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PubMed1998

Associations between HLA class II alleles in a North Indian population.

The HLA DR and DQ class II genes are in strong linkage disequilibrium and recombinaton is quite rare. However, many different DR-DQ haplotypes appear to have developed during evolution, giving rise to a variety of combinations with different distributions in populations. In the present report, 138 subjects from North India were studied for the alleles of HLA-DRB1, DRB3, DRB5, DQB1 and DQA1 loci using PCR-oligotyping. The probable haplotypes were constructed based on two-locus associations observed in this population. A frequent haplotype in this population, DRB1*1501-DRB5*0101-DQA1*0103-DQB1*0601, has been reported very rarely in other ethnic groups. Other DR2 haplotypes, like DRB1*1502-DRB5*0102-DQA1*0103-DQB1*0601, earlier reported in Caucasians, Chinese and Latin Americans, and DRB1*1502-DRB5*0102-DQA1*0103-DQB1*0503, earlier reported in Gypsies, were also observed. A relatively rare haplotype in Caucasians which was earlier reported in Gypsies from the Czech Republic, DRB1*1404-DRB3*0202-DQA1*0101-DQB1*0503, was observed frequently in Indians, suggesting the probable migration of Gypsies from India. The results suggest that the North Indian population contains a mixture of Caucasoid, Black and Chinese genes. Similarities with Gypsies and South-East Asian populations suggest the role of ancient migrations from India.

Alleles↗
PubMed1994

Molecular characterization of HLA class II genes in celiac disease patients of Latin American Caucasian origin.

In the present study, the polymorphic domain of HLA class II genes present in a pediatric population of Argentinian celiac disease patients was analyzed by hybridization to sequence-specific oligonucleotides and DNA sequencing. Sixteen out of 16 DR5/7 heterozygous patients bore the DQA1*0501 and DQB1*0201 alleles implicated in the DQ2 risk specificity. The second exon of DQA1, DQB1 and DRB1 genes from 2 DR5/7 patients was characterized by DNA sequencing. The following alleles were found in both patients: DRB1*1101 and DRB1*0701; DQB1*0301 and DQB1*0201; DQA1*0501 and DQA1*0201. Previous serological analysis in this population had shown the presence of DQ2 in 95% of the patients (40% in controls) and a negative association with DQ1 haplotypes, suggesting the presence of other "permissive" or neutral alleles. The following HLA-DQB1 alleles, besides DQB1*0201, were identified in 31 CD patients: DQB1*0301, 0302, 0401 and 0402. All these alleles share a common pattern of residues between positions 84 and 90, and distinct from that present in DQ1-related alleles.

Alleles↗
PubMed2004

HLA class II genotype and factor VIII inhibitors in mild haemophilia A patients with an Arg593 to Cys mutation.

We evaluated inhibitor formation in a group of patients with mild haemophilia A caused by an Arg593 to Cys mutation. A remarkably high cumulative inhibitor incidence of 14% over 22 years was observed. Three of 49 patients developed transient, low-titre inhibitors, which remained below 2.0 BU mL(-1). Four patients with an Arg593 to Cys mutation developed high-titre inhibitors (>5.0 BU mL(-1)). Three of these patients have been described previously. In this study, we characterized inhibitory antibodies in a fourth patient with high-titre inhibitors. Epitope mapping studies revealed that antibodies were predominantly directed to the A2 domain of factor VIII. We addressed the role of human leucocyte antigen (HLA) class II alleles in inhibitor development in patients with an Arg593 to Cys mutation by HLA genotyping. In the group of inhibitor patients raised frequencies of HLA-DRB1*01 and HLA-DQB1*05 were observed that did not reached statistical significance. Our data suggest that inhibitor development in mild haemophilia A patients with an Arg593 to Cys mutation is not linked to HLA class II profile.

Antibodies↗
PubMed1995

Distributions of HLA class II alleles in autoantibody subsets among Norwegian patients with systemic lupus erythematosus.

