INTRODUCTION — The major histocompatibility complex (MHC) is a term used to describe a group of genes in animals and humans that encode a variety of cell surface markers, antigen-presenting molecules, and other proteins involved in immune function. The human leukocyte antigen (HLA) complex is synonymous with the human MHC.
The earliest HLA associations with rheumatic diseases, such as the association of the HLA-B*27 allele at the HLA-B gene with ankylosing spondylitis (AS) risk and the association of the HLA-DRB1*04 allele at the HLA-DRB1 gene with rheumatoid arthritis (RA), were discovered several decades ago. As the study of HLA genetics has evolved and expanded, the nomenclature has been continually altered, posing challenges for those attempting to follow the science. However, knowledge concerning this genetic region has evolved sufficiently, so the overall nomenclature should be more stable in the future, even though new alleles will be identified and catalogued.
The genetics, nomenclature, and typing of HLA, as well as the relationships between HLA and rheumatic disease, are discussed here. The older nomenclature that may still be encountered in the literature is defined. The specific function of the MHC system, including the mechanisms of antigen presentation, is discussed separately.
GENETIC STRUCTURE OF THE HLA REGION — The major histocompatibility complex (MHC) in humans refers to a genetic region containing hundreds of genes, including the human leukocyte antigen (HLA) genes (figure 1). Thus, the human MHC region is also referred to as the HLA region. HLA genes express their gene products on the surface of white blood cells (hence the name "human leukocyte antigen," although HLA class I genes (see 'Class I region' below) are also expressed on all nucleated cells) and were originally recognized to contain the genes encoding "tissue antigens" or "tissue types." The function of these genes was revealed in rodent studies, in which they were identified as the factors responsible for rejection of tissue grafts between unmatched individuals (hence the name "major histocompatibility").
The HLA region lies on the short arm of chromosome six at position 6p21.3. The classical MHC spans 3.6 megabases (Mb) and comprises more than 200 genes, including many immune system genes, but also many genes without any known immune function. The localization of genes relevant to the MHC outside the classical boundaries of this region and confirmation of extended linkage disequilibrium have since led to the proposal for an extended MHC (xMHC). This region spans 7.6 Mb and contains over 400 loci. The complete structure and gene map of the HLA region have been published [1,2].
MHC ORGANIZATION — The human leukocyte antigen (HLA) region has been subdivided into three regions: class I, class II, and class III. Each region contains numerous gene loci, including expressed genes and pseudogenes. Some HLA loci are highly polymorphic; for example, over 6500 alleles are known for HLA-B and over 2500 alleles for HLA-DRB1. (See 'Class I region' below and 'Class II region' below and 'Class III region' below.)
A detailed description of the major histocompatibility complex (MHC), including a listing of the genes in each region, a discussion of standards for nomenclature, and additional information, is available online through the European Bioinformatics Institute and the International Immunogenetics Project . A brief review of MHC organization is provided in this section.
Class I region — The class I region contains the genes encoding the "classical" class I HLA antigens: HLA-A, B, and C. Class I antigens are expressed on almost all cells of the body, except erythrocytes and trophoblasts, at varying density . The class I antigens are made up of a heavy chain (alpha chain), which combines noncovalently with the nonpolymorphic light chain (beta chain) to form the final dimerized molecule. The class I alpha chains are coded for by genes within the MHC (eg, HLA-A, HLA-B), whereas the beta chain, beta-2 microglobulin, is encoded on chromosome 15, not in the MHC.
The class I region also contains other HLA class I genes such as HLA-E, HLA-F and HLA-G; MHC class I polypeptide-related (MIC) genes; and a variety of other genes, not all of which are immune-related. (See "Immunology of the maternal-fetal interface".)
Class II region — The class II region contains the genes encoding the HLA class II molecules, HLA-DP, DQ, and DR. Class II molecules are constitutively expressed on antigen-presenting cells (APC; for example, dendritic cells, macrophages, or B cells) and can be induced during inflammation on many other cell types that normally have little or no expression.
