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PubMed2001

Association analysis of HLA-class II and class III gene polymorphisms in the susceptibility to mediterranean visceral leishmaniasis.

HLA-DRB1, -DQB1, TNFalpha, TNFbeta, HSP70-2 and HSP70-hom genetic polymorphisms were analyzed in 156 unrelated patients who developed mediterranean visceral leishmaniasis (MVL) due to Leishmania infantum, and 154 unrelated healthy controls, who have got asymptomatic infection with this parasite and were selected on the basis of a positive leishmanin skin test (LST). A significantly reduced frequency of HLA-DR2 was observed among MVL patients (16.1%), compared with controls (26.3%) (relative risk = 0.54; p = 0.04). HLA-DR2/DR13 as well as HLA-DQB1*0201/- genotype frequencies were significantly lower in patients vs controls (relapse rate = 0.17 and 0.46, respectively; p < 0.05). However, using Bonferroni correction, none of these associations remained significant. No association was found, between either the -308 base pair TNFalpha gene polymorphism or the NcoI polymorphism in the first intron of the TNFbeta gene and susceptibility to MVL. Analysis of PstI and NcoI polymorphisms in the coding region of HSP70-2 and HSP70-hom genes, respectively, revealed a significantly higher frequency of homozygotes for the HSP70-2/PstI negative allele, among patients (21.8%) vs controls (12.6%) (relapse rate = 1.94; p = 0.04). Again, this result was not significant after using Bonferroni correction. These results do not support association between susceptibility to MVL and the MHC class II and class III loci analyzed in this study.

Animals↗
PubMed1996

Evidence for a complex role of HLA class II genotypes in susceptibility to multiple sclerosis in Iceland.

We analyzed the association of HLA-DR and -DQ haplotypes and alleles with multiple sclerosis (MS) in 91 patients and 91 controls from Iceland using the relative predispositional effect method. The aim was to establish whether there is heterogeneity in HLA associations with MS, whether there are both predispositional and protective haplotypes, and whether sequence motifs also contribute to MS susceptibility. MS was positively associated with a DR2 haplotype (DRB5*0101-DQA1*0102-DQB1*0602), and empirical logistic analysis indicated that this haplotype is MS-associated because of a primary MS association with the DR2 allele. A DR13 haplotype (DRB1*1302-DQA1*0102-DQB1*0604) was negatively associated with MS, i.e., protective. Study of DR2-negative patients and controls confirmed this negative association and identified a second protective DR haplotype (DRB1*0701-DQA1*0201-DQB1*0201). Within these protective haplotypes in DR2-negative individuals, both DQA1 alleles and one DQB1 allele (*0604) were protective, but neither DR allele was protective, i.e., DQ loci may be more important than DR loci in encoding molecules protective against MS. Predispositional (Phe67) and protective (Ile67) DR beta sequence motifs were present in the total and DR2-negative patient and control groups. Since DQ but not DR alleles appear to be protective, DR beta Ile67 may confer additional protection against MS. Study of family-normal controls confirmed the MS association with the DR2 haplotype, and the transmission-disequilibrium test showed cosegregation and linkage of DR2 alleles and MS in families.

Alleles↗
PubMed1990

[The effects of HLA class II genes on the susceptibility to autoimmune thyroid diseases].

