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 Table of Contents  
REVIEW ARTICLE
Year : 2019  |  Volume : 32  |  Issue : 4  |  Page : 1197-1207

Human leukocyte antigen in medicine


1 Department of Internal Medicine, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Internal Medicine, Shebin El-Kom Fever Hospital, Menoufia Health Directorate, Ministry of Health, Menoufia, Egypt

Date of Submission30-Apr-2016
Date of Decision03-Jul-2016
Date of Acceptance10-Jul-2016
Date of Web Publication31-Dec-2019

Correspondence Address:
Khairy A El-Hady
Bakhaty, Shebin El.Kom City, Menoufia Governorate
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_211_16

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  Abstract 


Objective
The aim was to evaluate human leukocyte antigen (HLA) biology and its importance in medicine.
Materials and methods
Medline databases (PubMed, Medscape, ScienceDirect, and MMJ) were searched. The initial search presented 500 articles, papers, and journals about immunity, major histocompatibility complex, HLA, minor histocompatibility complex, autoimmune diseases, infectious diseases, transplantation, and HLA application in medicine. Short reviews were made on HLA biology and different associated diseases.
Conclusion
Most of the genes in the major histocompatibility complex region express high polymorphism, which is fundamental to their function. The most important function of HLA molecule is in the induction and regulation of immune responses. Many human diseases, such as autoimmune, infectious, inflammatory, and malignant, are significantly more common among individuals carrying particular HLA alleles. HLA-disease association is the name of this phenomenon, and the mechanism underlying is still a hot debate topic.

Keywords: human leukocyte antigen, human leukocyte antigen application, human leukocyte antigen disease association, major histocompatibility complex


How to cite this article:
Shoeib S, El-Shebiny E, Efat A, El-Hady KA. Human leukocyte antigen in medicine. Menoufia Med J 2019;32:1197-207

How to cite this URL:
Shoeib S, El-Shebiny E, Efat A, El-Hady KA. Human leukocyte antigen in medicine. Menoufia Med J [serial online] 2019 [cited 2020 Jan 24];32:1197-207. Available from: http://www.mmj.eg.net/text.asp?2019/32/4/1197/274237




  Introduction Top


The major histocompatibility complex (MHC), referred as human leukocyte antigen (HLA) system in humans, is an extremely polymorphic region encoding for the major molecules in charge of antigen presentation on the cell surface, and it has been one of the most intensively studied areas in the human genome [1].

The MHC encompasses 7.6 Mb on chromosome 6 and is the most gene dense region within the human genome including several key immune response genes. MHC complex is divided into classes I, II, and III on the basis of chemical structure and biological properties [2].

MHC name is derived from its role in graft rejection and tissue compatibility between donor and recipient pair. MHC compatibility between individuals is responsible for successful graft transplant [3].

Furthermore, assessment and comparison of the polymorphism of HLA allow to better define the extent of the genetic variability in humans as well as the reasons of this diversity. The HLA region is associated with more diseases (mainly autoimmune and infectious diseases) than any other region of the genome [1].

It is paradoxical that genes evolved to protect the host against infectious diseases are cause of many genetic disorders themselves. It is often unclear what role HLA genes play in the risk of developing these diseases [4].


  Materials and Methods Top


Data sources

We reviewed papers on HLA system from Medline databases, which are PubMed, Medscape, ScienceDirect, and MMJ. We used immunity, major histocompatibility complex, HLA, minor histocompatibility complex, autoimmune diseases, infectious diseases, transplantation, and HLA application in medicine as searching terms. In addition, we examined references from the specialist databases EMF-Portal (http://www.emf-portal.de).

Article selection

All the studies were independently assessed for inclusion. They were included if they fulfilled the following criteria:

Inclusion criteria of the published studies were as follows:

  1. Published in English language
  2. Focused on HLA
  3. Discussed the relation between HLA and disease association
  4. If a study had several publications on certain aspects, we used the latest publication giving the most relevant data.