As with the class I molecules, the class II molecules also consist of an alpha (heavy) and a beta (light) chain. However, genes within the MHC (eg, HLA-DRA and HLA-DRB) code for both chains.
●The HLA-DQ and -DP proteins each have polymorphic alpha and beta chains, which can dimerize in various combinations.
●By contrast, HLA-DR dimers all share an essentially invariant alpha chain, while the beta chain carries the extreme polymorphism characteristic of these antigens.
●To add further complexity, the number of HLA-DR genes can vary among individuals. In some cases, two HLA-DR molecules are expressed on a single haplotype. Both dimers utilize the same invariant DR alpha chain, but one uses the beta chain encoded by the HLA-DRB1 locus gene, and the other uses a beta chain encoded by the second DR locus, called DRB3, DRB4, DRB5, etc. Alleles at this latter locus are usually expressed at much lower levels on the cell surface.
As with the class I region, the class II region also contains many other genes, several of which assist in the processing and presentation of antigen. The DMA and DMB genes, for example, lie within the class II region and have structural similarities to both class I and class II genes. Analysis of mutant cells lacking DM genes reveals that these genes are critical to the process of loading peptides into class II molecules in endosomal compartments within the cell; when this process is defective, the class II molecules cannot appropriately bind processed antigen, traffic to the cell surface, or present antigen for recognition to the immune system [5,6].
In the class I antigen processing and presentation system, two other sets of genes in the MHC class II region, which are not structurally related to class I or class II genes, have been shown to play a role. LMP2 and LMP7 encode components of a proteasome complex that degrades cytoplasmic proteins into peptides that are then capable of being bound to and presented by class I molecules [6,7]. These peptide fragments are then transported into the endoplasmic reticulum by products of the transporter associated with antigen processing (TAP) genes, TAP1 and TAP2, each of which exists in several allelic forms [7,8]. Without functional TAP genes, antigenic peptides cannot reach the endoplasmic reticulum, in which they normally bind to class I molecules and subsequently move to the cell surface, again to present peptides for recognition by the immune system.
Class III region — The region between class I and class II is known as the class III region. Although this region does not contain any of the HLA genes, it does contain many genes of importance in the immune response, a few examples of which are given below. Although we mention here some examples of genetic associations within the class III region with complex diseases, these associations should be interpreted with caution. (See 'Interpretation of HLA and disease associations' below.)
Complement — Several complement components (C2, C4, and factor B) are encoded in this region; diseases like systemic lupus erythematosus (SLE) have been associated with particular null alleles at these loci, although the mechanism whereby they may be important is not understood [9,10]. (See "Inherited disorders of the complement system".)
Tumor necrosis factor — Several cytokines known to play in role in various inflammatory pathways (tumor necrosis factor-alpha [TNF], lymphotoxin alpha, and lymphotoxin beta) are also encoded in the MHC. TNF polymorphisms have been associated with autoimmune diseases such as SLE. TNF has been shown to play an important role in regulating the inflammation of rheumatoid arthritis (RA) [11-13]. (See "Pathogenesis of rheumatoid arthritis".)
Heat shock protein — A heat shock protein gene, HSP-70, encodes a chaperone molecule that may be relevant to the pathogenesis of RA .
The importance to normal and aberrant immune function of these and other genes in the MHC whose function is not yet understood is the subject of ongoing research.
INDICATIONS FOR HLA TESTING IN RHEUMATOLOGY — Due to its limited clinical value, human leukocyte antigen (HLA) typing is rarely required in routine clinical practice in rheumatology. When HLA typing is done, it can usually be limited to testing for a specific disease-associated susceptibility allele. Examples include:
●Testing for HLA-B27 in certain patients being evaluated for axial spondylarthritis or reactive arthritis (see "Diagnosis and differential diagnosis of axial spondyloarthritis (ankylosing spondylitis and nonradiographic axial spondyloarthritis) in adults", section on 'Laboratory testing' and "Reactive arthritis", section on 'Diagnostic evaluation')
●Testing for HLA-B*5801 when considering starting allopurinol for patients identifying with ethnic groups with increased frequency of this variant (see "Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout", section on 'Choosing the urate-lowering drug')
The choice of typing methods differs between settings (eg, national or local donor registries, hospitals, research institutions, etc), available resources, and required typing resolution.
