HGNC Approved Gene Symbol: HLA-DRB1
Cytogenetic location: 6p21.32 Genomic coordinates (GRCh38): 6:32,578,775-32,589,848 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6p21.32 | {Multiple sclerosis, susceptibility to, 1} | 126200 | Multifactorial | 3 |
| {Sarcoidosis, susceptibility to, 1} | 181000 | Autosomal dominant | 3 |
By means of a large case-controlled study of malaria in West African children, Hill et al. (1991) showed that HLA-Bw53 and the HLA class II haplotype, DRB1*1302/DQB1*0501 (see HLA-DQB1, 604305), are independently associated with protection from severe malaria. The antigens listed are common in West Africans but rare in other racial groups. In this population, they account for as great a reduction in disease incidence as the sickle-cell hemoglobin variant. The findings support the hypothesis that the extraordinary polymorphism of major histocompatibility complex genes has evolved primarily through natural selection by infectious pathogens.
Delgado et al. (1996) compared the high-resolution typing of MHC class II loci, HLA-DRB1 and HLA-DQB1, in 21 patients with bullous pemphigoid (see 113810), 17 patients with ocular cicatricial pemphigoid (164185), and 22 patients with oral pemphigoid to a panel of 218 haplotypes of normal individuals. They found that the 3 diseases had significant association with DQB1*0301.
HLA-DRB1 allele mismatching between the donor and recipient is associated with an increased risk of acute graft-versus-host disease (GVHD; see 614395) after unrelated marrow transplantation (Petersdorf et al., 1995). Petersdorf et al. (1996) examined also the clinical importance of the HLA-DQ locus in unrelated transplantation. Linkage disequilibrium of DQA1 (146880), DQB1, and DRB1 alleles in defined populations produced predictable extended haplotypes. For Caucasian populations, most HLA-A (142800), -B (142830), and -DRB1 matched donor-recipient transplant pairs are also HLA-DQB1 and HLA-DQA1 allele matched, and thus the analysis of transplant cases with isolated HLA-DQB1 allele disparity was not possible until a large clinical experience had accumulated. With broadened racial diversity among volunteer donor registers worldwide, unusual HLA-DR/DQ associations were likely to become frequent among HLA-A, -B, and -DRB1 matched pairs. By retrospective analysis of 449 serologically matched transplants, Petersdorf et al. (1996) demonstrated that the relative risk of acute GVHD associated with a single locus HLA-DQB1 mismatch was 1.8, and the risk associated with any HLA-DQB1 and/or HLA-DRB1 mismatch was 1.6. These results provided evidence that HLA-DQ is a transplant antigen and suggested that evaluation of both HLA-DQB1 and HLA-DRB1 is necessary in selecting potential donors.
Nishi et al. (1995) found a significant increase in the frequency of the HLA-DRB1*1401 allele in Japanese patients with nonfamilial idiopathic cardiomyopathy. Hiroi et al. (1999) confirmed this association and presented a 2-locus analysis suggesting that DRB1*1401 and homozygosity for the V allele of the SOD2 gene (147460.0001) may act synergistically in controlling susceptibility to nonfamilial idiopathic cardiomyopathy.
Thursz et al. (1999) studied the distribution of MHC class II alleles in 85 patients with self-limiting hepatitis C infection versus 170 matched patients with persistent infection. They found that self-limiting and hepatitis C virus infection was associated with HLA-DRB1*1101, with an odds ratio of 2.14, and HLA-DQB1*0301, with an odds ratio of 2.22. Persistent hepatitis C virus infection was associated with HLA-DRB1*0701 (odds ratio 2.04) and HLA-DRB4*0101 (odds ratio 2.38). They confirmed their results with a second-stage study of 52 patients with self-limiting infection versus 152 with persistent infection.