In order to find potential correlations between HLA class II alleles and anti-SS-A, -SS-B, -Sm and anti-snRNP responses among Norwegian patients with systemic lupus erythematosus (SLE), HLA-DRB1, -DRB3*0101, -DQA1 and -DQB1 alleles were determined by DNA typing 50 patients and 108 controls. HLA distributions were analysed in the following autoantibody subgroups: anti-SS-A with -SS-B, anti-SS-A without -SS-B, anti-snRNP without -Sm, anti-SS-A without -snRNP and anti-snRNP without -SS-A. The autoantibodies were detected by EIA (enzyme immunuassay). Patients with anti-SS-A and -SS-B had significantly increased frequencies of DRB1*03, DRB3*0101, DQA1*0501, DQB1*0201 (in linkage disequilibrium) versus controls and versus patients without anti-SS-A and -SS-B. No differences in HLA distribution were found when the group with anti-SS-A alone was compared to the group with anti-SS-A and concomitant -SS-B. Comparing the groups with and without anti-SS-A and -SS-B, the highest RR were found for the alleles DRB1*03, DRB3*0101, DQB1*0501, DQB1*0201 (in linkage disequilibrium) with RR: 16.8, 5.0, 19.6, 10.3, respectively, P < 0.05). RR for DQw2/DQw6 heterozygotes was 3.5 (Ns.), and RR for cases having DQ alpha molecules with glutamine in position 34 and DQ beta molecules with leucine in position 26 on both chains was 6.3 (P < 0.05). No HLA associations were observed in the group with anti-snRNP without concomitant -Sm or without concomitant -SS-A. These results show that production of anti-SS-A and -SS-B is associated to the HLA alleles DRB1*03, DRB3*0101, DQA1*0501, DQB1*0201, and that this haplotype shows stronger correlation to these responses than DQw2/DQw6 heterozygosity or HLA molecules having glutamine in position 34 (DQ alpha) and leucine in position 26 (DQ beta). The failure to observe any correlation with DRBI*15,16 (DR2) in the group with anti-SS-A alone may demonstrate ethnic differences concerning this response. The failure to identify any HLA associations for the anti-snRNP response may reflect the heterogeneity of the molecules that constitute this antigen.

Adolescent↗
PubMed2003

HLA class II antigens associated with lupus nephritis in Italian SLE patients.

Human leukocyte antigen DR2 (HLA-DR2), namely the allelic variant HLA-DR15, have been associated with lupus nephritis (LN) in Caucasians. The study investigated the relationships between HLA class II alleles and lupus nephritis in Italian patients. Two hundred forty-four patients fulfilling the American Rheumatism Association criteria for systemic lupus erythematosus (SLE) were typed for HLA-DRB1*, -DQA1*, -DQB1*, and -DPB1* alleles by polymerase chain reaction-sequence-specific oligonucleotide and polymears chain reaction-single-strand polymorphism; 71 patients had renal damage assessed by renal biopsy. Glomerulonephritis was classified using WHO criteria. Significance was tested by X(2) on 2x2 tables. HLA-DQA1*0101 was strongly associated with LN (OR = 2.72 [1.43-5.19]; p = 0.002), whereas HLA-DRB1*1501 was only marginally associated (OR = 1.94 [0.88-4.26]; p = not significant). HLA-DQA1*0102 demonstrated a significant protective effect (OR = 0.31 [0.14-0.86]; p = 0.002). On analyzing the distribution of HLA-DRB1*1501 bearing haplotypes in our SLE patients we found that the HLA-DRB1*1501 greatly enhanced the risk of developing LN conferred by the DQA1*0101 allele (OR = 65.96 [9.35-1326.25]), whereas DQA1*0102 suppressed the nephritogenic effect of DRB1*1501. At renal biopsy, 80% of DRB1*15 positive patients were classified as having class IV LN with the remaining 20% having class III LN. The figures were 19% and 21%, respectively, among the HLA-DR15 negative patients. In the Italian population HLA-DQA and HLA-DR alleles interact in conferring susceptibility to or protection against lupus nephritis, the diffuse proliferative glomerulonephritis (i.e., the most severe form of nephritis) is associated with the HLA-DR15 bearing haplotypes.