METHODS OF HLA TYPING AND CHANGING NOMENCLATURE — As the technology used to genotype human leukocyte antigen (HLA) genes has evolved over the years, the nomenclature for the different alleles at individual HLA genes has evolved. Originally, before the widespread availability of sequence-based approaches, HLA typing was done by using immunological techniques to query the protein structures of the HLA gene products on cell surfaces. Different alleles code for different versions of the same protein, and immunological techniques are sensitive to some, but not all, of these differences. The original nomenclature used for different alleles referred to the specific immunological reagents used to type. As those alleles have been subdivided into different sets of alleles with gene sequencing methods, which can identify more subtle differences, the nomenclature has evolved. (See 'Nomenclature' below.)
Thus, the nomenclature has been frequently revised as advances were made in understanding HLA polymorphism. As a result, the literature is full of variations that can be frustrating to the nonspecialist: how would one know that DRB1*15:01 is a DR2 allele? A brief historical overview, using DR4 as an example, may make this clearer.
Immunological typing methods
Serology — The earliest typing was performed by serologic methods. Women are exposed to foreign, paternally derived HLA antigens during pregnancy and can develop antibodies to these antigens. Sera from numerous multiparous women were screened for those reacting reproducibly to certain HLA types. The epitopes recognized by these sera were generally shared, or "public," epitopes, which are present on a family of related alleles. Thus, a person would be labeled "DR4" if their cells reacted with sera characterized as seeing this epitope.
The presence of a second DR specificity in some individuals was also recognized. Sera were characterized that recognized these less polymorphic specificities. Most individuals positive for DR4 were also positive for the second DR specificity, DRw53. Similarly, haplotypes carrying the DR3, DR5, or DR6 specificities were normally positive for DRw52, which later was split into DRw52a, DRw52b, etc by more specific sera.
Cellular typing — It soon became clear that human T cells could distinguish more precise "splits" among some of the HLA specificities recognized by these sera. As a result, mixed lymphocyte typing was developed to allow more exact typing. A panel of reference cells was generated that were homozygous for different antigens, called homozygous typing cells (HTCs). Cells from an individual of unknown HLA type were tested for recognition by the panel cells. In this way, the DR4 "type" could be split into several subtypes, such as Dw4, Dw10, Dw14, etc.
Since both the sera from multiparous women and, especially, the HTCs were continually in need of replenishment and replacement, international histocompatibility workshops, under the auspices of the World Health Organization (WHO), were held periodically to compare and share reagents from around the world in an attempt to ensure some consistency. When consensus was reached on a new antigenic specificity, it would be given a new number with the designation "w" for "workshop." As a specificity became widely reproducible and accepted, the "w" would be dropped and a "permanent" name would be given. Thus, in one workshop, a newly identified specificity might be given the name DRw4, and in a few years it might be revised to DR4. "DR" implies a serologically based definition, and "D" means cellularly typed. In this way, one HLA specificity could be DR4,Dw4 or DR4,Dw10.
DNA-based typing — A history of HLA deoxyribonucleic acid (DNA) typing methods is provided here [15,16]. Briefly, two major developments occurred that have led to molecular-based HLA typing and that allowed a more stable nomenclature system to be developed. First, the gene structure and sequence for the HLA genes were determined, thus allowing the identification of the polymorphic regions of the genes. Second, polymerase chain reaction (PCR) technology was developed. This procedure permits amplification of specific DNA fragments that are then sufficiently abundant for analysis. PCR technology has provided the basis for development of convenient and rapid methods of HLA typing, based upon the exact nucleotide sequences of individual alleles.
Findings related to DR4 are illustrative of the historical development. Serologic typing allowed HLA-DR4 individuals to be identified. Cellular typing showed that HLA-DR4 could be split into a number of specificities (eg, DR4Dw4 or DR4Dw14), and molecular typing has been able to split these still further. Thus, Dw4 was determined to have a sequence now called DRB1*04:01, while Dw14 was found to include at least two alleles, called DRB1*04:04 and *04:08. Other alleles, such DRB1*04:09, *04:10, and *04:11, had not previously been identified. Over 400 DR4 alleles are known, and more are being discovered, particularly as HLA genes of many ethnic groups are being analyzed. A more detailed description of the nomenclature system is available online [17,18].