Data synthesis

If the studies did not fulfill the aforementioned criteria, they were excluded; moreover, letters/comments/editorials/news and studies not focused on HLA were excluded as well.


  Results Top


Data sources included Medline databases (PubMed, Medscape, ScienceDirect, and MMJ).

Article selection

The initial search presented 500 articles, papers, and journals about the title of the article with the key words mentioned; extraction was done, including assessment of quality and validity of papers. Studies concerning HLA biology and its importance in medicine were collected. Each study was reviewed independently. Obtained data were rebuilt in new language and arranged into topics within the article.

Data synthesis

Short reviews were made on different diseases associated with HLA.


  Discussion Top


History and discovery

The immunogenetics field was born in 1900, with the discovery of the ABO blood groups by Landsteiner, followed by the Rhesus system in 1940. Peter Gorer was the first to describe in 1936 a histocompatibility system in mice from his observations of the agglutination of erythrocytes by rabbit immune sera [5].

This research was advanced by George Snell who established that graft rejection in mice was owing to incompatibility at the level of certain antigens. The murine MHC was called 'H2' in honor of the antigen II discovered by Gorer. As for humans, the history of the HLA complex began in 1952, with the princeps observation made by Jean Dausset. He hypothesized that a similar antigenic system to that seen in mouse erythrocytes could exist in humans on the surface of leucocytes, which he demonstrated by showing a massive leukoagglutination by the serum of a poly transfused patient. However, the firm discovery of the first human MHC antigen, MAC (HLA-A2), was made only in 1958 following a classical segregation population analysis using a serum reacting in only a subset of the studied sample [Figure 1] [6].
Figure 1: Timeline of research in the major histocompatibility complex and human genome.

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This polymorphic system was then confirmed by the work of Jon van Rood, and of Rose Payne and Walter Bodmer, who defined respectively the antigens 4a and 4b (Bw4 and Bw6), and HLA-A2 and HLA-A3, through studies on multiparous women [7].

An international research effort involving the International Histocompatibility Workshops, initiated in 1964, led progressively to the characterization of a gene cluster on chromosome 6 with serologically defined alleles and including HLA-A, HLA-B, and HLA-C. The complement system was also mapped to the same genetic region. In the 1970s, HLA class II alleles were characterized through the identification of mixed lymphocyte reactions. Advances in molecular biology then allowed investigation of the HLA system directly at the level of the genes rather than of their products [6].

Nomenclature

The WHO established the most recent HLA naming system in 2010. The work was originally started in 1989 when a large number of HLA allele sequences were first analyzed and named [Figure 2] [2].
Figure 2: Convention for human leukocyte antigen allele naming.

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The HLA nomenclature updates are produced consistently (on a monthly basis), and the IGMT/HLA sequence database is the body appointed by WHO Nomenclature Committee as an official repository for HLA sequences [8].

This database contains sequence of HLA allele and provides users with online tools and facilities for analysis of data (which include allele report and detailed description of source cells) [Table 1] [2].
Table 1: Nomenclature of human leukocyte antigen alleles [9]

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As of April 2015, there are more than 3017 HLA-A, 2623 HLA-C, 3887 HLA-B, 1829 HLA-DRB1, 780 HLADQB1, and 520 HLA-DPB1 alleles recognized by the WHO Nomenclature Committee for Factors of the HLA System [Figure 3] [8].
Figure 3: Growth of the international IMMuno Gene Tics/human leukocyte antigen database.

