Human Leucocyte Antigen (HLA) System and Human Disorders

Abstract

The major histocompatibility complex (MHC) has been studied in depth because it is associated genetically with more human disorders than any other region in the human genome. In addition to the human leucocyte antigen (HLA) genes, the MHC contains a diverse array of multiallelic genes, many of which are involved in modulating the immune response to pathogens. Advanced mapping and sequencing approaches are helping to define more precisely contributions of MHC variants to disease. Class I or class II molecules are confirmed as the primary influence in most studies, attesting to their functional impact on antigenic peptide presentation to lymphocytes. Regulatory polymorphism controlling cell surface expression of HLA molecules has also been associated with disease. However, the precise causal nature of the majority of associated alleles and haplotypes with disease is still not understood.

Key Concepts

  • The MHC encodes genes essential for immunity in humans, including the HLA molecules.
  • With the exception of one gene, HLA‐DRA, the classical HLA genes are highly variable.
  • HLA class I and II genes are associated with many diseases, including infectious diseases, cancers and neuropathies but particularly autoimmunity.
  • Many HLA variants are concurrently associated with both infectious and autoimmune diseases.
  • The MHC may be considered as a cluster of genes with integrated functions.
  • A high proportion of MHC genes are involved in immunity.
  • The MHC contains nonclassical class I and II genes, such as HLA‐E, F and G, and HLA‐DM, DO, respectively.

Keywords: human leucocyte antigen; major histocompatibility complex; polymorphism; autoimmunity; antigen presentation

Figure 1. Gene map of the human MHC (major histocompatibility complex) showing the context and organisation of the polymorphic human leucocyte antigen (HLA) gene loci.
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References

Altfeld M, Addo MM, Rosenberg ES, et al. (2003) Influence of HLA‐B57 on clinical presentation and viral control during acute HIV‐1 infection. AIDS 17: 2581–2591.

Apps R, Qi Y, Carlson JM, et al. (2013) Influence of HLA‐C expression level on HIV control. Science 340: 87–91.

Braud VM, Allan DS, O'Callaghan CA, et al (1998) HLA‐E binds to natural killer cell receptors CD94/NKG2A, B and C. Nature 391: 795–799.

Carrington M, Nelson GW, Martin MP, et al. (1999) HLA and HIV‐1: heterozygote advantage and B*35‐Cw*04 disadvantage. Science 283: 1748–1752.

Chappell P, Meziane el K, Harrison M, et al. (2015) Expression levels of MHC class I molecules are inversely correlated with promiscuity of peptide binding. eLife 4: e05345.

Chen H, Li L, Weimershaus M, et al. (2016) ERAP1‐ERAP2 dimers trim MHC I‐bound precursor peptides; implications for understanding peptide editing. Science Reports 6: 28902.

Clements CS, Kjer‐Nielsen L, Kostenko L, et al. (2005) Crystal structure of HLA‐G: a nonclassical MHC class I molecule expressed at the fetal‐maternal interface. PNAS 102: 3360–3365.

Dulberger CL, McMurtrey CP, Hölzemer A, et al. (2017) Human leukocyte antigen f presents peptides and regulates immunity through interactions with NK cell receptors. Immunity 46: 1018–1029.

Gaczynska M, Rock KL and Goldberg AL (1993) Gamma‐interferon and expression of MHC genes regulate peptide hydrolysis by proteasomes. Nature 365: 264–267.

Fadda L, Borhis G, Ahmed P, et al. (2010) Peptide antagonism as a mechanism for NK cell activation. PNAS 107: 10160–10165.

Fellay J, Shianna KV, Ge D, et al. (2007) A whole‐genome association study of major determinants for host control of HIV‐1. Science 317: 944–947.

Groh V, Steinle A, Bauer S and Spies T (1998) Recognition of stress‐induced MHC molecules by intestinal epithelial gamma delta T cells. Science 279: 1737–1740.

Hiby SE, Walker JJ, O'shaughnessy KM, et al. (2004) Combinations of maternal KIR and fetal HLA‐C genes influence the risk of preeclampsia and reproductive success. Journal of Experimental Medicine 200: 957–965.

Horowitz A, Djaoud Z, Nemat‐Gorgani N, et al. (2016) Class I HLA haplotypes form two schools that educate NK cells in different ways. Science Immunology 1 (3): pii: eaag1672.

Horton R, Gibson R, Coggill P, et al. (2008) Variation analysis and gene annotation of eight MHC haplotypes: the MHC Haplotype Project. Immunogenetics 60: 1–18.

Illing PT, Vivian JP, Dudek NL, et al. (2012) Immune self‐reactivity triggered by drug‐modified HLA‐peptide repertoire. Nature 486: 554–558.

Jiang J, Natarajan K, Boyd LF, et al. (2017) Crystal structure of a TAPBPR‐MHC‐I complex reveals the mechanism of peptide editing in antigen presentation. Science 358 (6366): 1064–1068.

Kulkarni S, Savan R, Qi Y, et al. (2011) Differential microRNA regulation of HLA‐C expression and its association with HIV control. Nature 472: 495–498.

Lee N, Goodlett DR, Ishitani A, et al. (1998) HLA‐E surface expression depends on binding of TAP‐dependent peptides derived from certain HLA class I signal sequences. Journal of Immunology 160: 4951–4960.

