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The human leukocyte antigen ( HLA) system is a complex of on chromosome 6 in humans that encode Membrane protein responsible for regulation of the immune system. The HLA system is also known as the human version of the major histocompatibility complex (MHC) found in many animals.
Specific HLA genes may be linked to autoimmune diseases such as type I diabetes, and celiac disease. The HLA gene complex resides on a 3 base pair stretch within chromosome 6, p-arm at 21.3. HLA genes are highly polymorphic, which means that they have many different alleles, allowing them to fine-tune the adaptive immune system. The proteins encoded by certain genes are also known as , as a result of their historic discovery as factors in .
HLAs corresponding to MHC class I (HLA-A, HLA-B, and HLA-C), all of which are the HLA Class1 group, present peptides from inside the cell. For example, if the cell is infected by a virus, the HLA system brings fragments of the virus to the surface of the cell so that the cell can be destroyed by the immune system. These peptides are produced from digested proteins that are broken down in the . In general, these particular peptides are small , of about 8-10 in length. Foreign antigens presented by MHC class I attract T-lymphocytes called (also referred to as CD8-positive or cytotoxic T-cells) that destroy cells. Some new work has proposed that antigens longer than 10 amino acids, 11-14 amino acids, can be presented on MHC I, eliciting a cytotoxic T-cell response. MHC class I proteins associate with β2-microglobulin, which, unlike the HLA proteins, is encoded by a gene on chromosome 15.
HLAs corresponding to MHC class II (HLA-DP, HLA-DM, HLA-DO, HLA-DQ, and HLA-DR) present antigens from outside of the cell to T-lymphocytes. These particular antigens stimulate multiplication of (also called CD4-positive T cells), which in turn stimulate antibody-producing B cell to produce antibodies to that specific antigen. Self-antigens are suppressed by regulatory T cells. Predicting which (fragments of) antigens will be presented to the immune system by a certain HLA type is difficult, but the technology involved is improving.
HLAs corresponding to MHC class III encode components of the complement system.
HLAs have other roles. They are important in disease defense. They are the major cause of organ transplant rejection. They may protect against cancers or fail to protect (if down-regulated by an infection). HLA may also be related to people's perception of the odor of other people, and may be involved in mate selection, as at least one study found a lower-than-expected rate of HLA similarity between spouses in an isolated community.
Aside from the genes encoding the six major antigen-presenting proteins, many other genes, many involved in immune function, are located on the HLA complex. Diversity of HLAs in the human population is one aspect of disease defense, and, as a result, the chance of two unrelated individuals with identical HLA molecules on all loci is extremely low. HLA genes have historically been identified as a result of the ability to successfully transplant organs between HLA-similar individuals.
Through a similar process, proteins (both native and foreign, such as the proteins of viruses) produced inside most cells are displayed on HLAs (to be specific, MHC class I) on the cell surface. Infected cells can be recognized and destroyed by 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 viewed from the side. Disease-related peptides fit into these "slots" much like a hand fits into a glove.
When bound, peptides are presented to T-cells. T-cells require presentation via MHC molecules to recognize foreign antigens—a requirement known as MHC restriction. T-cells have receptors that are similar to B-cell receptors, and each T-cell recognizes only a few MHC 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 B-cell receptors. Thus, T-cells help B-cells make antibodies to the same foreign 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 is difficult for disease-related proteins to escape detection.
| + HLA and autoimmune diseases | |
| HLA-B27 | 12Table 5-7 in: (2025). 9781416029731, Saunders. ISBN 9781416029731 8th edition. |
| 14 | |
| 15 | |
| HLA-B47 | 15 |
| HLA-B51 | Behçet's Disease |
| HLA-DR2 | 2 to 3Values are given for Caucasians, according to Page 61 (right column) in: (2025). 9780781793940, Lippincott Williams & Wilkins. ISBN 9780781793940 |
| HLA-DR3 | 14 |
| 10 | |
| 5 | |
| 2 to 3 | |
| HLA-DR4 | 4 |
| 6 | |
| HLA-DR3 and -DR4 combined | 15 |
| HLA-DQ2 and HLA-DQ8 | 7 |
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 *02:01 from *02:02), 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 is the only effective means of discriminating between first-degree relatives that are at risk from those that are not at risk, prior to the appearance of sometimes-irreversible symptoms such as allergies and secondary autoimmune disease.
There are three major and three minor MHC class I genes in HLA.
Major MHC class I
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 three major and two 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 proteins only occur on antigen-presenting cells, , and .
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.
Six 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 2012, the number of alleles that have been determined are listed in the table below. To interpret this table, it is 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 at 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*05:01 and DQA1*05:05 encode proteins with identically processed products. Other alleles 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.
However, the gene frequencies of the most common alleles (>5%) of HLA-A, -B, -C and HLA-DPA1, -DPB1, -DQA1, -DQB1, and -DRB1 from South America have been reported from the typing and sequencing carried out in genetic diversity studies and cases and controls. In addition, information on the allele frequencies of HLA-I and HLA-II genes for the European population has been compiled. In both cases the distribution of allele frequencies reveals a regional variation related with the history of the populations.
| Minor Antigens | |
| HLA E | 27 |
| HLA F | 31 |
| HLA G | 61 |
Number of variant alleles at class II loci (DM, DO, DP, DQ, and DR):
| 1DRB3, DRB4, DRB5 have variable presence in humans | ||||
Common HLA alleles are defined as having been observed with a frequency of at least 0.001 in reference populations of at least 1500 individuals. Well-documented HLA alleles were originally defined as having been reported at least three times in unrelated individuals, and are now defined as having been detected at least five times in unrelated individuals via the application of a sequence-based typing (SBT) method, or at least three times via a SBT method and in a specific haplotype in unrelated individuals. Rare alleles are defined as those that have been reported one to four times, and very rare alleles as those reported only once.
| ~75% |
| ~75% |
| ~74% |
| ~77% |
| ~21% |
| ~53% |
| ~40% |
| ~88% |
| ~91% |
| ~88% |
| ~90% |
| ~76% |
There are several types of serotypes. A broad antigen serotype is a crude measure of identity of cells. For example, HLA A9 serotype recognizes cells of A23- and A24-bearing individuals. It may also recognize cells that A23 and A24 miss because of small variations. A23 and A24 are split antigens, but antibodies specific to either are typically used more often than antibodies to broad antigens.
