Major Histocompatibility Complex, Class I, B

For background information on the major histocompatibility complex (MHC) and human leukocyte antigens (HLAs), see HLA-A (142800).

Mapping

Cann et al. (1983) found a restriction fragment that segregated with HLA-B8. Either the fragment carried the B8 specificity or represented another class I gene (or pseudogene) in linkage disequilibrium with HLA-B8.

Dunham et al. (1987) used pulsed-field gel electrophoresis and 'cosmid walking' to establish a molecular map of the MHC region. They concluded that the MHC spans 3,800 kb. The HLA-B locus lies about 250 kb on the telomeric side of the tumor necrosis factor genes (see TNFA; 191160).

Spies et al. (1989) found that the HLA-B gene is 210 kb from the TNFA and TNFB (153440) genes. The class III gene C2 is separated from the HLA-B gene by 600 kb.

Spies et al. (1989) concluded that a 600-kb DNA segment between C2 and HLA-B contains a minimum of 19 genes. In addition to BAT1 (142560) through BAT5 (142620), which had been localized to the vicinity of the TNFA and TNFB genes, 4 genes, called BAT6 through BAT9, were mapped near C2 within a 120-kb region that also includes a pair of heat-shock protein genes (see 140550). A large number of BssHII and SacII restriction sites, known to indicate the presence of multiple islands of CPG-rich sequences and in turn the association of expressed genes, occurred within 140 kb of DNA upstream from C2. In contrast, no gene was found within the 175-kb interval between BAT1 and HLA-B, which is relatively devoid of CPG-rich sequences.

Bronson et al. (1991) isolated yeast artificial chromosome (YAC) clones carrying the HLA-B and HLA-C (142840) genes. The loci were found to be located about 85 kb apart, each in close association with a CpG island.

Gene Function

Fleischhauer et al. (1990) demonstrated that a single amino acid difference in the HLA-B molecule is sufficient for the development of alloreactivity in vivo. They reported the case of a 29-year-old man with chronic myelogenous leukemia who received a bone marrow transplant from an unrelated female donor who was serologically HLA identical and compatible in mixed lymphocyte culture. However, they differed with respect to HLA-B44 subtypes B44.1 and B44.2, which were distinguishable by their characteristic band patterns in isoelectric-focusing (IEF) gel electrophoresis. The IEF difference, based on differences in charged amino acids, was found to be due to leucine versus aspartic acid at position 156.

Leinders-Zufall et al. (2004) showed that small peptides that serve as ligands for MHC class I molecules function also as sensory stimuli for a subset of vomeronasal sensory neurons located in the basal G-alpha-o- (139311) and V2R receptor (see 605234)-expressing zone of the vomeronasal epithelium. In behaving mice, the same peptides function as individuality signals underlying mate recognition in the context of pregnancy block. MHC peptides constitute a previously unknown family of chemosensory stimuli by which MHC genotypic diversity can influence social behavior.

Molecular Genetics

HLA Bw4 and Bw6 Epitopes

Lutz (2014) reviewed HLA Bw4 and Bw6. As a result of transplantation, blood transfusion, or pregnancy, people are immunized and produce antibodies to 'private' epitopes, which are shared by few other HLA allele products, or 'public' epitopes, which are encoded by many HLA alleles. The most prominent public epitopes are Bw4 and Bw6. Either the Bw4 or the Bw6 epitope is expressed by virtually all HLA-B molecules, and Bw4 is also found on a few HLA-A proteins. Parham et al. (2012) reported that Bw4, along with HLA-A3, HLA-A11, HLA-C1, and HLA-C2, is a KIR (e.g., KIR3DL1; 604946) ligand. Habegger de Sorrentino et al. (2013) listed 14 HLA-B alleles and 4 HLA-A alleles expressing Bw4 epitopes.

Association With Protection From Severe Malaria

By means of a large case-controlled study of malaria (see 611162) in West African children, Hill et al. (1991) showed that HLA-Bw53 and the HLA class II haplotype, DRB1*1302/DQB1*0501, (see HLA-DRB1, 142857) 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. Although the relative strength of the protection is less than that of the sickle-cell variant, the greater frequency of the DQB1 (see HLA-DQB1, 604305) polymorphism makes the net effect on resistance to malaria comparable. The findings support the hypothesis that the extraordinary polymorphism of major histocompatibility complex genes has evolved primarily through natural selection by infectious pathogens.