MacDonald et al. (2000) examined the influence of HLA types on susceptibility to human immunodeficiency virus (HIV)-1 infection (609423) in a population of chronically and highly exposed commercial sex workers enrolled in a prospective study in Nairobi, Kenya. MHC class I serologically defined alleles HLA-A2, HLA-A28, and HLA-B18 were associated with decreased risk of HIV-1 infection in this population, while HLA-A23 was associated with increased risk. Molecular subtyping identified a supertype, which consisted of the HLA-A2 subtypes HLA-A*0202, -A*0205, and -A*0214 and an HLA-A28 subtype, HLA-A*6802, that was associated with a significantly decreased rate of HIV-1 seroconversion. Molecular typing for MHC class II alleles revealed a significantly decreased risk of HIV-1 seroconversion associated with the HLA-DRB1*0102 allele of the HLA-DRB1*01 determinant. MacDonald et al. (2000) noted that in this cohort resistance to HIV-1 infection was associated with immunologic responses to the virus but not with chemokine receptor polymorphisms (see CCR2; 601267). They proposed that the A2/6802 supertype and the DRB1*01 determinant may mediate protection against HIV-1 through the presentation and restriction of conserved epitopes; however, these alleles are neither completely necessary nor sufficient for resistance.
Vyakarnam et al. (2004) examined the effect of HLA class II polymorphisms on HIV-1 disease progression. Kaplan-Meier survival analysis showed a slower rate of CD4 (186940) T-cell decline in patients with the DRB1*15-DQB1*06 haplotype compared with those without the haplotype. In addition, DQB1*06 alleles were overrepresented in patients surviving more than 14 years. The rate of CD4 decline was not associated with expression of the DQB1 asp57 polymorphism.
Cooke and Hill (2001) summarized the evidence on associations between HLA alleles and infectious disease, implicating mainly HLA-B in class I and DRB1 and DR2 in class II. Resistance to hepatitis B, malarial anemia, hepatitis C, and typhoid fever shows association with DRB1*1302, DRB1*1352, DRB1*1101, and DRB1*04, respectively. DR2 is associated with susceptibility to pulmonary tuberculosis and leprosy; DR7 with susceptibility to hepatitis B (see Table 3 of Cooke and Hill, 2001).
Moffatt et al. (2001) examined the association between the HLA-DRB1 locus and quantitative traits underlying asthma (600807) in a population sample consisting of 1,004 individuals from 230 families from the rural Australian town of Busselton. They found no associations to the categorical phenotype of asthma or to the quantitative traits of blood eosinophil counts and bronchial hyperresponsiveness. The authors detected strong associations between HLA-DRB1 alleles and the total serum immunoglobin E (IgE; 147050) concentration and IgE titers against individual antigens. Alleles associated with elevations of the total serum IgE were different from those associated with specific allergens, suggesting separate genetic controls.
Lang et al. (2002) examined the association of multiple sclerosis (MS; 126200) with HLA-DRB1*1501 and -DRB5*0101 (604776) polymorphisms by determining the antigen-recognition profile of an MS patient with a relapsing-remitting disease course. A T-cell receptor (TCR) from the patient recognized both DRB1*1501-restricted myelin basic protein (MBP; 159430) (residues 85 to 99) and DRB5*0101-restricted Epstein-Barr virus DNA polymerase peptide. The crystal structure of both DRB-antigen complexes revealed a marked degree of structural equivalence at the surface presented for TCR recognition, with 4 identical TCR-peptide contacts. Lang et al. (2002) concluded that these similarities support the concept of molecular mimicry (in structural terms, a similarity of charge distribution) involving HLA molecules and suggested that these structural details may explain the preponderance of MHC class II associations in HLA-associated diseases. They noted the findings of Madsen et al. (1999) with transgenic mice, which also showed that MBP(85 to 99) associated with HLA-DRB1*1501 was involved in the development of an MS-like disease.
Oksenberg et al. (2004) noted that an association with the HLA-DRB1*1501-DQB1*0602 haplotype has been repeatedly demonstrated in high-risk (northern European) populations. African populations are characterized by greater haplotypic diversity and distinct patterns of linkage disequilibrium compared with northern Europeans. To better localize the HLA gene responsible for MS susceptibility, Oksenberg et al. (2004) performed case-control and family-based association studies for these 2 loci in a large and well-characterized African American dataset. A selective association with HLA-DRB1*15 was revealed, indicating a primary role for the DRB1 locus in MS independent of DQB1*0602. A substantial proportion of the susceptibility chromosomes from African American patients with MS displayed haplotypes consistent with an African origin.