DNA-based typing using sequence-specific oligonucleotide probes — In the past, the most common PCR-based approach for HLA typing used sequence-specific oligonucleotide probes (SSOPs) (figure 2). This technique used a set of carefully selected primers designed to amplify the desired portion of the HLA locus. The amplified section of DNA was then probed with various SSOPs, which were designed to bind only to specific sequences that discriminate among alleles. This approach has been superseded by next-generation sequencing (NGS).
Next-generation DNA-based typing — NGS has established itself as the method of choice for HLA typing in many laboratories. NGS refers to sequencing technologies that perform sequencing of millions of short DNA fragments in parallel [19-23] (see "Next-generation DNA sequencing (NGS): Principles and clinical applications"). NGS can be applied to sequence a whole genome or a targeted region of the genome. In both cases, the large number of overlapping short individual reads generated by NGS have to be assembled with bioinformatics algorithms and mapped to the human reference genome. NGS now offers high-throughput high-resolution at low costs, thus registries have questioned whether confirmatory typing for HLA for transplantation would still be necessary .
DNA-based typing with genotyping microarray — For research purposes, HLA typing can be performed from data generated from genotyping arrays . The first step consists of determining the genotype of single nucleotide polymorphisms (SNPs) located within the HLA region by using dense genotyping microarrays. Although dense genotyping is performed, it will not determine the carriage of each nucleotide at each position, and the DNA sequence of the HLA region will therefore be incomplete and contain gaps. Databases are now available (eg, from the 1000 Genome Project) which contain the complete DNA sequence of thousands of individuals (reference panel). By comparing an incomplete DNA sequence from a given person of a given ethnicity with the reference panel of that specific ethnicity, it is therefore possible to fill in the gaps, at least partially. This process is called "imputation." The second step of genotyping-based HLA typing consists, therefore, of a computational strategy to impute four-digit HLA allele by comparing the available genotypes of SNPs over the HLA region with a large, population-specific reference panel.
HLA typing resolution and ambiguity — "Low-resolution typing" (antigen or allele family level) was defined in 2011 by the Harmonization of Histocompatibility Typing Terms Working Group as being equivalent to serologic typing, such as typing at the level of the first two digits (eg, HLA-DRB1*01, -DRB1*03, -DRB1*04, etc) .
SSOP typing is usually considered as "intermediate resolution typing" (unless several SSOP reactions are combined to reach higher resolution and unambiguously define a specific allele).
"High-resolution typing" is considered to distinguish all the alleles at a specific locus (at the four-digit level [eg, HLA-DRB1*04:01] or protein level) and can be achieved by NGS.
"Ambiguity" refers to the inability to assign a single HLA-allele present in the IMGT/HLA sequence database  to the results of HLA typing. For example, ambiguity can typically result from the use of low-resolution typing methods but also from high-resolution typing if polymorphisms are present outside the region being typed. As the number of alleles added to the IMGT/HLA sequence database increases, the problem of ambiguity also becomes more difficult and the length of ambiguity strings (ie, lists of alleles and possible genotypes consistent with the typing data) increases.
Nomenclature — The 2010 naming convention for HLA alleles (WHO Nomenclature Committee for Factors of the HLA System) assigns a unique identifier to each HLA allele [3,17,18,27]. This identifier always starts with HLA, followed by a hyphen, the name of the gene (eg, A, B, or C for class I genes), an asterisk (*), and up to four sets of digits separated by colons (ie, HLA-A*XX:XX:XX:XX) (figure 3). All alleles receive at least a four-digit code, which corresponds to the first two sets of digits. The digits after the asterisk and before the first colon describe the allele group or type, which frequently corresponds to the serologic type. The second set of digits is used to define a specific HLA protein. Therefore, a so-called "four-digit HLA type" fully and unequivocally determines the protein structure, by definition. HLA alleles whose identifiers differ in the two first sets of digits must differ in at least one nucleotide substitution that changes the amino acid sequence of the encoded HLA protein. Alleles that differ only by non-coding nucleotide substitutions within the coding sequence are distinguished by the use of the third set of digits ("six-digit HLA typing"). A fourth set of digits is occasionally used to separate further sequence polymorphisms occurring in non-coding regions (introns, 5' or 3' untranslated regions).