Immunogenetic factors such as HLA, C4, T cell receptor and immunoglobulin allotypes were investigated in 115 Japanese patients with Graves' disease. The patients showed strong positive association with HLA-A2 (R.R. = 3.45, chi 2 = 14.93, Pc less than 0.002), Bw46 (R.R. = 6.47, chi 2 = 16.25, Pc less than 0.002), Cw11 (R.R. = 4.47, chi 2 = 9.19, Pc less than 0.04) and DRw8 (R.R. = 2.22, chi 2 = 5.62, P less than 0.03, Pc: n.s.) which form one of the typical HLA haplotypes in Japanese population due to the strong linkage disequilibria. On the other hand, the patients showed negative association with HLA-B7 (R.R. = 0.15, chi 2 = 7.15), Bw52 (R.R. = 0.24, chi 2 = 7.86), DR1 (R.R. = 0.07, chi 2 = 9.71) and DQw1 (R.R. = 0.45, chi 2 = 5.62), which form HLA-B7-DR1-DQw1 and Bw52-DR2-DQw1 haplotypes. Because HLA-A2 -Bw46-Cw11-DR9 haplotype was reported to be associated with Chinese Graves' patients, and because Bw46 showed the strongest association with the Japanese patients, it was suggested that HLA class 1 antigen, Bw46, might be the primary immunogenetic factor involved in the pathogenesis of Graves' disease. Since HLA-DQw6 was reported to be associated negatively with Hashimoto's thyroiditis as same as the current observation in Graves' disease, it was suggested that HLA-DQw6 may determine the resistance to autoimmune thyroiditis. The effect of HLA-DQw6 gene, therefore, on the experimental autoimmune murine thyroiditis (EAMT) was examined, using DQw6-transgenic mouse. F1 with C3H mouse, and backcross progeny between the F1 and C3H mouse which is a susceptible strain to EAMT. The measurement of anti-thyroglobulin antibody indicated that C3H mouse, (C3H x DQ-B6) F1 and backcross progeny between the F1 and C3H were high responders to the thyroglobulin, but that B6 mouse and DQ-B6 mouse were low responders. The histological examination of the thyroid gland of these mice failed to demonstrate the significant difference in susceptibility to EAMT among these mice. These results suggested that the immune response to the thyroglobulin was controlled by H-2k haplotype and that the effect of HLA-DQw6 gene on the immune response to thyroglobulin and on the autoimmune thyroiditis was marginal.

Animals↗
PubMed2006

Associations between HLA class II alleles and type 1 diabetes mellitus in the Slovak population.

OBJECTIVES: Several associations between HLA complex and diabetes mellitus type IA were found in various groups of patients of Caucasoid population. This study was therefore prompted to be conducted in Slovak population, since any such has not yet been performed in Slovak population. METHODS: Patients suffering from DM-1A originated from all regions of Slovakia. Their age ranged from 1 to 42 years; but the criterion for including the subject to the study was the definition of diagnosis in older patients before their age of 15 (Table 1). The diagnosis was set up according to internationally accepted criteria. A total of 460 patients was typed for HLA-DQB1 alleles, among them 97 also for HLA-DQA1 and 146 for HLA-DRB1 alleles. HLA-typing was performed by a PCR-SSP method. Control group consisted of 196 (DQA), 143 (DQB1) and 130 (DRB1) unrelated blood donors aged 19-55 years old irrespective of their age or sex. The data obtained were expressed in a 2 x 2 contingency table and statistical significance was calculated by the Fisher exact test. RESULTS: Among 11 HLA-DQB1 alleles tested DOB1*0302 was the most frequent in DM-1A patients (30.33% vs. 5.59% in healthy subjects (HS), followed by DQB1*0201 (22.93% vs. 12.94%, respectively). In contrast, the frequency rate of DQB1*0301 (10.66% vs. 24.48%), DOB1*0602 (2.17% vs. 10.14%) and DQB1*0603 (2.5% vs. 8.39 %) were decreased in DM-1A patients. Out of 14 DQA1 alleles the highest occurrence rate showed DQA1*0301 (30.93% vs. 17.09) and DQA1*0501 (34.02% vs. 25.76%), while DQA1*0102 (8.76% vs. 16.58%) and DQA1*0201 (6.18 % vs. 13.51%7), respectively, were found to be the least frequent. Among 13 HLA-DRB1 alleles tested, the most common occurrence rates showed DRB1*03 (26.37% vs. 9.62%) and DRB1*04 (7.19% vs. 14.23%), while the least frequent alleles were DRB 1*15 (2.74% vs. 12.31%), DRB1*07 (7.19% vs. 14.23%), and DRB1*11 (2.74% vs. 20.38%). The alleles DQB1*0302 and DQA1*0301, respectively, were present in the same individual in all DRB1*04 positive patients, suggesting that they belong to the haplotype. Similar situation was observed with the alleles DQB1*0201, DQA1*0501, and DRB*0301, respectively, forming the second HLA haplotype so characteristic for DM1A.