In a multistage genomewide association study involving a total of 1,540 MS family trios, 2,322 case subjects, and 5,418 control subjects, the International Multiple Sclerosis Genetics Consortium (2007) used the HLA-DRA A/G SNP rs3135388 as a proxy for the DRB1*1501 allele (complete concordance between the rs3135388 A allele and DRB1*1501 was found in 2730 of 2757 subjects in whom data were available) and confirmed the association with MS (p = 8.94 X 10(-81); OR, 1.99).
Rheumatoid arthritis (RA; 180300) is an inflammatory disease with a complex genetic component. An association between RA and the HLA complex has been observed in many different populations, and most studies have focused on the role of HLA-DRB1 in disease susceptibility. Using 54 markers distributed across the entire HLA complex, Jawaheer et al. (2002) performed an extensive haplotype analysis in a set of 469 multiplex families with RA. The results showed that, in addition to associations with the DRB1 alleles, at least 2 additional genetic effects are present within the major histocompatibility complex. One of these lies within a 497-kb region in the central portion of the HLA complex, an interval that excludes DRB1. Thus, the data indicated that HLA associations with RA are complex and cannot be completely explained by the DRB1 locus.
Three major risk factors reproducibly identified in rheumatoid arthritis are genetic variations in the HLA-DRB1 locus and protein tyrosine phosphatase (PTPN22; 600716) gene and 1 environmental risk factor, smoking (Padyukov et al., 2004). With regard to all 3 risk factors, the major effects were seen in 1 subset of RA, characterized by the presence of antibodies against citrullinated proteins (anti-CCB), but not in the subset of RA in which these antibodies were not detected. Kallberg et al. (2007) undertook studies to compare the interaction of 2 major genetic risk factors of RA, the HLA-DRB1 shared epitope (SE) alleles and the PTPN22 R620W allele (600716.0001), in 3 large case-control studies, 1 Swedish, 1 North American, and 1 Dutch (in total, 1,977 cases and 2,405 controls). The Swedish study was also used to analyze interactions between smoking in the 2 genes. No interaction was seen between smoking and PTPN22 R620W. A new pattern of interactions was described between the 2 major known genetic risk factors and the major environmental risk factor, smoking, concerning the risk of developing anti-CCB-positive RA. The data extended the basis for a pathogenetic hypothesis for RA involving genetic and environmental factors. Kallberg et al. (2007) cited Hill et al. (2003) as proposing an etiologic hypothesis that may explain the strong interaction between smoking and HLA-DRB1 SE alleles; the proposition was that smoking may contribute to citrullination of proteins in the lung and that immune activation against such posttranslationally modified proteins may occur preferentially in individuals carrying HLA-DRB1 SE alleles, since citrullination may specifically increase the affinity between a protein and an SE-containing HLA-DR-beta chain. This hypothesis was made even more attractive by the demonstration by Lundberg et al. (2005) that citrullination of self-antigens may make them more immunogenic and arthritogenic. Furthermore, transfer of antibodies to citrullinated fibrinogen (see 134820) enhances the development of antibody-transferred arthritis in mice (Hill et al., 2003).
Citrullination is a physiologic process in which arginine is converted to citrulline by peptidyl arginine deiminases (see 605347). Scally et al. (2013) showed how epitopes of citrullinated aggrecan (ACAN; 155760) and vimentin (VIM; 193060) bound to HLA-DRB1*01/04. Citrulline was accommodated within the electropositive P4 pocket of HLA-DRB1*01/04, whereas the electronegative P4 pocket of the RA-resistant HLA-DRB1*02 allomorph interacted with arginine- or citrulline-containing epitopes. Peptide elution studies revealed that arginine-containing peptides were present in P4 of HLA-DRB1*02, but not HLA-DRB1*01/04. As a consequence of citrullination, VIM protease susceptibility was altered and self-epitopes were generated and presented to T cells in healthy individuals, as well as in RA-affected HLA-DRB1*01-positive individuals, in whom citrullinated VIM- and ACAN-specific circulating CD4+ T cells were found. Autoreactive T-cell numbers in RA patients were correlated with disease activity, and regulatory T cells were deficient compared with those in healthy individuals. Scally et al. (2013) concluded that citrullination, the HLA-DRB1 locus, and T-cell autoreactivity in RA are associated.