INTERPRETATION OF HLA AND DISEASE ASSOCIATIONS — Over one hundred diseases are associated with classical human leukocyte antigen (HLA) class I and II genes, as well as with some of the non-HLA genes in the major histocompatibility complex (MHC) region (eg, C4 complement) [1,4]. More information on the contribution of genetic variation within the MHC to the pathogenesis, susceptibility or severity of specific diseases is presented in topic reviews that discuss these aspects of the relevant disease (see appropriate topics). A more detailed discussion of genetic association studies and their interpretation is provided elsewhere. (See "Genetic association and GWAS studies: Principles and applications".)
It is reasonable to ask whether these studies are relevant to clinical practice and why there are so many studies. Part of the confusion arises from the evolution of HLA typing methods as previously described. Many early studies used serologic typing methods, so the results might describe, for example, that rheumatoid arthritis (RA) was associated with DR4.
However, DR4 encompasses many different alleles, some of which are RA-associated and some of which are not; as a result, the associations were generally weaker than when the precise alleles were subsequently investigated. Subsequent studies using DNA-based methods have consistently shown that, in White American and European populations, the alleles DRB1*04:01, *04:04, *04:05, and *04:08 are highly associated with RA. (See "HLA and other susceptibility genes in rheumatoid arthritis".)
With ankylosing spondylitis (AS), HLA-B27 is estimated to contribute only 16 to 50 percent of the total genetic risk. Of the large number of documented HLA-B27 alleles, the strongest association with AS is with HLA-B*27:05; among the Japanese and Chinese, it is with HLA-B*27:04. However, there is no association with *27:06 and *27:09. (See "Pathogenesis of spondyloarthritis".)
One promising approach in understanding disease association has been the examination of variation at individual amino acid sites, as opposed to HLA alleles. In RA, for example, investigators were able to demonstrate that much of the association of HLA-DRB1 with RA is best explained by differences in the specific amino acid that occurs at position 11 in the DRB1 molecule encoded by the different HLA-DRB1 gene alleles . Position 11 is located at the base of the DRB1 binding groove and might modulate differential binding to key antigens involved in autoimmunity.
Ethnic differences must also be taken into account. The frequency of a particular allele in one population can be very different from that in another population. As an example, DR4 was shown not to be associated with RA in Israeli Jews . However, RA-associated DR4 alleles are rarely present in this Israeli population. The most common DR4 allele is DRB1*04:02, which is not disease-associated (or, at most, weakly), thereby explaining the apparent paradox. For the same reason, the control group with which the patient group is compared must be ethnically matched for the results to be valid.
Definition of the patient group is also responsible for some differences among studies. It now seems clear, for example, that the DRB1*04:01, *04:04, *04:05, and *04:08 alleles are associated with severe forms of RA . In studies of patient groups acquired from tertiary medical center practices, associations with these alleles are much stronger than in studies in which the patients come from primary care practices, presumably because of clinical differences in patient populations. (See "HLA and other susceptibility genes in rheumatoid arthritis", section on 'HLA alleles and susceptibility to rheumatoid arthritis'.)
HLA and drug-induced hypersensitivity — The role of HLA genes in drug-induced hypersensitivity (DIH) may have more immediate clinical relevance than HLA disease associations. Numerous studies have shown a relationship between HLA class I and class II molecules and DIH ; the most well-established of such relationships include the association of HLA-B*15:02 with carbamazepine-induced Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) in Southeast Asian populations, and HLA-B*57:01 with abacavir hypersensitivity. Screening for HLA-B*57:01 prior to abacavir use has now been implemented in clinical practice and provides an excellent example of the process that needs to be followed to translate association findings into routine clinical care. (See "Abacavir hypersensitivity reaction" and "Overview of pharmacogenomics", section on 'Effect on idiosyncratic reactions'.)