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Structure and function

HLA complex consists of more than 200 genes categorized into three basic groups: class I, class II, and class III [Figure 4]. Class I molecule is a heterodimer consisting of a heavy chain and a light chain, the β-2 microglobulin. HLA class I genetic region encodes the heavy chain of the classics HLA-A, HLA-B, and HLA-C molecules, besides HLA-E, HLA-F, HLA-G, and the MHC class I polypeptide-related sequence A (MICA) and MICB. Class I molecules are expressed in nearly all cells and play a central role in the immune system by presenting peptides derived from the endoplasmic reticulum lumen. Class II molecules are heterodimers formed by α and β chains. HLA class II genetic region, initially called immune response (Ir) genes owing to its role in controlling the immune response, encodes the α and β chains of the HLA-DR, HLA-DQ, HLA-DP, HLA-DM, and HLA-DO molecules and peptide transporter proteins (TAP) 1 and (TAP) 2. Class II molecules are predominantly expressed on antigen-presenting cells (APC), such as macrophages, dendritic cells, B cells, Langerhans cells, and Kupffer cells, although some cells may express class II molecules during inflammatory process [Figure 5] [10].
Figure 4: Schematic representation of the human chromosome 6 including the main major histocompatibility complex genes.

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Figure 5: Human leukocyte antigen class I and II are heterodimeric transmembrane proteins.

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The proteins produced from HLA class III genes have somewhat different functions, some of which involve participation in inflammation processes and other immune system activities. HLA-class III genetic region encodes C2 and C4 complement components and tumor necrosis factorsuperfamily. The functions of some HLA genes are unknown [1].

Inheritance

The normal way to present a tissue type is to list the HLA antigens as they have been detected. There is no attempt to show which parent has passed on which antigen. This way of presenting the HLA type is referred to as a phenotype [11].

Human leukocyte antigen phenotype examples

The examples include HLA-A1, HLA-A3; B7, B8; Cw2, Cw4; DR15, and DR4. When family data are available, it is possible to assign each of the antigens at each locus to a specific grouping known as a haplotype. An haplotype is the set of HLA antigens inherited from one parent [Figure 6] [12].
Figure 6: Mendelian inheritance of human leukocyte antigen haplotypes demonstrated in a family study.

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Detection and techniques of tissue typing

HLA typing and detection of anti-HLA antibody are used to determine the compatibility of grafts and to test for the presence of preformed antibodies, respectively [2].

Human leukocyte antigen typing methods

HLA typing was done by two methods: either serologic or molecular typing. Both methods are still being used in most HLA laboratories, although molecular techniques are superseding serologic methods [13].

Nowadays, with the advent of polymerase chain reaction, more precise DNA-based HLA typing methods such as sequence-specific oligonucleotide probe hybridization, sequence-specific primer amplification, sequencing-based typing, and reference strand-based conformation analysis have been developed and are frequently used. Molecular tissue typing, utilizing the sequence-specific oligonucleotide probe hybridization and sequence-specific primer amplification technologies, has been in routine use in many tissue-typing laboratories worldwide for more than 20 years. Both methods are very useful for clinical and research purposes and can provide generic (low resolution) to allelic (high resolution) typing results. The main advantage of DNA-based method is that it had more sensitivity, accuracy, and resolving power than serologic typing methods [Figure 7] [2].
Figure 7: Human leukocyte antigen typing resolution.

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Human leukocyte antigen disease association

Population studies carried out over the past several decades have identified a long list of human diseases that are significantly more common among individuals who carry particular HLA alleles [Table 2] [14].
Table 2: Human leukocyte antigen allele and associated diseases [14]

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The mechanism underlying HLA disease association is unclear; however, many hypotheses have been postulated and generally fall into two categories:

  1. Those that blame 'mistaken identity', in which an HLA allele appears to associate with the disease, although the actual culprit belongs to a different locus in the haplotype or associates through linkage disequilibrium [15]
  2. Those that implicate immune reactivity to self-antigens owing to aberrant T-cell repertoire selection, immune cross-reactivity with foreign antigens, or immune attack on 'altered self' antigens [16].


Human leukocyte antigen and autoimmune diseases

Strong association between the HLA region and autoimmune disease has been established for more than 50 years. Association of components of the HLA class II encoded HLA-DRB1–DQA1–DQB1 haplotype has been detected with some of autoimmune-related diseases, including rheumatoid arthritis (RA), type 1 diabetes (T1D), and Graves' disease (GD) [3].