Kotb et al. (2002) reported that the immunogenetics of the host influence the outcome of invasive streptococcal infection (see 607395). They found that specific HLA class II haplotypes conferred strong protection from severe systemic disease, whereas others increased the risk of severe disease. Patients with the DRB1*1501/DQB1*0602 haplotype mounted significantly reduced responses and were less likely to develop severe systemic disease (p less than 0.0001). Kotb et al. (2002) proposed that class II HLA allelic variation contributes to differences in the severity of invasive streptococcal infections through the ability of distinct HLA alleles/haplotypes to regulate cytokine responses triggered by streptococcal superantigens.
Moffatt et al. (2003) investigated the effects of the HLA-DRB1 locus on asthma and its intermediate phenotypes in Aboriginal people from the Kimberly region of Australia, who were suffering from endemic hookworm infection at the time of the study. Recognizable correlates of allergic asthma were present in the subjects, including skin test positivity to house dust mite (HDM), specific IgE responses to HDM, and elevated total serum IgE. HLA-DRB1 alleles did not predict the presence of asthma, but multiallelic tests of association showed that the locus accounted for 33% of the variance of the total serum IgE concentration and 17% of the variance of the specific IgE titers to HDM. These effects of the MHC on IgE levels were an order of magnitude greater than that seen in Caucasians, which is consistent with the hypothesis that the genetic predisposition to allergic disease may be driven by adaptation to helminth infection. The authors further suggested that parasitism per se is not protective against asthma.
In a study of 149 patients fulfilling the American-European Consensus Group criteria for Sjogren syndrome (270150) and 222 controls, Gottenberg et al. (2003) confirmed the association of Sjogren syndrome with HLA alleles DRB1*03 and DQB1*02 (see HLA-DQB1; 604305). They found, however, that the association was restricted to patients with anti-SSA (see 109092 and 600063) and/or anti-SSB (see 109090) antibodies. The absence of a difference in disease severity between patients with anti-SSA and those with anti-SSA and anti-SSB antibodies, together with a high frequency of HLA-DRB1*03 in the latter group, suggested to the authors that HLA alleles predispose to autoantibody secretion but are not associated with clinical outcome.
Goverdhan et al. (2005) investigated whether HLA genotypes were associated with age-related macular degeneration (ARMD; see 603075). They genotyped class I HLA-A (142800), -B (142830), -Cw (see 142840) and class II DRB1 and DQB1 in 200 patients with ARMD, as well as in controls. Allele Cw*0701 correlated positively with ARMD, whereas alleles B*4001 and DRB1*1301 were negatively associated. These HLA associations were independent of any linkage disequilibrium. Goverdhan et al. (2005) concluded that HLA polymorphisms influenced the development of ARMD and proposed modulation of choroidal immune function as a possible mechanism for this effect.
Chiaroni et al. (2006) analyzed allelic variations at pocket P4 of the HLA-DRB1 complex in 54 French patients with Kell blood group (see 110900) immunization. All patients had anti-K antibodies and K-negative phenotype. The frequency of HLA-DRB1*11 was significantly higher in patients (57%) compared to controls (28%), whereas HLA-DRB1*07 was less frequent in patients (4%) compared to controls (27%). Further analysis showed that the frequency of the epitope formed by residues S13, D70, and A74, common to both DRB1*11 and DRB1*13, was significantly higher in patients (83%) compared to controls (52%), yielding an odds ratio of 4.5. Chiaroni et al. (2006) concluded that the development of K immunization after exposure to K-positive blood, which occurs approximately 9% of the time, is due in part to genetic variation at the HLA-DRB1 locus, which is involved in K peptide presentation.
