Peptide motifs of HLA-B38 and B39 molecules.
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Amino Acid Sequence↗
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A cytotoxic human hybridoma monoclonal antibody (TrJ5) specific for HLA-B38(16) and -B39(16).
We have generated a cytotoxic IgM lambda human hybridoma mAb (TrJ5), that is specific for HLA-B38(16) and -B39(16). Among a panel of 42 HLA-defined cell lines, TrJ5 killed all five B38-positive and both B16-positive cell lines, as well as the single B39-positive cell line, but not any cell lines lacking these antigens. It could be ruled out that the TrJ5 epitope is located on the alpha 1 domain because TrJ5 did not react with cells bearing HLA-B14, the alpha 1 domain of which is identical to alpha 1 of B39. In the alpha 2 domain of B38 and B39, a unique threonine residue at position 158 (Thr-158) is not shared by any of 29 other HLA-B alleles. This suggests that Thr-158 of the alpha 2-domain helix is critical for the TrJ5 epitope.
Antibodies, Monoclonal↗
Cellular immunity and HLA.
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Autoantibodies↗
HLA-B67: a member of the HLA-B16 family that expresses the ME1 epitope.
HLA-B67 is an uncommon antigen that has been defined by serological crossreactivity with the HLA-B7 and HLA-B16 (B38 and B39) antigens. It is found at highest frequency in certain Oriental populations and has been best defined in the Japanese. Nucleotide sequencing of cDNA encoding B67 reveals the B*6701 allele to be a subtype of B39 which differs from B*39011 by substitution at residues 67-71 of the alpha 1 helix. In the region of difference B*6701 is identical in sequence to B7, B22, B27 and related molecules that express the epitope recognized by the ME1 monoclonal antibody. That the HLA-B67 molecule binds strongly to the ME1 antibody was demonstrated by immunoprecipitation and cell surface binding assays. Identical B*6701 nucleotide sequences were obtained for the B67 alleles isolated from 2 unrelated Japanese and 1 North American caucasoid.
Alleles↗
HLA-B38 and clozapine-induced agranulocytosis.
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Adult↗
HLA-B39 and the axial type of psoriatic arthritis.
The frequency distribution of HLA-B38 and HLA-B39 was studied in a group of 50 unrelated psoriatic arthritis patients. A high increase of HLA-B39 was noted in the subgroup with axial arthropathy. All B39 positive patients presented with spondylitis and/or sacroiliitis. The hypothesis is formulated that HLA-B39 may discriminate a genetic subset of psoriatic arthritis characterized by a particular susceptibility to develop axial involvement.
Arthritis↗
HLA associations in clozapine-induced agranulocytosis.
We previously reported preliminary results of association of clozapine-induced agranulocytosis (CA) with HLA-B38, DR4, DQ3 in five Ashkenazi Jewish patients and with HLA-DR2, DQ1 in four non-Jewish patients. In the present study, 31 additional patients with CA, 10 Ashkenazi Jewish, and 21 of non-Jewish ancestry, were studied. HLA alleles and haplotypes were compared among 52 patients (33 Ashkenazi Jewish, 19 non-Jewish) matched for ethnic background and clinical status. Our results show two associations and define the HLA allele markers for the Ashkenazi Jewish and non-Jewish haplotypes associated with CA. The most important markers for susceptibility for CA in Ashkenazi Jewish patients were DRB1*0402, DQB1*0302, and DQA1*0301, and in non-Jewish patients, HLA-DR*02, DQB1*0502, and DQA1*0102. HLA-DRB1*011 and DQB1*0301 were underrepresented in Ashkenazi Jewish patients when compared with controls. We hypothesize that genes of the major histocompatability complex, other than class I and class II, are responsible for CA; among them are the variants of the heat-shock proteins 70 or the tumor necrosis factor loci.
Adult↗
Presentation of human minor histocompatibility antigens by HLA-B35 and HLA-B38 molecules.
Cytotoxic T lymphocyte (CTL) clones specific for human minor histocompatibility antigens (hmHAs) were produced from a patient who had been grafted with the kidneys from his mother and two HLA-identical sisters. Of eight CTL clones generated, four recognized an hmHA (hmHA-1) expressed on cells from the mother and sister 3 (second donor); two recognized another antigen (hmHA-2) on cells from the father, sister 2 (third donor), and sister 3; and the remaining two clones recognized still another antigen (hmHA-3) on cells from the father and sister 3. Panel studies revealed that CTL recognition of hmHA-1 was restricted by HLA-B35 and that of hmHA-2 and hmHA-3 was restricted by HLA-B38. The HLA-B35 restriction of the hmHA-1-specific CTL clones was substantiated by the fact that they killed HLA-A null/HLA-B null Hmy2CIR targets transfected with HLA-B35 but not HLA-B51, -Bw52, or -Bw53 transfected Hmy2CIR targets. These data demonstrated that the five amino acids substitutions on the alpha 1 domain between HLA-B35 and -Bw53, which are associated with Bw4/Bw6 epitopes, play a critical role in the relationship of hmHA-1 to HLA-B35 molecules. The fact that the hmHA-1-specific CTLs failed to kill Hmy2CIR cells expressing HLA-B35/51 chimeric molecules composed of the alpha 1 domain of HLA-B35 and other domains of HLA-B51 indicated that eight residues on the alpha 2 domain also affect the interaction of hmHA-1 and the HLA-B35 molecules.
