The human leukocyte antigen system (HLA) is the name of the major histocompatibility complex (MHC) in humans. The superlocus contains a large number of genes related to immune system function in humans. This group of genes resides on chromosome 6, and encode cell-surface antigen-presenting proteins and many other genes. The proteins encoded by certain genes are also known as antigens, as a result of their historic discovery as factors in organ transplantations. The major HLA antigens are essential elements in immune function. Different classes have different functions.
HLA class I antigens (A, B & C) present peptides from inside the cell (including viral peptides if present). These peptides are produced from digested proteins that are broken down in the lysozomes. The peptides are generally small polymers, about 9 amino acids in length. Foreign antigens attract killer T-cells (also called CD8 positive cells) that destroy cells.
HLA class II antigens (DR, DP, & DQ) present antigens from outside of the cell to T-lymphocytes. These particular antigens stimulate T-helper cells to reproduce and these T-helper cells then stimulate antibody producing B-cells, self-antigens are suppressed by suppressor T-cells.
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. Historically, HLA genes were identified as a result of the ability to successfully transplant organs between HLA similar individuals.
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 is 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 is 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 as 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.
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:
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
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.
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 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 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.
|MHC class I|
Number of variant alleles at class II loci (DP and DQ):
|MHC class II|
|HLA||-A1||-B1||-B3 to -B51||Potential|
|1DRB3, DRB4, DRB5 have variable presence in humans|
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.
In the end, a workshop, based on sequence, decides which new allele goes into which serogroup either by sequence or reactivity. Once the sequence is verified it is assigned a number. For example, a new allele of B44 may get a serotype B*4465 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 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*0101/*0301, Cw*0701/*0702, B*0702/*0801, DRB1*0301/*1501, DQA1*0501/*0102, DQB1*0201/*0602
This is generally 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 were SSP-PCR or serotyping may be inadequate include Central Africa, Eastern Africa, parts of southern Africa, Arabia and S. Iran, Pakistan and India.
A*0101 : Cw*0701 : B*0801 : DRB1*0301 : DQA1*0501 : DQB1*0201 (By serotyping A1-Cw7-B8-DR3-DQ2)
which is called ' 'super B8' ' or ' 'ancestral haplotype' ' and
A*0301 : Cw*0702 : B*0702 : DRB1*1501 : DQA1*0102 : DQB1*0602 (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 only found 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 100000s of extended haplotypes but only a few show a visible and nodal character in the human population.
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 kidney, heart, lung and liver transplantation.