Type 1 diabetes

T1D is the most common endocrine metabolic disorder of childhood and adolescence, with important consequences for physical and emotional development [17].

T1D, a multifactorial disease with a strong genetic component, is caused by the autoimmune destruction of pancreatic β cells. The major T1D susceptibility locus maps to the class II loci HLA-DRB1 and HLA-DQB1[3].

The highest risk DR/DQ haplotypes for T1D are DR 3-DQA1* 0501-DQB1* 0201 (DR3) and DR 4-DQA1* 0301-DQB1* 0302 (DR4), and these alleles account for 30–50% of genetic T1D risk [18].

The association of specific HLA-DQB1 alleles and genotypes with T1D susceptibility/protection depends on the ethnicity and racial background of each population [19].

Multiple sclerosis

Multiple sclerosis (MS) is a chronic disabling disease of the central nervous system that results from the effects of unknown environmental risk factors acting in genetically susceptible individuals [20].

Susceptibility to MS has been linked mainly to the HLA-DRB1 locus, with the HLA-DR15 haplotype (DRB1* 1501-DQA1* 0102-DQB1* 0602-DRB5* 0101) dominating MS risk in whites. Although genes in the HLA-II region, particularly DRB1* 1501, DQA1* 0102-DQB1* 0602, are in close linkage disequilibrium, GWAS and gene candidate studies identified the DRB1* 15:01 allele as the primary risk factor in MS [21].

Ankylosing spondylitis

Ankylosing spondylitis (AS) is a complex disease involving multiple risk factors, both genetic and environmental. HLA-B27 has been known to be the major AS-susceptibility gene for more than 40 years and is present in more than 90% of patients with AS [22].

There are ∼31 HLA-B*27 alleles, with the B*2701, B*2704, and B*2705 alleles strongly associated with susceptibility and the B*2706 and B*2709 alleles associated with protection [23].

The current hypotheses linking HLA-B27 to spondyloarthritis pathogenesis include the following: first, arthritogenic peptides: self-peptides selected and presented by properly folded forms of HLA-B27 complexed with β2m have been hypothesized to be the target of autoreactive CD8+ T cells and serve as an upstream initiator of inflammation; second, recognition of noncanonical HLA-B27: naturally occurring cell surface HLA-B27 dimers are hypothesized to be recognized by killer immunoglobulin receptors (such as KIR3DL2) in the leukocyte immunoglobulin-like receptor family and trigger inflammation; and third, HLA-B27 misfolding: the formation of misfolded oligomers and BiP binding by newly synthesized HLA-B27 heavy chains causes endoplasmic reticulum stress, which has intrinsic effects on cellular function, which are hypothesized to promote development of spondyloarthritis. HLA-B27 can exhibit all three of these behaviors in the same cell, and these concepts are not mutually exclusive [24].

Rheumatoid arthritis

RA is one of the most important autoimmune disorders, with a worldwide prevalence of ∼0.5–1% [4].

RA is characterized by chronic inflammation of the synovial joints, with small joints of the hands and feet most commonly affected. RA pathogenesis is multifactorial, with both genetic and environmental risk factors (including smoking and diet) playing important roles. The genetic contribution to RA susceptibility is estimated to be 50–60% [3].

Regarding genetic factors, multiple genes are likely to be involved in RA susceptibility. However, HLA-DRB1 is the principal locus contributing to disease susceptibility, contributing an estimated 30–50% of overall susceptibility to RA [25].

Coeliac disease

Coeliac disease is an immunologically mediated disease of the small intestinal mucosa, characterized by flattening of the small intestinal villi, increased numbers of intraepithelial lymphocytes, and inflammatory cell infiltrates in the lamina propria, resulting in gut damage and nonspecific malabsorption of nutrients [4].