Adolescent↗
PubMed1997

Binding analysis of 95 HIV gp120 peptides to HLA-DR1101 and -DR0401 evidenced many HLA-class II binding regions on gp120 and suggested several promiscuous regions.

To identify HLA-DR-binding peptides within the human immunodeficiency virus (HIV)-1 proteins. 95 overlapping synthetic peptides representing the entire sequence of gp120-LAI were screened for their capacity to bind to two HLA-DR molecules with distant sequences (DR0401 and DR1101). By using a cell surface competitive binding assay, 56 DR-binding peptides were identified, of which 35 bound to both DR1101 and DR0401. A highly significant concordance was evidenced by statistical analysis between binding of peptides to one and to the other DR molecule, suggesting a high proportion of promiscuity among gp120 peptides, even though no clear sequence pattern accounting for such promiscuity was found. DR-binding peptides were located along the entire gp120 sequence. Yet, the majority of them (42 among 56) were concentrated in seven multiagretopic regions that were arbitrarily defined as regions containing four or more overlapping continuous peptides binding to DR1011 and/or DR0401. A good correlation was found between DR-binding regions or DR-binding peptides defined in this study and promiscuous T helper gp120 epitopes previously described in seropositive individuals. All these results suggest that the identification of multiagretopic DR-binding regions may be a great help for the predicition of protein determinants that have the likelihood of being promiscuous T helper epitopes in humans.

Amino Acid Sequence↗
PubMed1990

Polymorphic DQ alpha and DQ beta interactions dictate HLA class II determinants of allo-recognition.

18 transfected cell lines were generated that expressed distinct DQ molecules related to the serologically defined HLA-DQw3 specificity. These transfectants were constructed using site-directed mutagenesis to introduce nucleotide substitutions into DQ3.2 beta cDNA, followed by retrovirus-mediated gene expression of the mutagenized genes in human B cell lines with different endogenous DQ alpha chains. The capacity of particular class II dimers to stimulate alloreactive T cell clones was investigated. T cell activation was found to be dependent on both DQ alpha and DQ beta chains. In some cases, single amino acid substitutions at codons 13, 26, 45, or 57 of the DQ beta chain were sufficient to dramatically alter T cell reactivity; T cell recognition of these substitutions, however, was strongly influenced by the alpha chain polymorphisms present in the stimulatory class II dimer. Both gain and loss of major serologic and cellular specificities associated with specific DQw3+ alleles were observed with a limited array of site-directed substitutions.

Amino Acid Sequence↗
PubMed1992

[Immunological study of the HLA class II antigen associated with birch pollen allergy].

Pollinosis is known as a hereditary disease. Recently, association of HLA antigens and pollinosis caused by several pollen allergens has been reported. Furthermore, HLA antigens are considered to have a very important role in the development of pollinosis. We performed an HLA population study and tested the lymphocyte proliferative response (LPR) to birch pollen allergens with birch pollen allergic patients and healthy control subjects. The results of the HLA population study indicated that HLA-DR9 and HLA-DQw3 correlated with the development of birth pollinosis (relative risk [R. R] = 6.37 for DR9 and R. R = 7.92 for DQw3). DNA typing revealed that serotype DQw3 in patients were DQw9 specific. Two sources of birch pollen allergens, betula pendula and betula platyla var. japonica, were used in LPR. Lymphocytes from the patients, but not from the healthy control subjects, proliferated in response to these two allergens. Anti-HLA-DR antibody, but not anti-HLA-DQ antibodies, inhibited the patients' LPR. These results suggest that the HLA-DR molecules are responsible to present the pollen specific antigen to T lymphocytes inducing LPR in the patients. Furthermore, in some of the healthy control subjects, anti HLA-DQ antibodies enhanced this LPR almost to the same level as that of the patients'. This result indicates that HLA-DQ molecules might be associated with the suppression of T cell proliferation.

