The human leukocyte antigen (HLA) system is a complex of genes on chromosome 6 in humans that encode cell-surface proteins 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 other 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 Mbp 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 antigens, as a result of their historic discovery as factors in organ transplants.
HLAs corresponding to MHC class I (A, B, and 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 proteasomes. In general, these particular peptides are small polymers, of about 8-10 amino acids in length. Foreign antigens presented by MHC class I attract T-lymphocytes called killer T-cells (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 (DP, DM, DO, DQ, and DR) present antigens from outside of the cell to T-lymphocytes. These particular antigens stimulate multiplication of T-helper cells (also called CD4-positive T cells), which in turn stimulate antibody-producing B-cells 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.
Functions The proteins encoded by HLAs are those on the outer part of body cells that are (in effect) 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 is therefore not an invader.
In infectious diseases 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 on to HLA antigens (to be specific, MHC class II). They are then displayed by the antigen-presenting cells to CD4+ helper T cells, which then produce a variety of effects and cell-to-cell interactions 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 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.
In graft rejection Any cell displaying some other HLA type is "non-self" and is seen as an invader by the body's immune system, resulting in the rejection of the tissue bearing those cells. This is particularly important in the case of transplanted tissue, because it could lead to transplant rejection. Because of the importance of HLA in transplantation, the HLA loci are some of the most frequently typed by serology and PCR. It has been shown that high resolution HLA typing (HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DQB1 and HLA-DPB1) may be relevant in transplantation to identify a full match, even when the donor is related. + HLA and diseases HLA allele Diseases with increased risk Relative risk HLA-B27 Ankylosing spondylitis 12Table 5-7 in: 8th edition.Reactive arthritis 14 Acute anterior uveitis 15 HLA-B47 21-hydroxylase deficiency 15 HLA-B51 Behçet's Disease HLA-DR2 Systemic lupus erythematosus 2 to 3Values are given for Caucasians, according to Page 61 (right column) in: HLA-DR3 Autoimmune hepatitis 14 Primary Sjögren syndrome 10 Diabetes mellitus type 1 5 Systemic lupus erythematosus 2 to 3 HLA-DR4 Rheumatoid arthritis 4 Diabetes mellitus type 1 6 HLA-DR3 and -DR4 combined Diabetes mellitus type 1 15 HLA-DQ2 and HLA-DQ8 Coeliac disease 7
In autoimmunity HLA types are inherited, and some of them are connected with autoimmune disorders and other diseases like ankylosing spondylitis. People with certain HLA antigens are more likely to develop certain autoimmune diseases, such as type I diabetes, rheumatoid arthritis, celiac disease, SLE (systemic lupus erythematosus), myasthenia gravis, inclusion body myositis, Sjögren syndrome, and narcolepsy.
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.
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 enteropathy-associated T-cell lymphoma cases. More often, however, HLA molecules play a protective role, recognizing increases in antigens that are not tolerated because of low levels in the normal state. Abnormal cells might be targeted for apoptosis, which is thought to mediate many cancers before diagnosis. Moreover, variations in the HLA repertoire can be important for anticancer immunity in cancer patients.
In mate selection There is evidence for non-random mate choice with respect to certain genetic characteristics. This has led to a field known as genetic matchmaking.
Classification
MHC class I proteins form a functional receptor on most nucleated cells of the body.
There are three major and three minor MHC class I genes in HLA.
Major MHC class I 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 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, B cells, and T cells. 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.
Nomenclature Modern HLA alleles are typically noted with a variety of levels of detail. Most designations begin with HLA- and the locus name, then * and some (even) number of digits specifying the allele. The first two digits specify a group of alleles, also known as supertypes. Older typing methodologies often could not completely distinguish alleles and so stopped at this level. The third through fourth digits specify a nonsynonymous allele. Digits five through six denote any synonymous mutations within the coding frame of the gene. The seventh and eighth digits distinguish mutations outside the coding region. Letters such as L, N, Q, or S may follow an allele's designation to specify an expression level or other non-genomic data known about it. Thus, a completely described allele may be up to 9 digits long, not including the HLA-prefix and locus notation.
Variability
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 several times during its history 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.