MHC proteins are found in all higher vertebrates. The glycoprotein encoded by human MHC is called human leukocyte antigen (HLA), which specifically presents short peptides to T cells and haves a key role in the immune defense of the body [1]. HLA is a protein or antigen found on the surface of cells in the body. The HLA gene is a family of genes that encode HLA complexes. The HLA system and MHC help the body's immune system distinguish between autogenous and foreign or non-autogenous substances.
The HLA antigen was first discovered by JeanDausset in 1958. MHC map to the short arm of chromosome 6, spanning about 3600 kilobase DNA [2], contains more than 200 genes [3]. It is considered to be the most polymorphic genetic system in humans, providing the immune system with the ability to resist multiple antigens. These genes are all located on chromosome 6. According to the differences in antigen structure, function and tissue distribution, HLA/MHC genes are generally divided into three classes: class I, class II and class III.
Figure 1 The Classification of HLA
Table 1 The composition of HLA/MHC Class II
Composition | Structure |
---|---|
HLA-DP | α - chain encoded by HLA-DPA1 locus |
β - chain is encoded by HLA-DPB1 locus | |
HLA-DQ | α - chain is encoded by HLA-DQA1 locus |
β - chain is encoded by HLA-DQB1 locus | |
HLA-DR | α - chain is encoded by HLA-DRA site |
4β-chains are encoded by HLA-DRB1, DRB3, DRB4, and DRB5 sites. | |
HLA-DM | α - chain is encoded by HLA-DMA. |
β - chain is encoded by HLA-DMB. | |
HLA-DO | α - chain is encoded by HLA-DOA. |
β - chain is encoded by HLA-DOB. |
Figure 2 The structure of HLA class I and HLA class II
Proteins produced by HLA/MHC class III genes, including complementary components C2, C4 and factor B, tumor necrosis factor TNF, lymphotoxin and three heat shock proteins. They mainly play a role in the inflammatory response.
Both HLA-I and HLA-II have an antigen-binding groove that allows for the binding of the processed peptide. The biological role of HLA class I and class II molecules is to provide antigens that have been processed. The most important function of HLA molecules is to induce, regulate immune responses and select T cell banks [4].
Cells contain two different antigen-processing pathways that provide peptides to T cells.
Figure 3 HLA class I antigen-processing and presentation pathway
Figure 4 HLA class II antigen-processing and presentation pathway
Therefore, HLA class I usually detects the intracellular environment, while HLA class II detects antigens present in the extracellular environment [5].
The distribution of HLA antigens in different ethnic groups has a unique pattern. Take HLA-B27 as an example, which is a gene associated with the prevalence of AS. The areas with higher B27 positive rates are mainly American Columbia, the Indian population along the coast of Canada and Canadian Haida. The positive rate of B27 in other regions is as follows: It was 6%-8% in European and American Caucasians; less than 1% in Japan and Africa; in Chinese population is 4% ~ 8%.
MHC gene is the most polymorphic gene in human genome (total HLA allele 13023; HLA I allele 9749 and HLA II allele 3274) [6]. The specific information is shown in table 2 and table 3.
There are two main hypotheses about the polymorphism of HLA:
The polymorphism of MHC, on the one hand, is an obstacle to finding a match, and on the other hand, it enable the immune system to recognize any invading pathogens.
Table 2 The number of alleles of HLA Class I
HLA Class I | |||||||
---|---|---|---|---|---|---|---|
Gene | A | B | C | E | F | G | |
Alleles | 4,638 | 5,590 | 4,374 | 27 | 31 | 61 | |
Proteins | 3,172 | 3,923 | 2,920 | 8 | 6 | 19 | |
Nulls | 224 | 169 | 171 | 1 | 0 | 3 |
Table 3 The number of alleles of HLA Class II
HLA Class II | |||
---|---|---|---|
Gene | Alleles | Proteins | Nulls |
DRA | 7 | 2 | 0 |
DRB | 2,639 | 1,908 | 84 |
DQA1 | 100 | 36 | 4 |
DQB1 | 1316 | 878 | 35 |
DPA1 | 73 | 32 | 0 |
DPA2 | 5 | 2 | 0 |
DPB1 | 1097 | 728 | 34 |
DPB2 | 6 | 3 | 0 |
DMA | 7 | 4 | 0 |
DMB | 13 | 7 | 0 |
DOA | 12 | 3 | 1 |
DOB | 13 | 5 | 0 |
Data from IMGT - HLA database: https://www.ebi.ac.uk/ipd/imgt/hla/stats.html
Various HLA tests mainly include HLA typing, HLA antibody screening and identification.