Broad antigen types are still useful, such as typing very diverse populations with many unidentified HLA alleles (Africa, Arabia, Southeastern Iran and Pakistan, India). Africa, Southern Iran, and Arabia show the difficulty in typing areas that were settled earlier. Allelic diversity makes it necessary to use broad antigen typing followed by gene sequencing because there is an increased risk of misidentifying by serotyping techniques.
In the end, a workshop, based on sequence, decides which new allele goes into which serogroup either by sequence or by reactivity. Once the sequence is verified, it is assigned a number. For example, a new allele of B44 may get a serotype (i.e. B44) and allele ID i.e. B*44:65, as it is the 65th B44 allele discovered. Marsh et al. (2005) can be considered a code book for HLA serotypes and genotypes, and a new book biannually with monthly updates in Tissue Antigens.
For example, SSP-PCR within the clinical situation is often used for identifying HLA phenotypes. An example of an extended phenotype for a person might be:
A*01:01/*03:01, C*07:01/*07:02, B*07:02/*08:01, DRB1*03:01/*15:01, DQA1*05:01/*01:02, DQB1*02:01/*06:02
In general, this is identical to the extended serotype:
A1,A3,B7,B8,DR3,DR15(2), DQ2,DQ6(1)
For many populations, such as the Japanese or European populations, so many patients have been typed that new alleles are relatively rare, and thus SSP-PCR is more than adequate for allele resolution. Haplotypes can be obtained by typing family members in areas of the world where SSP-PCR is unable to recognize alleles and typing requires the sequencing of new alleles. Areas of the world where SSP-PCR or serotyping may be inadequate include Central Africa, Eastern Africa, parts of southern Africa, Arabia, S. Iran, Pakistan, and India.
The phenotype exampled above is one of the more common in Ireland and is the result of two common genetic haplotypes:
A*01:01 ; C*07:01 ; B*08:01 ; DRB1*03:01 ; DQA1*05:01 ; DQB1*02:01
(By serotyping A1-Cw7-B8-DR3-DQ2)
which is called ' 'super B8' ' or ' 'ancestral haplotype' ' and
A*03:01 ; C*07:02 ; B*07:02 ; DRB1*15:01 ; DQA1*01:02 ; DQB1*06:02
(By serotyping A3-Cw7-B7-DR15-DQ6 or the older version "A3-B7-DR2-DQ1")
These haplotypes can be used to trace migrations in the human population because they are often much like a fingerprint of an event that has occurred in evolution. The Super-B8 haplotype is enriched in the Western Irish, declines along gradients away from that region, and is found only in areas of the world where Western Europeans have migrated. The "A3-B7-DR2-DQ1" is more widely spread, from Eastern Asia to Iberia. The Super-B8 haplotype is associated with a number of diet-associated autoimmune diseases. There are 100,000s of extended haplotypes, but only a few show a visible and nodal character in the human population.
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 frequently have different haplotypes, and this results in many combinations, even in small groups. This diversity enhances the survival of such groups, and thwarts evolution of epitopes in pathogens, which would otherwise be able to be shielded from the immune system.
Antibodies against disease-associated HLA haplotypes have been proposed as a treatment for severe autoimmune diseases.
Donor-specific HLA antibodies have been found to be associated with graft failure in renal, heart, lung, and liver transplantation. These donor-specific HLA antibodies can exist pretransplant as consequence of sensitization to prior transplants or through pregnancies, but also occur de novo post-transplantation. There is a clear link between the risk of HLA antibody sensitisation and the donor-recipient HLA (molecular) mismatch.
Phenotyping
Gene typing is different from gene sequencing and serotyping.
With this strategy, PCR primers specific to a variant region of DNA are used (called sequence-specific primers). If a product of the right size is found, the assumption is that the HLA allele has been identified. New gene sequences often result in an increasing appearance of ambiguity. Because gene typing is based on SSP-PCR, it is possible that new variants, in particular in the class I and DRB1 loci, may be missed.
Haplotypes
An HLA haplotype is a series of HLA "genes" (loci-alleles) by chromosome, one passed from the mother and one from the father.
Role of allelic variation
Studies of humans and animals imply a heterozygous selection mechanism operating on these loci as an explanation for this variability.. One proposed mechanism is sexual selection in which females are able to detect males with different HLA relative to their own type. While the DQ and DP encoding loci have fewer alleles, combinations of A1:B1 can produce a theoretical potential of 7,755 DQ and 5,270 DP αβ heterodimers, respectively. While 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.
Antibodies
HLA antibodies are typically not naturally occurring, and with few exceptions are formed as a result of an immunologic challenge to a foreign material containing non-self HLAs via blood transfusion, pregnancy (paternally inherited antigens), or organ or tissue transplant.
HLA matching for sick siblings
In some diseases requiring hematopoietic stem cell transplantation, preimplantation genetic diagnosis may be used to give rise to a sibling with matching HLA, although there are ethical considerations.
See also
Bibliography
External links
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