Booth et al. (2006) examined HLA class II associations between alleles of HLA-DQB1, -DQA1, and -DRB1 loci and levels of IgE, IgG1, and IgG4 isotypes after praziquantel treatment of Schistosoma mansoni (schisto) infection. Only DRB1*13 was associated with significantly higher schisto-specific IgE and IgG4 responses. HLA-DRB1*13 carriers also had lower reinfection rates 1 to 6 years after treatment. Booth et al. (2006) concluded that genetic background has a prominent influence on the posttreatment Th2 immune response to S. mansoni antigens, as well as on reinfection levels.
Nejentsev et al. (2007) used several large type I diabetes datasets to analyze a combined total of 1,729 polymorphisms, and applied statistical methods--recursive partitioning and regression--to pinpoint disease susceptibility to the MHC class I genes HLA-B (142830) and HLA-A (142800) (risk ratios greater than 1.5; P(combined) = 2.01 x 10(-19) and 2.35 x 10(-13), respectively) in addition to the established associations of the MHC class II genes HLA-DQB1 (604305) and HLA-DRB1. Nejentsev et al. (2007) suggested that other loci with smaller and/or rarer effects might also be involved, but to find these future searches must take into account both the HLA class II and class I genes and use even larger samples. Taken together with previous studies, Nejentsev et al. (2007) concluded that MHC class I-mediated events, principally involving HLA-B*39, contribute to the etiology of type I diabetes.
Hoffmann et al. (2008) used high-resolution HLA class I and II typing to identify 2 HLA class II alleles associated with the development of antibodies to interferon-B (147640) in the treatment of multiple sclerosis (MS; 126200). In 2 independent continuous and binary-trait association studies, HLA-DRB1*0401 and HLA-DRB1*0408 (odds ratio: 5.15), but not other HLA alleles, were strongly associated with the development of binding and neutralizing antibodies to interferon-B. The associated HLA-DRB1*04 alleles differ from nonassociated HLA-DRB1*04 alleles by a glycine-to-valine substitution in position 86 (G86V) of the epitope-binding alpha-helix of the HLA class II molecule. The peptide-binding motif of HLA-DRB1*0401 and *0408 might promote binding and presentation of an immunogenic peptide, which may eventually break T cell tolerance and facilitate antibody development to interferon-beta. In summary, Hoffmann et al. (2008) identified genetic factors determining the immunogenicity of interferon-beta, a protein-based disease-modifying agent for the treatment of MS.
Secondary recurrent miscarriage (SRM) is defined as a minimum of 3 consecutive miscarriages subsequent to the birth of a child. Among SRM patients, a boy prior to a series of miscarriages is significantly more common than a girl and also reduces the chance of a subsequent live birth. Healthy females, pregnant with a boy, generate immune responses against male-specific minor histocompatibility (HY) antigens. Nielsen et al. (2009) genotyped HLA-A, -B, -DRB1, DRB3, -DRB4, -DRB5, and DQB1 in 358 SRM patients and in 203 of their children born prior to the miscarriages. The subsequent chance of live birth in women with boys prior to the miscarriages compared to women with girls was lower in women with with either the HLA-DRB1*15 or HLA-DQB1*0501/0502 allele (OR = 0.17, p = 0.0001). One HY-restricting HLA class II allele in women with first-born boys significantly reduced the chance of a live birth (OR = 0.46, p = 0.02). Two HY-restricting HLA class II alleles further reduced this chance (OR = 0.21, p = 0.02). HY-restricting HLA class II did not reduce the chance of a live birth in SRM women with first-born girls. Nielsen et al. (2009) proposed an aberrant maternal immune reaction against fetal HY-antigens in SRM.
