The human leukocyte antigen system (HLA) is the name of the human major histocompatibility complex (MHC). This group of genes resides on chromosome 6, and encodes cell-surface antigen-presenting proteins and many other genes. Aside from the genes encoding the 6 major antigens, there is a large number of other genes, many involved in immune function located on the HLA complex. Diversity of HLA in human population is one aspect of disease defense, and, as a result, the chance of two unrelated individuals having identical HLA molecules on all loci is very low, except for non-identical siblings, which have a 25% chance of being HLA-identical.

Importance of HLA allelic variation

Studies of humans and other animals infer a heterozygous selection mechanism operating on these loci as an explanation for this exceptional variability.[6] One credible mechanism is sexual selection in which females are able to detect males with different HLA relative to their own type.[7] While the DQ and DP encoding loci have fewer alleles combinations of A1:B1 can produce a theoretical potential of 1586 DQ and 2552 DP αβ heterodimers, respectively. While certainly nowhere near this number of isoforms exist in the human population, each individual can carry 4 variable DQ and DP isoforms increasing the potential number of antigens that these receptors can present to the immune system in individual immune system. Studies of the variable positions of DP, DR, and DQ reveal that peptide antigen contact residues on Class II molecules are most frequently the site of variation in the protein primary structure. Therefore, through a combination of intense allelic variation and/or subunit pairing the Class II 'peptide' receptors are capable of binding an almost endless variation of peptides of 9 amino acids or longer in length, protecting interbreeding subpopulations from nascent or epidemic diseases. Individuals in a population have frequently different haplotypes and as a result many combinations, even in small groups, affords the survival of the groups and thwarts evolution of epitopes in pathogens to hide from the immune system.

HLA functions

The proteins encoded by HLAs are the proteins on the outer part of body cells that are (effectively) unique to that person. The immune system uses the HLAs to differentiate self cells and non-self cells. Any cell displaying that person's HLA type belongs to that person (and therefore is not an invader).

In infectious disease. When a foreign pathogen enters the body, specific cells called antigen-presenting cells (APCs) engulf the pathogen through a process called phagocytosis. Proteins from the pathogen are digested into small pieces (peptides) and loaded onto HLA antigens (specifically MHC class II). They are then displayed by the antigen presenting cells for certain cells of the immune system called T cells, which then produce a variety of effects to eliminate the pathogen.

Through a similar process, proteins (both native and foreign, such as the proteins of viruses) produced inside most cells are displayed on HLA antigens (specifically MHC class I) on the cell surface. Infected cells can be recognized and destroyed by components of the immune system (specifically CD8+ T cells).

In graft rejection. Any cell displaying some other HLA type is "non-self" and is an invader, resulting in the rejection of the tissue bearing those cells. Because of the importance of HLA in transplantation, the HLA loci are amoung of the most frequently typed by serology or PCR relative to any other autosomal alleles.

In autoimmunity. HLA types are inherited, and some of them are connected with autoimmune disorders and other diseases. People with certain HLA antigens are more likely to develop certain autoimmune diseases, such as Ankylosing spondylitis, Celiac Disease, SLE (Lupus erythematosus), Myasthenia Gravis, inclusion body myositis and Sjögren's Syndrome. HLA typing has lead to some improvement and acceleration in the diagnosis of Celiac Disease and Type 1 diabetes; however for DQ2 typing to be useful it requires either high resolution B1*typing (resolving *0201 from *0202), DQA1*typing, or DR serotyping. Current serotyping can resolve, in one step, DQ8. HLA typing in autoimmunity is being increasingly used as a tool in diagnosis. In GSE is the only effective means of determing 1st degree relative who are at risk from those who are not at risk, prior to the appearance of sometimes irreversible symptoms such a allergies and secondary autoimmune disease.

In cancer. Some HLA mediated diseases are directly involved in the promotion of cancer. Gluten sensitive enteropathy is associated with increased prevelance of enteritus associated T-cell Lymphoma, and DR3-DQ2 homozygotes are within the highest risk group with close to 80% of gluten sensitive EATL cases. More often; however, HLA molecules play a protective role, recognizing the increase in antigens that were not tolerated because of low levels in the normal state. Abnormal cells may be targeted for aptosis mediating many cancers before clinical diagnosis. Prevention of cancer may be a portion of heterozygous selection acting on HLA.

HLA antibodies

HLA antibodies are typically not naturally occurring, with few exceptions are formed as a result of an immunologic challenge of a foreign material containing non-self HLAs via blood transfusion, pregnancy (paternally-inherited antigens), or organ or tissue transplant.

Antibodies against disease associated HLA haplotypes have been proposed as a treatment for severe autoimmune diseases.[8]

Donor-specific HLA antibodies have been found to be associated with graft failure in kidney, heart, lung and liver transplantation.

External links

HLA Informatics Group at The Anthony Nolan Trust IMGT/HLA Sequence Database at European Bioinformatics Institute American Society for Histocompatibility and Immunogenetics European Federation for Immunogenetics HistoCheck HLA matching tool for organ and stem cell transplantation Allele Frequencies at Variable Immune related Loci MeSH Human+leukocyte+antigens

References

a b c d e f Marsh SG, Albert ED, Bodmer WF, Bontrop RE, Dupont B, Erlich HA, Geraghty DE, Hansen JA, Hurley CK, Mach B, Mayr WR, Parham P, Petersdorf EW, Sasazuki T, Schreuder GM, Strominger JL, Svejgaard A, Terasaki PI, and Trowsdale J. (2005). "Nomenclature for factors of the HLA System, 2004.". Tissue antigens 65: 301-369. PMID 15787720.  ^ P. Parham and T. Ohta (1996). "Population Biology of Antigen Presentation by MHC Class I Molecules.". Science 272. PMID 8600539. . ^ Valluri V, Mustafa M, Santhosh A, Middleton D, Alvares M, El Haj E, Gumama O, and Abdel-Wareth L (2005). "Frequencies of HLA-A, HLA-B, HLA-DR, and HLA-DQ phenotypes in the United Arab Emirates population". Tissue Antigens 66 (2): 107-113. PMID 16029430.  ^ Farjadian S, Naruse T, Kawata H, Ghaderi A, Bahram S, and Inoko H (2004). "Molecular analysis of HLA allele frequencies and haplotypes in Baloch of Iran compared with related populations of Pakistan". Tissue Antigens 64 (5): 581-587. PMID 15496201.  ^ Shankarkumar U, Prasanavar D, Ghosh K, and Mohanty D (2003). "HLA A*02 allele frequencies and B haplotype associations in Western Indians". Hum Immunol. 64 (5): 562-566. PMID 12691707.  ^ V. Apanius, D. Penn, P.R. Slev, L.R. Ruff, and W.K. Potts (1997). "The nature of selection on the major histocompatibility complex.". Critical Reviews in Immunology 17: 179-224. PMID 9094452. . ^ Wedekind C, Seebeck T, Bettens F, and Paepke AJ (1995). "MHC-dependent mate preferences in humans". Proc Biol Sci. 260 (1359): 245-249. PMID 7630893.  ^ Oshima M, Deitiker P, Ashizawa T, Atassi M (2002). "Vaccination with a MHC class II peptide attenuates cellular and humoral responses against tAChR and suppresses clinical EAMG.". Autoimmunity 35 (3): 183-90. PMID 12389643. 

Antibodies to HLA 1

Antibodies to HLA 2