Use of p values — The methods used to assess statistical significance are also critical. Most straightforward population studies of disease association use the chi-squared test to compare the frequency of a particular allele in the patient population with its frequency in a control population. If the p value is less than 0.05, the association is said to be statistically significant; this means that the chance of this association occurring by chance alone is less than 1 in 20.
However, if one is analyzing dozens of different alleles for possible association, it becomes likely that one or more alleles will result in a spurious association in which p is less than 0.05 simply because of the many comparisons being made. As a result, the p value must be corrected for the number of tests performed. In other words, if one studies 10 different DR alleles for association with a particular disease, the p value for each one must be multiplied by 10. Thus, if the uncorrected p value is 0.05, the value becomes 0.5, or statistically nonsignificant, after correction. If, on the other hand, the original p value is 0.0005, the corrected value of p = 0.005 is still significant.
Linkage disequilibrium — One must also keep in mind the concept of linkage disequilibrium when interpreting association studies. As noted above, a set of alleles are often inherited together. For example, the ancestral 8.1 haplotype spans the MHC region and includes the *01:01 allele at HLA-A, the *07:01 allele at HLA-C, the *08:01 allele at HLA-B, the *03:01 allele at HLA-DRB1, the *01:01 allele at HLA-DRB3, the *05:01 allele at HLA-DQB1, and the *02:01 allele at HLA-DQB1. As a result, all of the alleles can be seen together, and it can therefore be difficult in a genetic study to say which locus is primarily responsible for the association in such cases. An apparent association of a particular disease with, for example, HLA-DRB1*03:01 might actually be due to an association with a linked gene, such as HLA-DQB1*02:01, or even with a non-HLA gene such as a tumor necrosis factor (TNF) polymorphism.
Relative risk — Finally, one must remember that these are population studies and that the results cannot be easily transferred to an individual patient. The alleles that have been shown to be associated with disease are susceptibility alleles and identical to genes that are present among normal individuals, albeit with lower frequency. One can use the calculation of relative risk (RR) to indicate the odds that the disease will occur among individuals positive for the allele compared with individuals negative for the allele. The RR is calculated from the following formula:
RR = (the number of patients positive for the allele divided by the number of controls positive for the allele) divided by (the number of patients negative for the allele divided by the number of controls negative for the allele)
The RR for developing RA in White individuals if one carries DRB1*04:01, for example, is about 6.
HOW DO HLA ANTIGENS CONFER DISEASE SUSCEPTIBILITY? — Data regarding the relationship of human leukocyte antigen (HLA) antigens to disease susceptibility remain at the level of associations, not disease mechanisms, apart from few exceptions (eg, celiac disease). Nevertheless, HLA associations that are reproducible and robust are giving us important clues about the development of certain rheumatic diseases. A variety of models have been postulated to explain these associations functionally . These include the importance of HLA polymorphisms in:
●Shaping the T-cell repertoire during development.
●Shaping the peripheral T-cell repertoire.
●Determining which antigenic peptides are bound and therefore presented to the immune system for recognition . Celiac disease is a cardinal example, with HLA-DQ2.5 presenting antigenic gluten peptides . (See "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in adults", section on 'Genetic factors'.)
●Affecting HLA protein presentation of either foreign or self-antigenic peptides to autoreactive T cells  (eg, celiac disease).
●Generating molecular mimicry between self-antigens and either the HLA molecule itself or peptides that it recognizes.
●Influencing how infection, exogenous agents, or "molecular mimicry" may reactivate silenced T cells in autoimmune diseases .
●Affecting immune suppression and cancer development in important ways through the loss of HLA gene expression because of viral infection, somatic mutations, or other causes .
●Influencing antigen processing and presentation.
Identifying the mechanistic basis of these disease associations should lead to novel and specific treatment and even to preventive strategies.
