T cells. Individuals heterozygous at HLA loci are able to present a greater repertoire of peptides, potentially allowing a more productive immune response against a greater variety of pathogenic threats. We have developed a metric to quantitate the similarity between pairs of HLA-I alleles based on the set of peptides they present, which we term "functional distance". We propose that functional distance between pairs of HLA alleles will provide greater sensitivity in distinguishing the breadth of peptides any given individual can present to T cells than a simple binary division of homozygosity vs. heterozygosity. Those individuals carrying HLA-I genotypes with greater functional distance may be particulary resistant to infectious diseases, but perhaps more susceptible to inflammatory/autoimmune disease, a hypothesis that we would like to pursue.