Adult↗
PubMed1984

Role of HLA class II products in proliferative T-lymphocyte responses to PPD. Evidence of a regulatory influence associated with MB1.

HLA class II determinants were analysed for their role in monocyte-T-cell interactions in the proliferative response to purified protein derivative (PPD). Allogeneic cell combinations of monocytes and T cells were tested with a range of suboptimal PPD concentrations. For each cell combination tested, a summary measure to characterize the antigen-induced response curve was calculated by means of regression analysis of the response to the dose of PPD added, thus obviating a further need to correct for mixed lymphocyte reactivity. In 200 distinct monocyte-T-cell combinations, HLA-DR appeared to be the major restricting element. Additionally, a marginal influence of HLA-MB or -MT matching was observed and no evidence of HLA-SB-restricted responses. Remarkably, the HLA-MB1 specificity was significantly associated with low responsiveness in DR sharing monocyte-T-cell combinations, indicating a modulating role of MB1 in DR-restricted T-cell responses.

Epitopes↗
PubMed2004

Variation of HLA class II genes in the Nganasan and Ket, two aboriginal Siberian populations.

Allelic frequencies at the three most polymorphic loci of the HLA class II region (DRB1, DQA1 and DQB1) were determined in the Nganasan and Ket, the remnants of the two most ancient groups in the Lower Yenisey River/Taimyr Peninsula region in northern Siberia. By single-stranded conformational polymorphism typing, verified by sequencing, 19 HLA-DRB1-DQA1-DQB1 haplotypes and 15 HLA-DRB1, seven DQA1 and 11 DQB1 alleles were found. The most frequent alleles were DRB1*1301 (23.5%), DQA1*0103 (29.4%), *0501/03/05 (29.4%), and DQB1*0301/09 (32.4%) in the Ket, and DRB1*0901 (25%), DQA1*0301 (39.6%), and DQB1*0301/09 (37.5%) in the Nganasan. The distribution patterns and comprehensive phylogenic analysis based on the haplotype frequencies of 17 Siberian populations suggest that the founders of both the Ket and the Nganasan came from Palaeolithic populations in the Altai-Sayan Upland.

Alleles↗
PubMed1988

A supertypic HLA class II determinant shared by DR1 and DRw9, and crossreactive with DR2, defined by human monoclonal antibody.

A human monoclonal antibody Pez.2F5, produced by a lymphoblastoid cell line, has been established in vitro by Epstein-Barr virus (EBV) transformation of B lymphocytes isolated from the blood of a volunteer immunized with allogeneic peripheral blood leukocytes (PBLs). The antibody reacted with a new supertypic determinant expressed on all lymphoblastoid cell lines homozygous for HLA-DR1, -2, and -w9. The genetic linkage of the Pez.2F5 determinant to the HLA region was demonstrated by family segregation studies. Quantitative absorption studies indicated that DR2-positive cells required more Pez.2F5 antibody for lysis, and since their absorption capacity was significantly lower than that of DR1- or DRw9-positive cells, it is likely that the Pez.2F5 determinant of the DR2 haplotype is crossreactive but not identical with the determinant found on the latter haplotypes. In addition, on a test panel of HLA-typed B lymphocytes, Pez.2F5 showed perfect correlation with DR1 and DRw9, but reacted with only a fraction of DR2-positive cells. The Pez.2F5 determinant was found to be absent from resting T lymphocytes, but its expression could be identified on IL-2-dependent T-cell lines by cytotoxicity and flow cytofluorometric analysis. By sequential immunoprecipitation and SDS gel analysis of antigens of DR1 cells it was determined that the Pez.2F5 determinant is carried by HLA class II DR molecules. Thus, the Pez.2F5 is the first described human monoclonal antibody able to immunoprecipitate HLA class II-related molecules.

Antibodies, Monoclonal↗
PubMed1989

Inappropriate expression of HLA class II molecules in endocrine epithelial cells: the phenomenon, the new experimental data and comparison with animal models.