Antigen-Presenting Cells↗
HLA class I self peptides isolated from a T-cell leukemia reveal the allele-specific motif of HLA-B38.
Naturally-processed self peptides bound to HLA class I molecules of a T-cell leukemia (HLA-A1, A31, B38, B58) were isolated for sequence analysis. Acid-eluted peptides were subjected to reversed-phase HPLC separation and single-fraction sequencing was performed by Edman degradation. The peptides were found to be mostly nonamers and could be grouped into three distinct structural motifs. One of the peptide groups consistently displayed histidine at position 2 and a bulky hydrophobic residue at the C-terminus (XHXPXXXXY/F). The only HLA class I structure expressed by this T-cell leukemia which is consistent with the binding of peptides carrying this sequence motif is HLA-B38. A peptide binding assay confirmed this assignment. HLA-B38 is present in 10-12% of the Jewish population and is associated with several autoimmune disorders. The HLA-B38 motif may be an important tool for identifying potential T-cell epitopes involved in these diseases and for designing peptide vaccines.
Alleles↗
HLA-B38, DR4, DQw3 and clozapine-induced agranulocytosis in Jewish patients with schizophrenia.
Agranulocytosis develops in approximately 1% of patients with chronic schizophrenia treated with the atypical neuroleptic drug clozapine. Previous studies have not identified the mechanism or risk factors for this adverse reaction. Because of an observed association between Jewish ethnic background and the development of agranulocytosis in our patient sample treated with clozapine for refractory symptoms, HLA typing was performed in 31 patients (19.4% of whom had developed agranulocytosis). The HLA-B38 phenotype was found in 83% of patients who developed agranulocytosis and in 20% of clozapine-treated patients who did not develop agranulocytosis. Because B38 is part of a haplotype known to occur frequently in the Ashkenazi Jewish population, the frequencies of the combined alleles HLA-B38, DR4, and DQw3 were examined. The incidence of HLA-B38, DR4, DQw3 was significantly increased in patients with agranulocytosis (five of five patients) compared with control patients of Ashkenazi Jewish ancestry (two of 17 patients). These findings indicate that genetic factors marked by major histocompatibility complex haplotypes may be associated with the susceptibility of Jewish schizophrenic patients treated with clozapine to develop agranulocytosis. We postulate that gene products contained in the haplotype may be involved in mediating drug toxicity.
Agranulocytosis↗
Differential regulation of HLA class I genes by interferon.
Allele-specific differences in the regulation of HLA class I genes by type I interferon (IFN) were observed after transfection of eight HLA-B, -A, or -C genes into mouse L cells. HLA-B7 and -Bw64 gene expression was significantly more inducible by type I IFN than the genes coding for HLA-B27, HLA-B51, HLA-B38, HLA-B39, HLA-Cw3, and HLA-A2 antigens. Modification of the 5' end of HLA-B7 and HLA-B27 genes revealed the presence of enhancer sequences responding to IFN treatment in the 5' untranslated region of HLA-B7, but not of HLA-B27 and suggested further, independently acting enhancer elements downstream of the transcription initiation site. Comparison of 5' enhancer region sequences in correlation with type I IFN inducibility of the different HLA class I alleles indicated that the exchange of only two nucleotides in the interferon response sequence (IRS) or enhancer A region of HLA-B7 or -Bw64 could account for nonregulated promoters in all other HLA-A, -B, or -C alleles analyzed. Thus, type I IFN stimulation of HLA class I genes in mouse L cells appears to predominantly operate in most alleles by a mechanism targeted to enhancer sequences downstream of the gene's transcription initiation site.
Alleles↗
Association of polymorphisms in the HLA-B region with extended haplotypes.