Hill et al. (1992) further investigated the protective association between HLA-B53 and severe malaria by sequencing peptides eluted from this molecule followed by screening of candidate epitopes from pre-erythrocytic-stage antigens of Plasmodium falciparum in biochemical and cellular assays. Among malaria-immune Africans, they found that HLA-B53-restricted cytotoxic T lymphocytes recognized a conserved nonamer peptide from liver-stage-specific antigen-1 (LSA-1), but no HLA-B53-restricted epitopes were identified in other malaria antigens. The findings of this 'reverse immunogenetic' approach indicated a possible molecular basis for this HLA-disease association and supported the candidacy of LSA-1 as a component for a malaria vaccine.

Association With HIV-1 Disease Progression

Carrington et al. (1999) reported that the extended survival of 28 to 40% of HIV-1-infected Caucasian patients who avoided AIDS for 10 or more years (see 609423) could be attributed to their being fully heterozygous at HLA class I loci, to lacking the AIDS-associated alleles B*35 and Cw*04, or to both.

Gao et al. (2001) examined subtypes of HLA-B*35 in 5 cohorts and analyzed the relation of structural differences between subtypes to the risk of progression to AIDS. Two subtypes were identified according to peptide-binding specificity: the HLA-B*35-PY group, which consists primarily of HLA-B*3501 and binds epitopes with proline in position 2 and tyrosine in position 9; and the more broadly reactive HLA-B*35-Px group, which also binds epitopes with proline in position 2 but combines several different amino acids (not including tyrosine) in position 9. The influence of HLA-B*35 in accelerating progression to AIDS was completely attributable to HLA-B*35-Px alleles, some of which differ from HLA-B*35-Py alleles by only 1 amino acid residue. Gao et al. (2001) concluded that the previously observed association of HLA-Cw*04 with progression to AIDS was due to its linkage disequilibrium with HLA-B*35-Px alleles. The fact that the association with B*35-Px was observed in both blacks and whites supported the hypothesis that these HLA-B alleles exert an effect on the immune response to HIV-1 infection.

Gao et al. (2005) found that HLA-B alleles acted during distinct intervals after HIV infection. HLA-B35-Px and HLA-B57 were associated with rate of progression to 4 outcomes: (1) progression to CD4+ T cells less than 200 (CD4 less than 200), (2) CD4 less than 200 and/or an AIDS-defining illness, (3) an AIDS-defining illness, and (4) death. HLA-B27 (142830.0001), on the other hand, was only associated with the last 3 outcomes. Protection mediated by HLA-B57 occurred early after infection, whereas HLA-B27-mediated protection instead delayed progression to an AIDS-defining illness after the decline in CD4 counts. HLA-B35-Px showed an early susceptibility effect associated with rapid progression from seroconversion to CD4 less than 200. Gao et al. (2005) proposed that the presence of the various HLA-B alleles may lead to different scenarios for viral escape from cytotoxic T-lymphocyte pressure and virus subtypes with different fitnesses.

Martin et al. (2002) reported that the activating KIR allele KIR3DS1 (604946), in combination with HLA-B alleles that encode molecules with isoleucine at position 80 (HLA-B Bw4-80Ile), is associated with delayed progression to AIDS in individuals infected with HIV-1 (604946.0001). In the absence of KIR3DS1, the HLA-B Bw4-80Ile allele was not associated with any of the AIDS outcomes measured. By contrast, in the absence of HLA-B Bw4-80Ile alleles, KIR3DS1 was significantly associated with more rapid progression to AIDS. These observations strongly suggested a model involving an epistatic interaction between the 2 loci. The strongest synergistic effect of these loci was on progression to depletion of CD4+ T cells, which suggested that a protective response of NK cells involving KIR3DS1 and its HLA class I ligands begins soon after HIV-1 infection.