Matzaraki V, Kumar V, Wijmenga C, et al. (2017) The MHC locus and genetic susceptibility to autoimmune and infectious diseases. Genome Biology 18: 76.

van Meijgaarden KE, Haks MC, Caccamo N, et al. (2015) Human CD8+ T‐cells recognizing peptides from Mycobacterium tuberculosis (Mtb) presented by HLA‐E have an unorthodox Th2‐like, multifunctional, Mtb inhibitory phenotype and represent a novel human T‐cell subset. PLoS Pathogens 11 (3): e1004671.

Migueles SA, Sabbaghian MS, Shupert WL, et al. (2000) HLA B*5701 is highly associated with restriction of virus replication in a subgroup of HIV‐infected long term nonprogressors. PNAS 97: 2709–2714.

Naiyer MM, Cassidy SA, Magri A, et al. (2017) KIR2DS2 recognizes conserved peptides derived from viral helicases in the context of HLA‐C. Science Immunology 2 (15): pii: eaal5296.

Nitta T, Murata S, Sasaki K, et al. (2010) Thymoproteasome shapes immunocompetent repertoire of CD8+ T cells. Immunity 32: 29–40.

Ortmann B, Copeman J, Lehner PJ, et al. (1997) A critical role for tapasin in the assembly and function of multimeric MHC class I‐TAP complexes. Science 277: 1306–1309.

Raj P, Rai E, Song R, et al. (2016) Regulatory polymorphisms modulate the expression of HLA class II molecules and promote autoimmunity. eLife 5. pii: e12089.

Rao X, Hoof I, van Baarle D, et al. (2015) HLA preferences for conserved epitopes: a potential mechanism for hepatitis c clearance. Frontiers in Immunology 6: 552.

Rölle A, Pollmann J, Ewen EM, et al. (2014) IL‐12‐producing monocytes and HLA‐E control HCMV‐driven NKG2C+ NK cell expansion. Journal of Clinical Investigation 124: 5305–5316.

Sharon E, Sibener LV, Battle A, et al. (2016) Genetic variation in MHC proteins is associated with T cell receptor expression biases. Nature Genetics 48: 995–1002.

Shatz CJ (2009) MHC class I: an unexpected role in neuronal plasticity. Neuron 64: 40–45.

Sollid LM (2017) The roles of MHC class II genes and post‐translational modification in celiac disease. Immunogenetics 69: 605–616.

Thomas C and Tampé R (2017) Structure of the TAPBPR‐MHC I complex defines the mechanism of peptide loading and editing. Science 358 (6366): 1060–1064.

Vince N, Li H and Ramsuran V (2016) HLA‐C level is regulated by a polymorphic Oct1 binding site in the HLA‐C promoter region. American Journal of Human Genetics 99: 1353–1358.

Williams AP, Peh CA, Purcell AW, et al. (2002) Optimization of the MHC class I peptide cargo is dependent on tapasin. Immunity 16: 509–520.

Yang Y, Chung EK, Wu YL, et al. (2007) Gene copy‐number variation and associated polymorphisms of complement component C4 in human systemic lupus erythematosus (SLE): low copy number is a risk factor for and high copy number is a protective factor against SLE susceptibility in European Americans. American Journal of Human Genetics 80: 1037–1054.

Further Reading

Blum JS, Wearsch PA and Cresswell P (2013) Pathways of antigen processing. Annual Review of Immunology 31: 443–473.

Cresswell P, Bangia N, Dick T and Diedrich G (1999) The nature of the MHC class I peptide loading complex. Immunological Reviews 172: 21–28.

Davis DM (2014) The Compatibility Gene. London: Penguin Books (ISBN 978-0-241-95675-5).

Illing PT, Vivian JP, Purcell AW, et al. (2013) Human leukocyte antigen‐associated drug hypersensitivity. Current Opinion in Immunology 25: 81–89.

Kelly A, Powis SH, Glynne R, et al. (1991) Second proteasome‐related gene in the human MHC class II region. Nature 353: 667–668.

Mellins ED and Stern LJ (2014) HLA‐DM and HLA‐DO, key regulators of MHC‐II processing and presentation. Current Opinion in Immunology 26: 115–122.

Parham P and Moffett A (2013) Variable NK cell receptors and their MHC class I ligands in immunity, reproduction and human evolution. Nature Reviews Immunology 13: 133–144.

Saunders PM, Vivian JP, O'Connor GM, et al. (2015) A bird's eye view of NK cell receptor interactions with their MHC class I ligands. Immunological Reviews 267: 148–166.

Trowsdale J and Knight JC (2013) Major histocompatibility complex genomics and human disease. Annual Review of Genomics and Human Genetics 14: 301–323.

Web Links

HFE (hemochromatosis); MIM number: 235200 OMIM: http://omim.org/entry/235200

HLA‐E (major histocompatibility complex, class I, E); MIM number: 143010. OMIM: http://omim.org/entry/143010

MIC‐A (MHC class I polypeptide‐related sequence A); MIM number: 600169. OMIM: http://omim.org/entry/600169

dbMHC database; https://www.ncbi.nlm.nih.gov/gv/mhc/

Human leukocyte antigens at the US National Library of Medicine Medical Subject Headings (MeSH); https://meshb.nlm.nih.gov/record/ui?name=Human%20leukocyte%20antigens

IPD‐IMGT/HLA Database; https://www.ebi.ac.uk/ipd/imgt/hla/

Nomenclature for Factors of the HLA System; http://hla.alleles.org/nomenclature/index.html

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Traherne, James A(Feb 2018) Human Leucocyte Antigen (HLA) System and Human Disorders. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0005171.pub2]