HLA-DQ Antigens↗
PubMed1993

Comparison of HLA class II genes in Caucasoid, Chinese, and Japanese patients with primary Sjögren's syndrome.

To better define the genetic factors that predispose to primary Sjögren's syndrome (SS), we have used polymerase chain reaction in combination with oligonucleotide probe hybridization and DNA sequencing to analyze HLA-DRB1, -DQA1, -DQB1, and -DPB1 alleles in Caucasoid (California), Japanese (Tokyo), and Chinese (Shanghai and Beijing) SS patients. In comparison to local controls in each region, we found: 1) increased frequency of the predicted haplotype HLA-DRB1*0301-DRB3*0101-DQA1*0501-DQB1*0201 in Caucasoid patients (p < 0.001); 2) increased frequency of the predicted haplotype HLA-DRB1*0405-DRB4*0101-DQA1*0301-DQB1*0401 in Japanese patients (p < 0.05); 3) increased frequency of the predicted haplotype DRB1*0803-DQA1*0103-DQB1*0601 in Chinese patients (p < 0.05); and 4) no statistically significant association with DPB1 alleles in any group, although an increased number of Caucasoid and Japanese SS patients possessed DPB1*0301. Comparison of DNA sequences for the three disease-associated haplotypes in these ethnic groups revealed a shared region of predicted amino acids from positions 58 to 69 in the first domain of HLA-DQB1. These results extend previous studies by demonstrating that no single class II allele was associated with 1 degree SS in the different ethnic groups. However, a shared amino acid motif in the DQB1 first domain was present in each disease-associated haplotype.

Alleles↗
PubMed2001

Role for HLA class II molecules in HIV-1 suppression and cellular immunity following antiretroviral treatment.

HIV-1-infected patients treated early with combination antiretrovirals respond favorably, but not all maintain viral suppression and improved HIV-specific Th function. To understand if genetic factors contribute to this variation, we prospectively evaluated over 18 months 21 early-treated patients stratified by alleles of class II haplotypes. All seven subjects with the DRB1*13-DQB1*06 haplotype, but only 21% of other subjects, maintained virus suppression at every posttreatment measurement. Following HIV-1 p24 antigen stimulation, PBMCs from patients with this haplotype demonstrated higher mean lymphoproliferation and IFN-gamma secretion than did cells from patients with other haplotypes. Two DRB1*13-restricted Gag epitope regions were identified, a promiscuous one that bound its putative restriction element with nanomolar affinity, and another that mapped to a highly conserved region. These findings suggest that class II molecules, particularly the DRB1*13 haplotype, have an important impact on virologic and immunologic responses. The advantage of the haplotype may relate to selection of key HIV-1 Th1 epitopes in highly conserved regions with avid binding to class II molecules. Eliciting responses to the promiscuous epitope region may be beneficial in vaccine strategies.

Acquired Immunodeficiency Syndrome↗
PubMed1988

Recombination sites in the HLA class II region are haplotype dependent.

We have analyzed DNA sequence polymorphisms of DQ alpha and DQ beta chains from three haplotypes from the DRw52 family: DR5 DQw1 (FPA, GM3106), DRw6 DQw1 (CB6B, 10w9060), and DRw6 DQw3 (AMALA, 10w9064). The results indicate that the DR5 DQw1 and DRw6 DQw1 haplotypes have arisen by recombination between the DR beta 1 and DQ alpha loci. This contrasts with our previous analysis of DR4 DQ"Wa", DR3 DQ"Wa", and DR7 DQw3 haplotypes, all of which appear to have arisen by virtue of recombination between DQ alpha and DQ beta. Thus, there appear to be at least two different sites where recombination has occurred within the DR and DQ subregions. These differing patterns of recombination were interpreted in the context of the three major family groups of class II haplotypes, the DRw53, DRw52, and DR1/2 haplotype families. The data indicate that haplotypes from these family groups tend to undergo recombination at different locations. We propose that these differences in site of recombination are a reflection of differences in the molecular organization of the haplotypes belonging to each family group.

Amino Acid Sequence↗