Ramagopalan et al. (2009) identified a vitamin D response element (VDRE) in the promoter region of HLA-DRB1. Sequencing of this promoter in HLA-DRB1 homozygotes showed absolute conservation of this putative VDRE on HLA-DRB1*15 haplotypes in 322 MS-affected and unaffected individuals. In contrast, there was striking variation among 168 individuals with non-MS-associated haplotypes. Electrophoretic mobility shift assays showed specific recruitment of the vitamin D receptor to the VDRE in the HLA-DRB1*15 promoter, confirmed by chromatin immunoprecipitation experiments using lymphoblastoid cells homozygous for HLA-DRB1*15. Transient transfection of the promoter in B cells showed increased expression on stimulation with 1,25-dihydroxyvitamin D3 that was lost both on deletion of the VDRE. This study further implicated vitamin D as a strong environmental candidate in MS by demonstrating direct functional interaction with the major locus determining genetic susceptibility. These findings support a connection between the main epidemiologic and genetic features of this disease.
Li et al. (2009) analyzed antibody responses to hepatitis B vaccination and HLA-DRB1, -DQA1, and -DQB1 alleles and haplotypes in 255 HIV-1-seropositive and 80 HIV-1-seronegative youth. Collectively, DRB1*03 and DRB1*0701 were found in 54% of nonresponders, 41% of medium responders, and 28% of high responders. DRB1*08 was positively associated with the responder phenotype, mostly due to DRB1*0804. Li et al. (2009) noted that the immunogenetic relationships were independent of HIV-1 infection status and immunodeficiency and that there were no associations with SNPs in the noncoding regions of the 3 HLA class II genes.
Karp et al. (2010) described an approach to genetic association analyses with proteins by considering biologically relevant smaller sequence features and their variant types (SFVT). In a cohort of 1,300 systemic sclerosis (181750) patients and 1,000 controls, SFVT analysis showed that a combination of sequence features implicating specific amino acid residues in peptide binding pockets 4 (26F_28E) and 7 (67F_71R) of HLA-DRB1 explained much of the molecular determinant of risk for the HLA-DRB1*1104 allele and systemic sclerosis.
In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, the International Multiple Sclerosis Genetics Consortium and Wellcome Trust Case Control Consortium 2 (2011) replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci for multiple sclerosis. Within the MHC the International Multiple Sclerosis Genetics Consortium and Wellcome Trust Case Control Consortium 2 (2011) refined the identity of the HLA-DRB1 risk alleles as DRB1*15:01 (142857.0002) and DRB1*13:03, and confirmed that variation in the HLA-A gene (142800) underlies the independent protective effect attributable to the class I region. Immunologically relevant genes were significantly overrepresented among those mapping close to identified loci and particularly implicated T helper cell differentiation in the pathogenesis of multiple sclerosis.
Foo et al. (2013) conducted imputation, HLA typing, and sequencing in 3 independent populations for a total of 689 cases of follicular lymphoma (613024) and 2,446 controls. Foo et al. (2013) identified a hexa-allelic amino acid polymorphism at position 13 in exon 2 of the HLA-DR beta chain that showed the strongest association with follicular lymphoma within the major histocompatibility complex (MHC) region (multiallelic p = 2.3 x 10(-15)). Out of 6 possible amino acids that occurred at that position within the population, Foo et al. (2013) classified 2 as high risk (tyr and phe), 2 as low risk (ser and arg), and 2 as moderate risk (his and gly). There was a 4.2-fold difference in risk (95% CI, 2.9-6.1) between subjects carrying 2 alleles encoding high-risk amino acids and those carrying 2 alleles encoding low-risk amino acids (p = 1.01 x 10(-14)). This coding variant might explain the complex SNP associations identified by GWAS studies and suggests a common HLA-DR antigen-driven mechanism for the pathogenesis of follicular lymphoma and rheumatoid arthritis (180300) .
Using ELISA to assess IgG responses to 14 pathogenic viruses in 2,363 immunocompetent adults of European ancestry, followed by genomewide SNP genotyping, Hammer et al. (2015) found significant associations between class II HLA variation, particularly HLA-DRB1 haplotypes, and responsiveness to influenza A virus, Epstein-Barr virus, JC polyomavirus, and Merkel cell polyomavirus. Hammer et al. (2015) proposed that small differences in the capacity of HLA-DRB1 proteins to bind specific viral peptides and present them efficiently to CD4 T cells can have a measurable impact on antibody production.
