Human leukocyte antigen Totally Explained

Everything about The Human Leukocyte Antigen totally explained

The human leukocyte antigen system (HLA) is the name of the major histocompatibility complex (MHC) in humans. This group of genes resides on chromosome 6, and encodes cell-surface antigen-presenting proteins and many other genes.
The major HLA antigens are essential elements in immune function:

Different classes have different functions
- class I antigens (A, B & C) - Present peptides from inside the cell (including viral peptides if present)
- class II antigens (DR, DP, & DQ) - Present phagocytosed antigens from outside of the cell to T-lymphocytes

HLAs also have a role in:

disease defense

reproduction (may be involved in mate selection)

cancer (may be protective or fail to protect)

human disease:

in autoimmunity - known to mediate many autoimmune diseases
as antigens - responsible for organ transplant rejection.

Aside from the genes encoding the 6 major antigens, there are 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.

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 isn't 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).
The image off to the side shows a piece of a poisonous bacterial protein (SEI peptide) bound within the binding cleft portion of the HLA-DR1 molecule. In the illustration far below, a different view, one can see an entire DQ with a bound peptide in a similar cleft, as view from the side. Disease-related peptides fit into these 'slots' much like a hand fits into a glove or a key fits into a lock. In these configurations peptides are presented to T-cells. The T-cells are restricted by the HLA molecules when certain peptides are within the binding cleft. These cells have receptors that are like antibodies and each cell only recognizes a few class II-peptide combinations. Once A T-cell recognizes a peptide within an MHC class II molecule it can stimulate B-cells that also recognize the same molecule in their sIgM antibodies. Therefore these T-cells help B-cells make antibodies to proteins they both recognize. There are billions of different T-cells in each person that can be made to recognize antigens, many are removed because they recognize self antigens. Each HLA can bind many peptides, and each person has 3 HLA types and can have 4 isoforms of DP, 4 isoforms of DQ and 4 Isoforms of DR (2 of DRB1, and 2 of DRB3,DRB4, or DRB5) for a total of 12 isoforms. In such heterozygotes it's difficult for disease related proteins to escape detection. 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 among 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 Type I Diabetes, Ankylosing spondylitis, Celiac Disease, SLE (Systemic Lupus Erythematosus), Myasthenia Gravis, inclusion body myositis and Sjögren's syndrome. HLA typing has led 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 Celiac Disease it's the only effective means of discriminating between 1st degree relatives who are at risk from those who are not at risk, prior to the appearance of sometimes irreversible symptoms such an 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 prevalence of Enteropathy-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 apoptosis mediating many cancers before clinical diagnosis. Prevention of cancer may be a portion of heterozygous selection acting on HLA.

Classification of HLAs/alleles

MHC class I form a functional receptor on most nucleated cells of the body.
There are 3 major and 3 minor MHC class I genes in HLA:

HLA-A

HLA-B

HLA-C

minor genes are HLA-E, HLA-F and HLA-G

β₂-microglobulin binds with major and minor gene subunits to produce a heterodimer

There are 3 major and 2 minor MHC class II Proteins encoded by the HLA. The genes of the class II combine to form heterodimeric (αβ) protein receptors that are typically expressed on the surface of antigen presenting cells. Major MHC class II

HLA-DP

α-chain encoded by HLA-DPA1 locus
β-chain encoded by HLA-DPB1 locus

HLA-DQ

α-chain encoded by HLA-DQA1 locus
β-chain encoded by HLA-DQB1 locus

HLA-DR

α-chain encoded by HLA-DRA locus
4 β-chains (only 3 possible per person), encoded by HLA-DRB1, DRB3, DRB4, DRB5 loci

The Other MHC class II proteins, DM and DO are used in the internal processing of antigens, loading the antigenic peptides generated from pathogens onto the HLA molecules of antigen-presenting cell.

HLA are extremely variable loci

MHC loci are some of the most genetically variable coding loci in mammals, and the human HLA loci are no exceptions. Despite the fact that the human population went through a constriction more than 150 000 years ago that was capable of fixing many loci, the HLA loci appear to have survived such a constriction with a great deal of variation. Of the 9 loci mentioned above, most retained a dozen or more allele-groups for each locus, far more preserved variation than the vast majority of human loci. This is consistent with a heterozygous or balancing selection coefficient for these loci. In addition, some HLA loci are among the fastest evolving coding regions in the human genome. One mechanism of diversification has been noted in the study of Amazonian tribes of South America that appear to have undergone intense gene conversion between variable alleles and loci within each HLA gene class. Less frequently, longer range productive recombinations through HLA genes have been noted producing chimeric genes.
Five loci have over 100 alleles that have been detected in the human population, of these the most variable are HLA B and HLA DRB1. As of 2004, the number of alleles that have been determined are listed in the table below. To interpret this table, it's necessary to consider that an allele is a variant of the nucleotide (DNA) sequence at a locus, such that each allele differs from all other alleles in a least one (single nucleotide polymorphism, SNP) position. Most of these changes result in a change in the amino acid sequences that result in slight to major functional differences in the protein.
There are issues that limit this variation. Certain alleles like DQA1*0501 and DQA1*0505 encode proteins with identically processed products. Other proteins like DQB1*0201 and DQB1*0202 produce proteins that are functionally similar. For class II (DR, DP and DQ), amino acid variants within the receptor's peptide binding cleft tend to produce molecules with different binding capability.

Tables of variant alleles

Number of variant alleles at class I loci according to the IMGT-HLA database, last updated August 2007:
MHC class I locus

Major Antigens
#
HLA A	580
HLA B	921
HLA C	312
Minor Antigens
HLA E	9
HLA F	21
HLA G	28

Number of variant alleles at class II loci (DP and DQ):

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