Kiepiela et al. (2004) performed a comprehensive analysis of class I restricted CD8+ T cell responses against HIV-1, immune control of which depended upon virus-specific CD8+ T cell activity. In 375 HIV-1 infected study subjects from southern Africa, a significantly greater number of CD8+ T cell responses were HLA-B restricted compared to HLA-A (142800) (2.5-fold; P = 0.0033). Kiepiela et al. (2004) showed that variation in viral set point, in absolute CD4 count and, by inference, in rate of disease progression in the cohort, was strongly associated with particular HLA-B but not HLA-A allele expression (P less than 0.0001 and P = 0.91, respectively). Moreover, substantially greater selection pressure was imposed on HIV-1 by HLA-B alleles than by HLA-A (4.4-fold, P = 0.0003). Kiepiela et al. (2004) concluded that their data indicated that the principal focus of HIV-specific activity is at the HLA-B locus. Furthermore, HLA-B gene frequencies in the population are those likely to be most influenced by HIV disease, consistent with the observation that B alleles evolve more rapidly than A alleles.

By testing the effects on HIV disease progression and viral load of inhibitory KIR3DL1 subtypes in combination with HLA-B allelic groups, Martin et al. (2007) determined that highly expressed, highly inhibitory KIR3DL1*h alleles strongly enhance protection conferred by HLA-Bw4-80Ile alleles, including HLA-B*57. Martin et al. (2007) proposed that greater dependency on the expression of specific KIR3DL1-Bw4 receptor-ligand pairs for NK cell inhibition in the resting state results in more pronounced NK cell responses when the inhibition is abrogated in the face of infection.

To define host genetic effects on the outcome of a chronic viral infection, The International HIV Controllers Study (2010) performed genomewide association analysis in a multiethnic cohort of HIV-1 controllers and progressors, and analyzed the effects of individual amino acids within the classical human leukocyte antigen (HLA) proteins. The International HIV Controllers Study (2010) identified more than 300 genomewide significant SNPs within the MHC and none elsewhere. Specific amino acids in the HLA-B peptide binding groove, at positions 62, 63, 67, 70, and 97, as well as an independent HLA-C effect, explained the SNP associations and reconciled both protective and risk HLA alleles. The International HIV Controllers Study (2010) concluded that their results implicated the nature of the HLA-viral peptide interaction as the major factor modulating durable control of HIV infection.

Association With Abacavir Hypersensitivity

Abacavir is a commonly used nucleoside analog with potent antiviral activity against HIV-1. Approximately 5 to 9% of patients treated with abacavir develop a hypersensitivity reaction characterized by multisystem involvement that can be fatal in rare cases (Mallal et al., 2002; Hetherington et al., 2002). Symptoms usually appear within the first 6 weeks of treatment and include fever, rash, gastrointestinal symptoms, and lethargy or malaise. Symptoms related to the hypersensitivity reaction worsen with continued therapy and improve within 72 hours of discontinuation of abacavir. Rechallenging with abacavir after a hypersensitivity reaction typically results in recurrence of symptoms within hours. Genetic predisposition for this idiosyncratic hypersensitivity syndrome was suggested by its occurrence in a small percentage of abacavir recipients during a short period of drug exposure, and familial occurrence and decreased incidence in individuals of African American origin (Symonds et al., 2002). Consistent with these clinical observations, a strong predictive association of HLA-B*5701 (142830.0003) was demonstrated, with further evidence from recombinant haplotype mapping that the susceptibility locus or loci reside specifically with the 57.1 ancestral haplotype, identified by the haplospecific alleles HLA-B*5701 and C4A6 (see 120810) and the HLA-DRB1*0701, HLA-DQ3 combination (Mallal et al., 2002). Martin et al. (2004) reported that the combination of HLA-B*5701 and a haplotypic M493T polymorphism of HSP70-HOM (140559) is highly predictive of abacavir hypersensitivity.