HLA has long been implicated as strongly associated with susceptibility to CD. Various studies in the late 1980s and early 1990s, including those under the auspices of the International Histocompatibility Workshops, led to definition of the DQA1*05:01, DQB1*02:01 heterodimer, encoded in cis or trans, as being the principal HLA association [3].

This is one of the strongest HLA and disease associations described, with a relative risk for disease greater than 200. There is also a secondary association with DQA1*03, DQB1*03:02, along with a number of other possible weaker associations [4].

Graves' disease

Early studies of HLA in GD have found that HLA-B8 was associated with GD with relative risks for GD ranging from 1.5 to 3.5. Subsequent research, however, found that GD was more strongly associated with HLA-DR3, which is now known to be in linkage disequilibrium with HLA-B8. The frequency of DR3 in patients with GD was generally 40–55% and ~15–30% in the general population, resulting in a relative risk for people with HLA-DR3 of 3–4 [26].

Confirming the results of the case–control studies was a family-based association study from the UK, using the transmission disequilibrium test. Additionally, among whites, HLA-DQA1*0501 was also shown to be associated with GD, but recent studies have suggested that the primary susceptibility allele in GD is indeed HLA-DR3 (HLA-DRB1*03) [27].

Systemic lupus erythematosus

The familial occurrence of systemic lupus erythematosus has been well recognized. This was well documented by the classical study of Arnett and Shulman. Studies on identical twins have documented the high to moderate rate of concordance in monozygotic twins. These studies support the thesis that genetics plays a significant role in systemic lupus erythematosus. Shortly after the description of human HLA-D-related serology, it was demonstrated that the HLA-D region contained lupus susceptibility gene(s) [28].

Human leukocyte antigen and infectious diseases

For an efficient immune response to a pathogen to occur, HLA molecules must bind peptides derived from microbial proteins and the T-cell repertoire must include clones that can be activated by such HLA-bound peptides. Nonfulfillment of either of these requirements may render a person carrying a particular combination of HLA alleles more susceptible to a particular infectious disease than one who has a different combination of alleles [29].

Malaria

The best example of this resistance is the association of specific HLA class I and class II alleles with protection against severe malaria in sub-Saharan Africa. In the Gambia, infection with Plasmodium falciparum, which causes malaria, is extremely common, although the mortality rate among children with malarial anemia or cerebral malaria is low. HLA typing of the relevant population revealed the presence of the HLA-B*53 allele at a frequency of ∼25% among healthy people or children with mild malaria (the allele is rare in non-African populations) [3].

By contrast, the frequency of HLA-B*53 among patients with severe malaria was ∼15%. The comparison suggests that possession of the HLA-B*53 allele reduces the risk of death from severe malaria by ∼40%. Protection against severe malarial anemia is also afforded by possession of the class II HLA-DRB1*1302/DQB1*0501 haplotype. In other sub-Saharan populations, different HLA class I and class II alleles are involved in the resistance to severe malaria [30].

HIV/AIDS

HIV/AIDS is one of only a few infectious diseases showing a clear-cut and consistent HLA association [31].

HIV infection typically manifests with an acute viral syndrome, followed by a period of immune control with relatively low viral loads and stable CD4+ cell counts. After this asymptomatic period of usually 8–10 years, viral loads increase, CD4+ T-cell counts drop, and AIDS-defining opportunistic infections or malignancies occur in untreated patients. There are, however, some patients who display a superior HIV control. These 'elite controllers' or 'long-term nonprogressors' have low viral loads and remain asymptomatic even for decades before the onset of AIDS [32].

Kaslow and colleagues assessed the role of HLA class I alleles in HIV infection and found that HLA-B27 and B57 were strongly associated with slow progression to AIDS. Importantly, several independent studies have confirmed this finding, including a recent study that included more than 2700 HIV-infectedpatients [33].