Genomic probes from the HLA-B region of the major histocompatibility complex (MHC) were used to study the association of restriction fragment length polymorphisms (RFLPs) with various MHC alleles, complotypes, and extended haplotypes. The two DNA probes, M20A and R5A, were derived from previously cloned cosmids and are located 38 and 110 kilobases (kb) centromeric to HLA-B, respectively. Five different RFLP variants occurring in five different haplotypic combinations were detected within a panel of 40 homozygous-typing cells and cells from 21 families using Bst EII. In two informative families with HLA-B/DR recombinations the inheritance of the RFLP variants was consistent with their mapping between HLA-B and complotypes. The R5A/M20A haplotypic pattern 6.5 kb/3.0 kb (A) had a normal Caucasian frequency of approximately 0.43 and was found in all independent examples of the extended haplotypes [HLA-B8,SC01,DR3], [HLA-B18,F1C30,DR3], [HLA-Bw62,SC33,DR4], [HLA-B44,SC30,DR4], and [HLA-Bw47,FC91,0,DR7]. The patterns 6.9 kb/3.0 kb (B), 6.5 kb/4.7 kb (C), 1.45 kb/3.0 kb (D), and 6.9 kb/4.7 kb (E) had normal Caucasian frequencies of approximately 0.23, 0.15, 0.15, and 0.04 and were found on all independent examples of [HLA-B38,SC21,DR4], [HLA-Bw57,SC61,DR7], [HLA-B7,SC31,DR2], and [HLA-B44,FC31,DR7], respectively. Individual complotypes or HLA-B alleles which were markers of extended haplotypes showed variable associations. For example, HLA-B7 and the complotype SC31 were associated with all R5A/M20A RFLP haplotypes except haplotype E, although [HLA-B7,SC31,DR7] was associated exclusively with haplotype D. HLA-B27, not known to be part of an extended haplotype, was surprisingly exclusively associated with the 6.5 kb/4.7 kb or C haplotypic pattern in all five instances tested. These findings support the concept of regional conservation of DNA on independent examples of extended haplotypes. The results also further characterize these haplotypes.
Alleles↗
HLA-C "blank" alleles express class I gene products. Biochemical analysis of four different HLA-C "blank" polypeptides.
Monoclonal antibodies (mAbs) W6/32, HC10, and 4E were used to precipitate class I antigens from 21 selected individuals with at least one HLA-C "blank" allele. In 19 of these individuals, characteristic HLA-C banding patterns which could be precipitated by all three HLA class I mAbs were observed on one-dimensional isoelectric focusing gels--obviously the gene products of HLA-C "blank". At least four allelic HLA-C "blank" gene products with different isoelectric points could be discerned. All of them segregated with HLA-C "blank" haplotypes in informative families; two of them were associated with HLA-B51, one with HLA-B38, and one with HLA-B18. Reactivity of the HLA-C "blank" heavy chains with mAb W6/32 indicates that they are able to associate with beta-2 microglobulin, and hence are most probably expressed at the cell surface.
Alleles↗
Major histocompatibility complex haplotype studies in Ashkenazi Jewish patients with pemphigus vulgaris.
Of 26 Ashkenazi Jewish patients with pemphigus vulgaris, 24 (92.3%) carried the major histocompatibility complex (MHC) class II alleles HLA-DR4, DQw3, of which all were of the subtype DR4, DQw8. From studies of the patients and their families, haplotypes were defined. It was found that, of the patients who carried HLA-DR4, DQw8, 75% carried one or the other (and in one case, both) of two haplotypes [HLA-B38, SC21, DR4] or HLA-B35, SC31, DR4. The former is a known extended haplotype among normal Jews, with a frequency of 0.102, and the latter may also be an extended haplotype in this ethnic group, with a frequency of 0.017 among normal haplotypes from Jews. Of the remaining DR4-positive patients, all but one had a presumed D-region segment (defined as SC21, DR4, DQw8 or SC31, DR4, DQw8 with variable HLA-B) of these haplotypes. Only one patient had DR4, DQw8 without any other markers of the extended haplotypes. The number of homozygotes and heterozygotes for DR4, DQw8 was consistent with dominant but not recessive (P less than 0.01) inheritance of a class II or a class II-linked susceptibility gene for the disease. Since the disease is entirely attributable to the presence of an antibody to an intraepidermal intercellular cement substance, it is likely that the class II susceptibility gene (on [HLA-B38, SC21, DR4, DQw8], HLA-B35, SC31, DR4, DQw8, or their segments, in Jewish patients) controls the production of the antibody as a dominantly expressed immune response gene.
Alleles↗
HLA- and H-2-associated variations of intra- and extracellular magnesium content.