Association With Ankylosing Spondylitis

In a study of 15 multiplex families with ankylosing spondylitis (106300), Rubin et al. (1992, 1994) found that 13 of 15 affected females and 46 of 49 affected males were HLA-B27 (142830.0001) positive, as compared with 22 of 43 unaffected females and 16 of 40 unaffected males. The risk of ankylosing spondylitis for homozygotes was placed at 99.5% and for heterozygotes at 43% with a sporadic risk of 0.1%. The B27 haplotype did not consistently segregate with disease in 2 families, but both families still supported linkage to the major histocompatibility complex. Identity-by-descent analyses showed a significant departure from random segregation among affected avuncular (uncle/nephew-niece) and cousin pairs. The presence of HLA-B40 in HLA-B27 positive individuals increased the risk for disease more than 3-fold, confirming previous reports. Disease susceptibility modeling suggested an autosomal dominant pattern of inheritance with penetrance of approximately 20%. In this study, which involved families from Toronto and Newfoundland, B27 alleles were detected by hybridization with sequence-specific oligonucleotide probes after amplification of genomic DNA by PCR.

Association With Age-Related Macular Degeneration

Goverdhan et al. (2005) investigated whether HLA genotypes were associated with age-related macular degeneration (ARMD; see 603075). They genotyped class I HLA-A, -B, and -Cw (see 142840) and class II DRB1 (142857) and DQB1 (604305) 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.

Association With Type I Diabetes

Nejentsev et al. (2007) used several large type I diabetes data sets 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 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 (142857). 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.

Association With Chronic Synovitis

Chronic synovitis occurs in about 10% of Indian patients with severe hemophilia (HEMA, 306700; HEMB, 306900). Ghosh et al. (2003) reported an association between the development of chronic synovitis in patients with hemophilia and the HLA-B27 allele (142830.0001). Twenty-one (64%) of 33 patients with both disorders had HLA-B27, compared to 23 (5%) of 440 with severe hemophilia without synovitis (odds ratio of 31.6). There were 3 sib pairs with hemophilia in whom only 1 sib had synovitis; all the affected sibs had the HLA-B27 allele, whereas the unaffected sibs did not. Chronic synovitis presented as swelling of the joint with heat and redness and absence of response to treatment with factor concentrate. Ghosh et al. (2003) suggested that patients with HLA-B27 may not be able to easily downregulate inflammatory mediators after bleeding in the joints, leading to chronic synovitis.

Association With Severe Cutaneous Adverse Reaction

Chung et al. (2004) studied 44 patients with carbamazepine-induced Stevens-Johnson syndrome (608579), including 5 with overlapping toxic epidermal necrolysis, in whom the clinical morphology fulfilled Roujeau's diagnostic criteria (Roujeau, 1994). Controls included 101 patients who had been treated with carbamazepine for at least 3 months without adverse reaction and 93 normal individuals. All participants were Han Chinese residing in Taiwan. One hundred percent of the patients who developed Stevens-Johnson syndrome carried the HLA-B*1502 allele (142830.0002), while only 3% of the carbamazepine-tolerant individuals and 8.6% of the normal controls carried this allele. When the carbamazepine-tolerant group was used as the control, the presence of HLA-B*1502 had a 93.6% positive predictive value for developing carbamazepine-induced Stevens-Johnson syndrome, whereas its absence had a negative prediction value of 100%.

To identify genetic markers for allopurinol-induced severe cutaneous adverse reaction (SCAR; 608579), Hung et al. (2005) genotyped 51 patients with allopurinol-SCAR and 228 controls (135 allopurinol-tolerant patients and 93 healthy individuals) for 823 SNPs in genes related to drug metabolism and immune response. All participants were unrelated Han Chinese residing in Taiwan. The HLA-B*5801 allele (142830.0004) was present in all 51 of the patients with allopurinol-SCAR, but in only 15% of allopurinol-tolerant controls and 20% of healthy controls (p = 4.7 x 10(-24) and p = 8.1 x 10(-18), respectively). Hung et al. (2005) concluded that the HLA-B*5801 allele is an important genetic risk factor for severe cutaneous adverse reactions to allopurinol in the Han Chinese population.