HCV

In the same time, there is a striking concordance between several of the HLA alleles associated with clearance in both HIV and HCV infection, including, in particular, HLA-B*27. Other associations with HLA-B*57 and HLA-B*08 DR3 are less consistent and may relate to differences in viral sequences in certain subpopulations [34].

Both HLA-B*57 and HLA-B*27 have been identified as protective in terms of both HIV and HCV infection. The mechanisms for this joint efficacy could be manifold. First, it is possible that both HLA alleles could be in LD with other genes in the MHC which are more directly responsible for their effects. Second, it is possible that both HLA molecules select for epitopes that may have an influence on viral fitness. Third, it is possible that such associations are simply related to the prevalence of a particular gene in a population as it is likely that in any given population there will be less exposure to, and consequently less selection against, rare alleles, particularly in populations where the prevalence of the condition has increased recently. It is worth noting that there are also striking differences between HIV and HCV in HLA types associated with protection [34].

Human leukocyte antigen and cancer

Interestingly, none of the HLA class I and II alleles have been demonstrated to be associated with an increased incidence per se of any cancer. However, individual alleles are known to be overrepresented in certain cancers or correlate with survival, prognosis, higher tumor staging, grading, disease progression, and failure to CD8+ T-cell-based immunotherapies [3].

HLA-A*02 allele is associated with poor prognosis in different cancers such as ovarian, prostate, melanoma, and lung cancer. At the same time, in advanced ovarian cancer, HLA-A2 is a negative clinical prognostic factor, and its phenotype was overrepresented in both ovarian and prostate cancer in Swedish patients compared with the normal population [35].

Human leukocyte antigen and drug sensitivity

The HLA genes are well recognized as influencing select drug responses. For example, by prospectively HLA typing patients with HIV-positive status to identify those with HLA-B*57:01, a significant reduction was seen in the risk of adverse events owing to the strong association of hypersensitivity with the use of abacavir in these patients. In European populations, this allele is relatively common with a frequency of 6–7%. The highest frequency of HLA-B*57:01 has been reported in southwestern Asian populations in which up to 20% of the population are carriers. The US Food and Drug Administration recommends prescreening patients for B*57:01 before starting treatment with this antiretroviral medication [Table 3].
Table 3: Examples of important drug adverse events and their human leukocyte antigen associations [14]

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Human leukocyte antigen applications

The human MHC is associated with more diseases than any region of the genome particularly related to infection and autoimmunity. Even more spectacular is the role of the HLA system in organ and hematopoietic stem cell transplantation, and its importance in the development of vaccines, particularly cancer vaccines, is well recognized [36].

Human leukocyte antigen and transfusion

The HLA class I antigens are carried in high concentration by leukocytes and platelets, but only in trace amounts on erythrocytes. Each transfusion of either platelets or leukocytes therefore carries a risk of immunizing the patient. Patients, with an intact immune system, who require multiple transfusions of whole blood, platelets, or leukocyte concentrates, will therefore usually develop antibodies to HLA antigens. Anti-HLA antibodies may lead to two problems. First, these patients become refractory to platelet transfusions, which they destroy rapidly; and second, nonhaemolytic transfusion reactions may occur in response to HLA antigen [13].

Refractoriness to platelet transfusion

Platelet transfusion refractoriness is a consistently insufficient response to platelet transfusions. Platelets express platelet-specific antigens and HLA class I antigens. The development of antibodies to these antigens can cause immune destruction of transfused incompatible platelets, resulting in an immune refractoriness to random donor platelet transfusions [37].

When patients are suspected for immune refractoriness, HLA, and platelet-specific antibody screening is performed. Definite diagnosis of platelet immune refractoriness is confirmed if antibodies against HLA and/or platelet-specific antigens are detected and nonimmune causes of platelet refractoriness are ruled out. Once the clinical and laboratory diagnosis of immune refractoriness is made, the use of special platelet products is indicated. Most patients who are refractory to random donor platelets because of HLA antibodies respond to HLA-matched platelets [38].

