Histocompatibility Antigen Complex of Man

Abstract

The histocompatibility antigens are cell surface glycoproteins expressed on nucleated cells whose major function is to bind peptides within the cell or from outside and present them at the cell surface for inspection by T cells of the immune system. These antigens are a part of the major histocompatibility complex (MHC), which exists in most vertebrate species and whose products were originally defined as the most crucial elements controlling graft rejection. Human MHC research has revealed human leucocyte antigen (HLA) to be the most polymorphic genetic system in the mammalian genome, and this unique diversity parallels the need for diverse peptide sites within the MHC to combat a fast‐evolving range of pathogens. Clinical screening of HLA polymorphism is now an important prophylactic biomarker system for various diseases and a useful tool for development of peptide‐based vaccination approaches.

Key Concepts

  • HLA is the most polymorphic component of the human genome. It is a part of the major histocompatibility complex that exists in many animal species.
  • The major function of HLA molecules is antigen presentation.
  • High degree of molecular diversity of classical HLA class I and II molecules is a reflection of their direct role as antigen‐presenting molecules against a wide range of pathogens.
  • The MHC region is characterised by strong linkage disequilibrium between its loci such that conserved ancestral haplotypes can be identified.
  • There are population‐based differences in allelic distribution of MHC molecules primarily due to historical human migration patterns and varying microbial pressures in different geographical regions.
  • An individual heterozygous at a particular HLA locus has an added advantage than homozygous as the two different HLA molecules can bind and present a large number of peptides.
  • The function of the ubiquitous HLA class I gene products (HLA‐A, HLA‐B and HLA‐C) is to present endogenous peptides to responding CD8+ T cells, whereas the class II coded molecules (HLA‐DR, HLA‐DQ and HLA‐DP) have restricted tissue distribution and process exogenous peptides for presentation to CD4+ helper T cells.
  • The antigen‐binding cleft of HLA class I molecules can bind peptides that are usually nonamers, whereas the HLA class II antigen‐binding cleft can bind longer peptides of 11–18 mers.
  • Polymorphisms in the MHC have been associated with disease susceptibility, varying rates of disease progression and drug‐induced hypersensitivities.
  • MHC matching is crucial in donor selection for haematopoietic stem cell and organ transplantation.

Keywords: major histocompatibility complex (MHC); heterodimeric glycoproteins; polymorphism; graft‐versus‐host disease (GVHD); MHC restriction; peptide–MHC interactions

Figure 1. Schematic representation of the HLA complex on chromosome 6. The extent of the class I, II and III regions is marked and the major genes are marked by bars. MHC, major histocompatibility complex. Reproduced from Mehra NK and Kaur G (2003) MHC based vaccination approaches: progress and perspectives.
Figure 2. Biochemical structure and three‐dimensional folding of HLA class I and II molecules. The two antigen‐binding domains in class I molecules are contributed by the heavy α chain, whereas both α and β chains contribute the same in the class II molecule.
Figure 3. Number of HLA class I and II antigens and alleles identified over the years.
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Mehra, Narinder K, and Kaur, Gurvinder(Feb 2016) Histocompatibility Antigen Complex of Man. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0001234.pub4]