The Origins of HLA‐A,B,C Polymorphism

  title={The Origins of HLA‐A,B,C Polymorphism},
  author={Peter Parham and Erin J. Adams and Kelly L Arnett},
  journal={Immunological Reviews},
Polymorphism of HLA-A,B and C genes determines the repertoire of receptor specificities expressed by cytolytic CDS T lymphocytes (CTL) and the response of natural killer (NK) cells. In the performance of these functions HLA-A,B,C heavy chains interact with ^i-microglobulin (/A-m), a multitude of peptides of 810 amino acids, diverse T-cell receptors (TcR), the CD8 co-receptor, class I receptors of NK cells, the TAP peptide transporter, and the chaperonins calnexin and heavy chain binding protein… 

HLA-C revisited

Understanding of this novel mode of negative regulation of cytotoxicity was remarkably influenced by HLA-C since these were the first HLA class I molecules found to have such inhibitory potential.

Distinguishing functional polymorphism from random variation in the sequences of >10,000 HLA-A, -B and -C alleles

Most alleles of HLA class I (>80%) are very rare, often identified in one person or family, and they differ by point mutation from older, more common alleles, reflect the germ-line mutation rate.

Interactions of HLA-B*4801 with peptide and CD8.

Despite the low affinity of B*4801 for CD8 alpha, alloreactive T-cells that recognize B* 4801 molecules expressed by the 221 transfectant are inhibited by anti-CD8 monoclonal antibodies.

Contribution of HLA class I and class II alleles to the regulation of antibody production to hepatitis B surface antigen in humans.

The predicting equation of anti-HBs antibody levels for individuals with any HLA phenotype was proposed based on a multiple regression analysis, suggesting that HLA class I and class II loci within the HLA multigene family are dynamically involved in regulation of the immune response to HBsAg.

The molecular basis for peptide repertoire selection in the human leukocyte antigen (HLA) C*06:02 molecule

The endogenous peptide repertoire of ∼3,000 sequences for HLA-C*06:02 that defines the peptide-binding motif for this HLA allomorph is described, which provides the structural basis for understanding peptide repertoires selection in HLA -C* 06:02.

MHC Polymorphism Can Enrich the T Cell Repertoire of the Species by Shifts in Intrathymic Selection

The results demonstrate that repertoire diversification occurred by a gain in intrathymic positive selection of T cell repertoire specific for another Ag, OVA-8, and indicates that a reciprocal loss-and-gain pattern of intrATHymic selection exists between H-2Kb and H- 2Kbm8.



Polymorphism in the α3 domain of HLA-A molecules affects binding to CD8

Site-directed mutagenesis shows that this single substitution in the α3 domain is responsible for the CD8 binding phenotype and also affects recognition by alloreactive and influenza-specific CTL.

Distinctive polymorphism at the HLA-C locus: implications for the expression of HLA-C

It is evident that HLA-C genes have been the target of past selection for polymorphism, and conserved motifs in the alpha 1 helix and the conserved glycine at the base of the B pocket provide a combination of features that is uniquely found in H LA-C molecules.

HLA-A and B polymorphisms predate the divergence of humans and chimpanzees

The results show that a considerable proportion of contemporary HLA-A and B polymorphism existed before divergence of the chimpanzee and human lines, and the stability of the polymorphism indicates that hyper-mutational mechanisms are not necessary to account for Hla-A, B and C diversity.

HLA Class I Gene Family: Characterization of Genes Encoding Non-HLA-A,B,C Proteins

The extensive characterization at the DNA level of the murine Qa/Tla region genes made the apparent absence of human class I nonmajor transplantation genes a notable distinction between the H-2 and HLA complexes.

Diversity and diversification of HLA-A,B,C alleles.

Comparison of human and chimpanzee alleles reveals extensive sharing of polymorphisms, confirming that diversification is a slow process, and that much of contemporary polymorphism originated in ancestral primate species before the emergence of Homo sapiens.

The complete primary structure of HLA-Bw58.

Nature of polymorphism in HLA-A, -B, and -C molecules.

  • P. ParhamC. Lomen P. Ennis
  • Biology
    Proceedings of the National Academy of Sciences of the United States of America
  • 1988
The results indicate that genetic exchange between alleles of the same locus has been a more important mechanism in the generation of HLA-A, -B, and -C diversity than genetic exchange events between allele of different loci.

The HLA-B73 antigen has a most unusual structure that defines a second lineage of HLA-B alleles.

B*7301 represents a newly discovered but ancient lineage of HLA-B alleles that appears poorly represented in the modern human population and has a unique cysteine at position 270 of the alpha 3 domain.

Structural heterogeneity in HLA-B70, a high-frequency antigen of black populations.

Cloning and sequencing of cDNA encoding B70 antigens from six cell lines has identified a group of three closely related alleles that form a subgroup of the B15 family that are close to that of the HLA-B consensus consistent with the difficulty in their serological definition.