Physiologically, HLA Class II molecules are primarily expressed on immunoregulatory cells. In recent years, it has been shown that tissues affected by autoimmunity, including beta cells of 'diabetic' pancreases, 'inappropriately' express these glycoproteins. Cytokines are potent Class II inducers on a variety of cells but they exert a heterogenous effect when incubated with different human endocrine cells, i.e. thyroid cells are readily inducible, beta cells are much more resistant. The fine modulation of Class II expression by cytokines has been extensively studied and recent information on their action on endocrine cells is reported here. The possibility that distinct environmental factors from those postulated until now may be responsible for triggering the inappropriate expression of MHC molecules in epithelial cells in vivo is also emphasized. Despite several similarities between human Type I diabetes and spontaneous animal models of the disease, major differences still exist. Transgenic models have now been produced. However, even if they offer interesting new insights, they have not so far provided the decisive answer to explain the pathogenesis of human autoimmune diseases.

Animals↗
PubMed2005

HLA Class II molecules on haplotypes associated with type 1 diabetes exhibit similar patterns of binding affinities for coxsackievirus P2C peptides.

Enteroviruses such as coxsackievirus B4 (CVB4) are proposed as possible environmental triggers or accelerants of the autoimmune process that leads to type 1 diabetes mellitus. One putative mechanism to account for this association is mimicry between virus components and islet autoantigens. Particular interest has focused on the CVB4 non-structural protein P2C, which we previously showed to be a major target of the effector memory anti-CVB4 CD4 T-cell response, and which harbours a region of sequence similarity with the islet autoantigen, glutamic acid decarboxylase (GAD65). Since several distinct human leucocyte antigen (HLA) Class II molecules are associated with development of type 1 diabetes, we hypothesized that for functional mimicry to be important, any potential region(s) of mimicry in P2C should bind to each of these susceptibility molecules. In the present study therefore we examined the affinity of 20-mer overlapping P2C peptides for soluble HLA-DR4, -DR3, -DQ2 and -DQ8. We identified one discrete region of P2C with high binding affinities for all of these HLA Class II molecules. Moreover, the binding affinity of P2C peptides was significantly correlated between HLA molecules present on the same susceptibility haplotype (e.g. DR4 and DQ8, P =0.0076; DR3 and DQ2 P = 0.002). We conclude that possession of these haplotypes favours restricted presentation of viral epitopes, and speculate that this could promote the potential for mimicry between microbial proteins and islet autoantigens.

Amino Acid Sequence↗
PubMed2005

HLA class II alleles and measles virus-specific cytokine immune response following two doses of measles vaccine.

Measles virus-specific T cells and the production of cytokines play a critical role in the immune response following measles immunization. To understand the genetic factors that influence variation in IFN-gamma and IL-4 responses following measles immunization and to provide insight into the factors influencing both cellular and humoral immunity to measles, we assessed associations between human leukocyte antigen (HLA) class II genes and measles-specific Th1 and Th2-type cytokine responses in peripheral blood lymphocytes from 339 children previously vaccinated with two doses of measles-mumps-rubella vaccine (MMR-II). Median values for measles-specific IFN-gamma and IL-4 secretion levels were 40.73 and 9.71 pg/ml, respectively. The global tests suggested associations between measles-specific IFN-gamma response and alleles of the DRB1 and DQB1 loci (P=0.07 and P=0.02, respectively). Specifically, DRB1*0301, *0901, and *1501 alleles were significantly associated with IFN-gamma secretion. The alleles that suggested evidence of an HLA association with IL-4 secretion were DRB1*0103, *0701, and *1101. Th1 cytokine responses and DQB1 allele associations revealed that the alleles with the strongest association with IFN-gamma secretion were DQB1*0201, *0303, *0402, and *0602. Specific alleles with a suggestive association with low measles-specific Th2 cytokine responses were DQB1*0202 and *0503. In addition, DPB1*0101, *0201, and *0601 alleles provided suggestive evidence of an HLA association with measles-induced IFN-gamma response, while DPB1*0501 was associated with an IL-4 response. These data suggest that IFN-gamma and IL-4 cytokine responses to measles may be genetically restricted in part by HLA class II genes, which in turn can restrict the cellular immune response to measles vaccine.