Transplantation

This is the case when one attempts to transplant tissues or organs between genetically disparate individuals of the same or different species (allografts and xenografts, respectively). The T-cell receptors of the recipient's lymphocytes recognize either the donor's (allogeneic) HLA molecules on APCs of the graft (a process known as direct presentation) or the donor's HLA molecules on APCs of the recipient (a process known as indirect presentation). During indirect presentation, the peptides are generated by the degradation of the allogeneic HLA molecules released from the graft [3].

Hematopoietic stem cell transplant

The HLA system is the primary immunologic barrier to successful stem cell transplant. Therefore, the clinical outcomes of hematopoietic stem cell transplant are dependent on optimizing the histocompatibility matching between the patient and the donor. The HLA antigens (HLAs) are effective stimulators and targets of graft-versus-host disease and graft rejection. HLAs possess outstanding ability to elicit an immune response either by presentation of variable peptides or by recognition of polymorphic fragments of foreign HLA molecules. In the future, evaluation before hematopoietic stem cell transplant is likely to comprise a more detailed genetic analysis of patient and donor, but currently the standard is HLA typing at A, B, C, DRB1, and DQB1 genetic loci [39].

Renal transplantation

Although the effect of HLA compatibility has been recognized for two decades, the advances in immunosuppression protocols are such that rejection episodes are managed more efficiently, thus minimizing the importance of HLA matching. A study based on the United Network for Organ Sharing data reported that the effect of HLA compatibility had greatly diminished. Consequently, some allocation programs have gradually toned down the role of HLA matching from the algorithms used for prioritizations on the waiting list. The lower importance of HLA matching was also favored in the early years of the 21st century with the advent of the microarray-based luminex technology for detecting DSA, thus allowing organ allocation around well-characterized HLA specificities [3].

However, the results of Opelz and Dohler on a large study cohort (135 970 kidney transplants) clearly showed that the significance of HLA matching on graft survival rate has not lost its importance, and this is obvious when comparing the decades 1985–1994 and 1995–2004. Even when analyzing the past 5 years of the study period separately (2000–2004), a significant correlation of graft survival with HLA matching was disclosed [40].

DNA vaccines

DNA vaccines contain the gene or genes for an antigenic portion of a virus, such as the core protein or the envelope protein. Host cells take up the foreign DNA, express the viral gene, and make the corresponding viral protein inside the cell. An important advantage of this system is that the viral protein enters the cell's (MHC) class I pathway. Only proteins that originate inside a cell are processed by this pathway. MHC class I molecules carry peptide fragments of the viral protein to the cell surface, where, by stimulating CD8 cytotoxic T cells, they evoke cell-mediated immunity. By contrast, standard vaccine antigens are taken up into cells by phagocytosis or endocytosis and are processed through the MHC class II system, which primarily stimulates antibody responses. It must be kept in mind that there is considerable 'cross-talk' throughout the immune system. Even so, the preferential stimulation of cytotoxic T cells is a desirable property of a vaccine against a virus or parasite [41].

Major histocompatibility complex-based immunotherapy

Since the peptides presented by MHC molecules have allele-specific motifs and certain HLA alleles are associated with different autoimmune disorders, antigen/peptide-based immunotherapy can be developed to induce antigen-specific tolerance [42].


  Conclusion Top


  1. HLA system contains the most diverse genes known in vertebrates, the class I and II loci. These highly polymorphic genes located in the region of chromosome encode cell surface receptors that play a central role in controlling immunological self/nonself recognition, and subsequently tissue rejection, autoimmunity, adverse drug reaction, cancer development, and immune responses to infectious diseases
  2. HLA typing is very important for both clinical laboratories and biomedical research. Even more spectacular is the role of the HLA system in organ and haematopoietic stem cell transplantation, and its importance in the development of vaccines, particularly cancer vaccines, is well recognized.


Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

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