For a discussion of a possible association between the HLA-DRB1*0701 allele and susceptibility to podoconiosis, see 614590.
Dunstan et al. (2014) conducted a genomewide association study of 432 individuals with blood culture-confirmed enteric fever and 2,011 controls from Vietnam and observed strong association at rs7765379 (OR for the minor allele = 0.18, p = 4.5 x 10(-10)). They replicated this association in 595 enteric fever cases and 386 controls from Nepal and also in a second independent collection of 151 cases and 668 controls from Vietnam. Imputation-based fine mapping across the extended MHC region showed that the classical HLA-DRB1*04:05 allele (OR = 0.14, p = 2.60 x 10(-11)) could entirely explain the association at rs7765379, thus implicating HLA-DRB1 as a major contributor to resistance against enteric fever, presumably through antigen presentation.
Class II molecules of the major histocompatibility complex (MHC) are cell surface alpha/beta heterodimeric proteins whose function is to present processed foreign antigens to T cells. Several class II beta-chain loci are exceedingly polymorphic. The ratio of replacement to silent nucleotide substitutions among these sequences is relatively high, suggesting that these loci are under strong positive selection. Although polymorphism may have arisen de novo in various species, polymorphic regions from class II alleles of different species of mice, and from chimpanzees and humans, appear to be related, as do alleles at the MHC class I locus between chimpanzees and humans. The observations that allelic polymorphism predated divergence of these species at least 3 to 10 million years ago gave rise to the 'trans-species' hypothesis of MHC evolution. The high degree of polymorphism in class II loci is a feature unique to MHC. Most of the beta-chain polymorphism is located in 'hypervariable' regions (HVRs). HVR amino acid sequence similarity between distantly related species is observed. Lundberg and McDevitt (1992) used a Monte-Carlo statistic to show that shared HVR polymorphism between beta-chain genes of humans and mice represent direct descent of ancestral sequences rather than convergent evolution. Furthermore, half the sequence polymorphism seen in class II beta-chain genes of mice persists in evolution and is encoded by the same DNA sequence in humans. No evidence for increased mutation rate within the HVR was found. Lundberg and McDevitt (1992) postulated that the HVR is a genetic unit of recombination, with selection for HVR sequences and combinations of HVRs constrained by functional considerations.
Polymorphism at the DRB1 locus, represented by 58 known alleles in humans, has existed for at least 30 million years and is shared by humans, apes, and other primates. Ayala et al. (1994) pointed out that the coalescence theory of population genetics leads to the conclusion that DRB1 polymorphism requires that the population ancestral to modern humans has maintained a mean effective size of 100,000 individuals over the 30 Myr that this polymorphism has persisted. Ayala et al. (1994) explored the possibility of occasional population bottlenecks and concluded that the ancestral population could not have at any time consisted of fewer than several thousand individuals. The MHC polymorphisms exclude the theory claiming, on the basis of mitochondrial DNA polymorphisms, that a constriction down to one or a few women occurred in Africa at the transition from archaic to anatomically modern humans some 200,000 years ago. The data were considered consistent with, but not providing specific support for, the claim that human populations throughout the world were at that time replaced by populations migrating from Africa. The MHC and other molecular polymorphisms are consistent with a 'multiregional' theory of Pleistocene human evolution that proposes regional continuity of human populations since the time of migrations of Homo erectus to the present, with distinctive regional selective pressures and occasional migrations between populations.