HLA genes play an important role in transplant rejection as well as infective and autoimmune diseases [7]. For these reasons, accurate HLA typing is important both in clinical and research. HLA typing has been performed using a variety of techniques, such as serology, cellular and molecular analysis [8].With the birth of DNA sequencing and polymerase chain reaction (PCR), specific oligonucleotide probe hybridization, sequence specific primer amplification, sequence typing (SBT) and other molecular typing techniques have been developed.
HLA antibody test: an HLA antibody test is performed on the recipient of a transplant to determine whether antibodies against the donor tissue or organ exist to determine whether they can be successfully transplanted to another individual.
The clinical application of HLA is mainly the matching of donor and recipient in organ transplantation [9]. Human leukocyte antigen (HLA) typing can be used to match patients and donors of bone marrow or cord blood transplantation.
HLA-B27 is a human leukocyte antigen and belongs to the MHC class I gene. In clinical work, B27 positive can help us diagnose ankylosing spondylitis (AS). However, the diagnosis of AS needs to be judged by combining clinical symptoms, physical examination, imaging examination and laboratory examination. HLA-B27 alone cannot diagnose and exclude AS. Nevertheless, B27 still has an important auxiliary value for the diagnosis of AS.
Currently, there are four commonly used methods for B27 detection: flow cytometry, PCR-SSP, ELISA and microcytotoxic assay. Flow cytometry is currently the most ideal method to detect B27, and it is also recommended internationally to detect B27.
Many HLA genes are linked to human diseases, including some autoimmune diseases and cancer. But the underlying mechanism has not been fully explained.
Human diseases associated with the HLA gene:
Many studies have shown that HLA alleles are associated with various aspects of HIV disease. Existing evidence indicates that HLA is the most important site for human HIV differential control [12]. Kaslow et al. evaluated the role of HLA I alleles in HIV infection and found that HLA B27 and B57 were closely related to the slow progress of AIDS [13].
HLA homozygous individuals are more likely to become infected with HIV than HLA heterozygous individuals. The reason is that individuals heterozygous at HLA sites will be able to provide T cells with a wider pool of antigenic peptides than homozygous individuals, thus exerting greater pressure on pathogens.
Problems that can occur in pregnant women: recurrent miscarriage, pre-eclampsia, or hemolytic disease in the newborn. These conditions are considered to be an immune rejection.
Some mechanisms have been proposed to explain the immune privilege state of the diaphragm. Different assumptions can be grouped into five main points:
There is such an interesting phenomenon in fetal tissues: low HLA - C expression, lack of highly polymorphic HLA - A molecule.
However, the tissues of fetal origin in the placenta expressed low polymorphism of HLA class I B molecules, HLA - E, HLA - F and HLA - G, which made people more and more interested in the immunological effects of these three proteins during pregnancy [14].
Allergic drug reactions usually occur in low molecular weight drugs. There are several explanations for the mechanism of drug allergy associated with HLA.
There is a certain correlation between the human leukocyte antigen and mate selection [18]. Individuals prefer to have a partner that is relatively different from their own HLA genotype. Choosing a different HLA partner can increase the heterozygosity of the offspring on HLA, potentially increasing the resistance of the offspring to the pathogen.
Human life span may be directly related to the optimal function of the immune system. Studies conducted in mice have shown that HLA, which is known to control multiple immune functions, is associated with the lifespan of strains. But a conflicting results have been found in a number of cross-sectional studies comparing the frequency of HLA antigens in young and old people.
References
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