Association With Drug-Induced Liver Injury Due To Flucloxacillin

In a genomewide association study of 51 patients with flucloxacillin-induced liver injury and 282 controls, Daly et al. (2009) found an association with rs2395029 in the HCP5 gene (604676) in the MHC region (p = 8.7 x 10(-33)). The SNP is in complete linkage disequilibrium with HLA-B*5701 (142830.0003). Further MHC genotyping of 64 flucloxacillin-tolerant controls confirmed the association with HLA-B*5701 (odds ratio of 80.6; p = 9.0 x 10(-19)). The association was replicated in a second cohort of 23 patients. In HLA-B*5701 carriers, rs10937275 in the ST6GAL1 (109675) gene on chromosome 3q also showed genomewide significance (odds ratio of 4.1; p = 1.4 x 10(-8)).

Association With Chronic Thromboembolic Pulmonary Hypertension Without Deep Vein Thrombosis

For a discussion of a possible association between variation in the HLA-B gene and chronic thromboembolic pulmonary hypertension (CTEPH) without deep vein thrombosis, see 612862.

Association with Tuberculosis

Using direct sequencing, Salie et al. (2014) typed the HLA class I alleles from 300 South African patients with tuberculosis (TB; see 607948). The patients were recruited from suburban Cape Town, where TB prevalence is high, HIV infection is low, and the population is highly admixed. Salie et al. (2014) also genotyped the Mycobacterium tuberculosis (Mtb) strains in each patient. They found that the Beijing Mtb strain occurred more frequently in individuals with multiple disease episodes and that the HLA-B27 allele lowered the odds of having an additional episode and of developing an infection with another Mtb strain. Salie et al. (2014) showed that various HLA types were associated with strains originating from both the European American and East Asian lineages, suggesting coevolutionary events between host and pathogen.

Reviews

Cooke and Hill (2001) reviewed the genetics of susceptibility to human infectious disease. Association with class I HLA alleles and infectious disease have been demonstrated mainly with HLA-B: B8 with susceptibility to pulmonary tuberculosis, B35 with susceptibility to AIDS, B53 with resistance to severe malaria, and B57 with resistance to AIDS (see Table 3 of Cooke and Hill, 2001).

Evolution

All Amerindian groups show limited HLA polymorphism which probably reflects the small founder populations that colonized America by overland migration from Asia 11,000 to 40,000 years ago. Belich et al. (1992) found that the nucleotide sequences of HLA-B alleles from 2 culturally and linguistically distinct tribes of Southern Brazil are distinct from those in Caucasian, Oriental, and other populations. By comparison, the HLA-A (142800) and HLA-C alleles are similar. These results and those reported by Watkins et al. (1992) from studies of a tribe in Ecuador showed that a marked evolution of HLA-B occurred after humans first entered South America. New alleles were formed through recombination between preexisting alleles, not by point mutation, giving rise to distinctive diversification of HLA-B in different South American Indian tribes. Segmental exchanges of this type, even if they occur at a lower frequency than point mutations, could be useful in the development of resistance to infectious disease, for example, inasmuch as the probability of an adaptively useful variant is much higher when there is segmental exchange of already structurally valid coding sequence rather than random point mutation.

Although most of the human MHC loci are relatively stable, the HLA-B locus appears to be capable of rapid changes, especially in isolated populations. To investigate the mechanisms of HLA-B evolution, McAdam et al. (1994) compared the sequences of 19 HLA-B homologs from chimpanzees (Pan troglodytes) and bonobos (Pan paniscus) to 65 HLA-B sequences. Despite obvious similarities between chimpanzee and human alleles in exon 2, there was little conservation of exon 3 between human and the 2 chimpanzee species. This finding suggested to McAdam et al. (1994) that, unlike all other HLA loci, recombination has characterized the HLA-B locus and its homologs for over 5 million years.

By genotyping individuals from 30 distinct populations, Single et al. (2007) detected strong negative correlations between the presence of activating KIR genes and their corresponding HLA ligand groups across populations, particularly for KIR3DS1 (604946) and its putative HLA-B Bw4-80Ile ligands. Weak positive relationships, on the other hand, were found between inhibitory KIR genes and their HLA ligands. A negative correlation was observed between distance from East Africa and the frequency of activating KIR genes and their corresponding ligands. Single et al. (2007) concluded that activating, rather than inhibitory, receptor-ligand pairs show the strongest signature of coevolution between the complex KIR and HLA genetic systems.