The HLA class I and class II loci are the most highly polymorphic coding regions in the human genome. Based on the similarity of the coding sequences of alleles between species, HLA polymorphism had been thought to be ancient and to predate separation of human (Homo) and chimpanzee (Pan), 4 to 7.4 Myr ago. Analysis of intron sequences, however, provided support for a more recent origin and for rapid generation of alleles at the HLA class II DRB1 locus. Bergstrom et al. (1998) divided the human DRB1 alleles into groups (allelic lineages); most of the lineages had diverged from each other before the separation of Homo and Pan. Alleles within such a lineage, however, appeared to be, on average, 250,000 years old, implying that greater than 90% of the more than 135 contemporary human DRB1 alleles have been generated after the separation of Homo and Pan. The coalescence time of alleles within allelic lineages indicated that the effective population size for early hominids (over the last 1 Myr) was approximately 10,000 individuals, similar to estimates based on other nuclear loci and mitochondrial DNA. With a single exception, the genetic mechanisms (gene conversion and point mutation) that have diversified the exon-2 sequences do not appear to extend into the adjacent intron sequences. The part of exon 2 encoding the beta-sheet evolves in concert with the surrounding introns, while the alpha-helix appears to have been subjected to gene conversion-like events, suggesting that such exchange events are highly localized and occur over extremely short sequence tracts.
By analyzing sequences of 15 full-length HLA-DRB1 alleles, in addition to 49 complete coding sequences and 322 exon-2 sequences, von Salome et al. (2007) found that the diversity at synonymous sites was similar to intron diversity. With the exception of exon 2, both coding and noncoding diversity suggested a recent origin for most of the more than 400 HLA-DRB1 alleles since divergence from the DRB1*03 lineage common to humans and apes. Antigen-binding sites appeared to have a more ancient origin. Von Salome et al. (2007) concluded that HLA-DRB1 has undergone a relatively rapid generation of novel alleles by gene conversion-like events.
Teshima et al. (2002) transferred bone marrow into irradiated wildtype and MHC class II-deficient recipient mice. Donors and recipients differed at only a single class II allele. The class II-knockout recipient chimeras, therefore, expressed class II only on hemopoietic cells or antigen-presenting cells (APCs). CD4+ T lymphocytes expressing CD25 (147730) and CD49 expanded in the wildtype but not the class II-null mice. Wildtype mice also had increased serum Ifng (147570). All wildtype but no knockout mice succumbed to acute graft versus-host disease (GVHD) by day 7 after transplant. Other experiments showed that host APC, but not epithelial cell, class II alloantigens are sufficient to induce CD4+ T cell expansion, cytokine secretion, and lethal GVHD. Furthermore, blockade of inflammatory cytokines TNF (191160) and IL1B (147720) can block the effector phase of acute GVHD without blocking CD4 T cell expansion. Similarly, in mice lacking class I expression, host APC alloantigen expression is required for the development of CD8+ T lymphocyte-mediated GVHD. Fatal disease onset, but not target organ damage in surviving mice, is reduced in mice lacking epithelial cell class I expression. Teshima et al. (2002) concluded that host APCs are sufficient in both activation and effector phases of acute GVHD and that alloantigen expression on target cells is not always required, particularly for CD4-mediated disease. They proposed that blockade of inflammatory cytokines could be beneficial in clinical bone marrow transplantation by preventing the toxicity of GVHD while allowing beneficial graft-versus-leukemia effects.
Rossman et al. (2003) concluded that HLA-DRB1 alleles were differentially distributed between cases of sarcoidosis (181000) and case-matched controls. The HLA-DRB1*1101 allele was associated (P less than 0.01) with sarcoidosis in blacks and whites and had a population attributable risk of 16% in blacks and 9% in whites. Phenylalanine-47 (F47) of the HLA-DRB1 allele was the amino acid residue most associated with sarcoidosis and independently associated with sarcoidosis in whites; it was present on the 3 alleles most associated with sarcoidosis (HLA-DRB1*1101, HLA-DRB1*1201, and HLA-DRB1*1501). F47 may be the most important amino acid residue associated with peptide binding in sarcoidosis. Rossman et al. (2003) quoted evidence that amino acid residues at position 47 would affect pocket 7, and mutations of the amino acid residues of pocket 7 peptides affect T-cell recognition.
The International Multiple Sclerosis Genetics Consortium and Wellcome Trust Case Control Consortium 2 (2011) performed a collaborative GWAS involving 9,772 multiple sclerosis (126200) cases of European descent collected by 23 research groups working within 15 different countries and identified the DRB1*1501 allele as a risk allele with consistent effect across populations (p = 1 x 10(-320)) and a combined odds ratio of 3.1 in individuals of European ancestry.
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