SUMMARY AND RECOMMENDATIONS
●Overview of HLA and MHC – The human leukocyte antigen (HLA) complex is synonymous with the human major histocompatibility complex (MHC). The classical MHC describes a group of genes on chromosome 6 that encode a variety of cell surface markers, antigen-presenting molecules, and other proteins; most are involved in immune function. The extended MHC (xMHC) includes MHC-related genes outside these boundaries. (See 'Introduction' above and 'Genetic structure of the HLA region' above.)
●MHC organization – The HLA region has been subdivided into three regions: class I, class II, and class III. Each region contains numerous gene loci, including expressed genes and pseudogenes. Some HLA loci are highly polymorphic. (See 'MHC organization' above.)
●Class I region – The class I region contains the genes encoding the class I HLA antigens, which include HLA A, B, and C. Almost all cells of the body express class I antigens at varying levels. A class I antigen is a dimerized molecule made of a heavy (alpha) chain encoded within the MHC that noncovalently combines with a nonpolymorphic light (beta) chain encoded on chromosome 15. (See 'Class I region' above.)
●Class II region – The class II region contains the genes encoding the HLA class II molecules, HLA-DP, -DQ, and -DR. Class II molecules are constitutively expressed on antigen-presenting cells (APC; for example, dendritic cells, macrophages, or B cells) and can be induced during inflammation on many other cell types that normally have little or no expression. A class II molecule is made of a heavy (alpha) and light (beta) chain which are both encoded within the MHC. (See 'Class II region' above.)
●Class III region – The class III region contains many genes of importance in the immune response, including several complement components (C2, C4, and factor B); several cytokines known to play a role in inflammatory pathways, such as tumor necrosis factor (TNF)-alpha, lymphotoxin alpha, and lymphotoxin beta; and a heat shock protein gene, HSP-70, that encodes a chaperone molecule. (See 'Class III region' above.)
●Indications for HLA typing in rheumatology – HLA typing is rarely required in routine clinical practice in rheumatology. Checking for a specific disease-associated susceptibility allele may be considered for selected patients in certain clinical scenarios. (See 'Indications for HLA testing in rheumatology' above.)
●Methods of HLA typing – HLA typing is most commonly done with DNA-based typing that determines the exact nucleotide sequences of individual alleles, due to developments in (a) the determination of the gene structure and sequence for the HLA genes and (b) the development of polymerase chain reaction (PCR) technology. In particular, next-generation sequencing (NGS) offers a rapid, convenient way to obtain high-resolution HLA typing. (See 'Methods of HLA typing and changing nomenclature' above.)
●HLA allele nomenclature – Advances in HLA typing methods have led to more accurate testing and therefore revision of the nomenclature. The 2010 naming convention for HLA alleles (World Health Organization [WHO] Nomenclature Committee for Factors of the HLA System) assigns a unique identifier to each HLA allele. This identifier follows a strict syntax (HLA-A as an example): HLA-A*XX:XX:XX:XX (figure 3). All alleles receive at least a four-digit code, which fully and unequivocally determines the protein structure, by definition.
●Ordering HLA testing – Full HLA typing is required for hematopoietic stem cell transplantation. However, more commonly patients need testing for a specific allele that is associated with susceptibility to a medical condition, such as HLA-B27 in ankylosing spondylitis. Methods for doing this vary by institution. We prefer NGS.
●Interpretation of HLA and disease associations – Many diseases are associated with classical HLA I and II genes, as well as with some of the non-HLA genes in the MHC region. Results among different ethnicities may vary, and definition of the patient group may influence degrees of association. Attention should be given to the statistical methods used when interpreting association studies. (See 'Interpretation of HLA and disease associations' above.)
●Theories explaining disease association – Apart from rare examples (celiac disease), data regarding HLA molecules and disease remain at the level of associations, not disease mechanisms. Nevertheless, HLA associations that are reproducible and robust provide important clues about the development of certain disorders. A variety of models have been postulated to explain these associations functionally. (See 'How do HLA antigens confer disease susceptibility?' above.)
ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Wendy Thomson, MD, and Soumya Raychaudhuri, MD, PhD, who contributed to earlier versions of this topic review.
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