Erythrocyte and plasma magnesium (EMg, PMg) levels have been shown to be genetically controlled in human and mouse. The possible association of these genetic factors with the major histocompatibility complex (MHC) (HLA and H-2) was investigated. Among unrelated adult male blood donors, HLA-B35 carriers have PMg (P less than 0.01) and EMg (P less than 0.0005) levels lower than those of noncarriers, while HLA-B38 carriers exhibit a significant (P less than 0.05) increase of both PMg and EMg levels when compared to the other individuals. Furthermore, HLA identical sibs have EMg values more similar than those of HLA different sibs. In the mouse, erythrocyte (P less than 0.001), plasma (P less than 0.001), liver (P less than 0.03), and spleen (P less than 0.04) Mg contents vary significantly according to H-2, with higher values being found in H-2k than in H-2q or H-2b congenic strains. However, non-MHC genes also have an influence on erythrocyte (P less than 10(-10], plasma (P less than 10(-10], spleen (P less than 10(-5], and kidney (P less than 10(-6] Mg contents as shown by differences between H-2 identical strains, which differ by the C3H and B10 genetic backgrounds. In conclusion, genetic factors controlling intra- and extracellular Mg levels are composed of at least three components: MHC (HLA and H-2)-associated genes, non-MHC genes, and tissue factors modulating the respective importance of the first two sets of factors. The mechanisms underlying this genetic system are discussed.
Adult↗
Major histocompatibility complex haplotypes and class II genes in non-Jewish patients with pemphigus vulgaris.
Previous studies demonstrated that HLA-DR4 was markedly increased among Ashkenazi Jewish patients with pemphigus vulgaris (PV), almost entirely as the common Jewish extended haplotype [HLA-B38, SC21, DR4, DQw8] or as the haplotype HLA-B35, SC31, DR4, DQw8, and that HLA-DR4, DQw8 was distributed among patients in a manner consistent with dominant expression of a class II (D-region or D-region-linked) susceptibility gene. In the present study of major histocompatibility complex (MHC) haplotypes in 25 non-Jewish PV patients, DR4, DQw8 was found in 12 of the patients and DRw6, DQw5 was found in 15. Only 3 patients had neither. Only 1 of the DR4, DQw8 haplotypes was [HLA-B38, SC21, DR4, DQw8] and 2 were HLA-B35, SC31, DR4, DQw8; most were the presumed fragments (SC31, DR4, DQw8) or (SC21, DR4, DQw8) or DR4, DQw8 with some other complotype. Of the patients with DRw6, DQw5, all were DRw14, DQw5, and 6 had a rare Caucasian haplotype, HLA-Bw55, SB45, DRw14, DQw5. Four of 6 of these were found in patients of Italian extraction, as was the 1 normal example. The non-Jewish patients were of more Southern European extraction than our controls. This suggests that there are two major MHC susceptibility alleles in American patients with PV. The more ancient apparently arose on a haplotype in the Jews, HLA-B38(35), SC21(SC31), DR4, DQw8, and spread to other populations largely as D-region segments. The other arose in or near Italy on the haplotype HLA-Bw55, SB45, DRw14, DQw5 and has also partially fragmented so that many patients carry only DRw14, DQw5. The available data do not permit the specific localization of either the DR4, DQw8- or the DRw14, DQw5-linked susceptibility genes.
Alleles↗
Possible interaction between HLA and Ig light chain markers in susceptibility to uveitis.
We detected and analysed the Gm and Km allotype markers of Ig in 57 patients affected by uveitis, an ocular inflammation with multifactorial etiology. The aim of the present study has been to investigate the possibility that different immunogenetic factors predispose to the various forms of the disease. We found a statistically significant alteration of Km(1) allele frequency (relative risk = 2.65). That seems to predispose to anterior uveitis, especially when associated with a blank at HLA-A locus (RR = 7.83) but predispose to the posterior form when in combination with HLA-B38 (RR = 19.24). Moreover, a high frequency of Km(1)/A blank phenotypic association was noticed in uveitis with infectious aetiology (RR rising to 10.44). The Km(1) genotype may itself predispose to uveitis and its combination with different HLA alleles could enhance the susceptibility to one particular form rather than to another.
Adolescent↗
Association of DR4 with pemphigus.
HLA typing for the A, B, C, and D locus antigens was performed on 65 patients with pemphigus vulgaris and on 558 controls living in the Los Angeles area. The patients were divided into several categories. These included Jewish and non-Jewish patients, patients with only mucous membrane involvement, only skin or both mucous membrane and skin involvement, and those with a single-episode or recurrent disease. Depending on the highest titer of anti-intercellular cement substance antibody titer, the patients were categorized into those whose titers were 0-80, 160-320, and 640 or greater. A statistically increased incidence of HLA-A25, HLA-B38, and HLA-DR4 antigens was observed in patients compared to controls. This incidence was significantly higher in Jewish compared to non-Jewish patients. The correlations were insignificant in the group with an antibody titer of 0-80, but significant in those with a titer of 160-320, and even more significant in those with titers greater than 640. No significant differences were present between patients who had a single-episode or recurrent disease or in those that had only mouth or only skin involvement. In all categories tested, the association was stronger with DR4 than with A26 or B38. DR4 was present equally in B38-positive and B38-negative patients. The primary association of pemphigus vulgaris may be with the DR4 antigen, and it may be a marker for the severity of the disease.
Autoantibodies↗