Adolescent↗
PubMed1987

Expression of HLA class II determinants by normal and chronic myeloid leukemia progenitors.

It has been suggested that the expression of some HLA class II antigens, derived from three loci (DR, DP, DQ) is important in the regulation of both the immune response and the response of haemopoietic progenitors to regulation factors, such as acidic isoferritins (AIF), as well as in the interaction between T lymphocytes and erythroid progenitors (BFU-E). Changes in the expression of class II antigens have been reported on the surface of granulo-monocyte progenitors in chronic myeloid leukemia (CML) and correlated to the abnormal proliferation of such cells. In this study, monoclonal antibodies against DR and DQ monomorphic determinants were used to investigate the expression of these antigens on the surface of normal and CML bone marrow and peripheral blood BFU-E by means of complement mediated cytotoxicity. It was found that most normal and leukemic BFU-E express DR antigens. Antigens density tends to be greater on marrow as opposed to peripheral precursors. In addition, leukemic BFU-E are more sensitive to cytolytic treatment than their normal counterparts. Normal BFU-E do not express detectable amounts of DQ antigens, whereas these are present on a proportion of leukemic BFU-E.

Antibodies, Monoclonal↗
PubMed1996

Evidence of involvement of cytotoxic antibodies directed against patients's HLA class II produced by transfused donor-derived B cells in post-transfusion graft-versus-host disease.

Post-transfusion graft-versus-host disease (PTGVHD) is one of the most severe side-effects of blood transfusion. To characterize the effector cells causing this disease, we cloned lymphocytes from a PTGVHD patient's peripheral blood. T-cell and B-cell clones were established, the origins of which were proven to be transfused donor lymphocytes. It was found that the B cells produced IgG that mediated complement-dependent cytotoxicity to the cells bearing the patient's HLA class II genotype. Our results suggest, for the first time, the involvement of B-cell-produced cytotoxic antibodies directed against patient's HLA class II in the pathogenesis of PTGVHD.

Antibodies↗
PubMed1985

Isolation and characterization of the cDNA clone and genomic clones of a new HLA class II antigen heavy chain, DO alpha.

From a human cDNA library constructed from a consanguineous HLA-homozygous cell line, AKIBA (HLA-A24, Bw52, DR2, Dw12, DQw1, and Cp63) (Cp63, a new SB type), a cDNA clone encoding a new HLA class II antigen heavy chain named DQ alpha was isolated, and was analyzed by Southern blot hybridization and by nucleotide sequence determination. The nucleotide sequence of the DO alpha cDNA was distinct from those of the DR alpha, the DQ alpha, and the DP alpha cDNA, but showed some characteristic features of the class II antigen alpha-chains. We also isolated and identified genomic clones specifying the DO alpha gene. Genomic analyses of cell lines with different HLA-DR serotypes with the use of the DO alpha cDNA as a probe indicated the existence of a single DO alpha gene that exhibited little restriction enzyme polymorphism.

Amino Acid Sequence↗
PubMed1995

Characterization and epitope mapping of four HLA class II reactive mouse monoclonal antibodies using transfected L cells and human cells transfected with mutants of DQB1*0302.

To study epitopes of HLA class II molecules, four mouse monoclonal antibodies (mAbs) 13B6, 17F8, 19A1 and 12G6 were made using HLA-DQ8, DP2 and DP4 expressing mouse transfectants for immunization. Three of the mAbs, 13B6, 17F8 and 19A1, bound to all DQ1, 4, 8 or 9 positive B-lymphoblastoid cell lines (B-LCLs) and transfectants tested, i.e. cells carrying the DQB1 genes 0302-3, 0401-2, 0501-3, 0601-4 and 0609 irrespective of the accompanying DQA1 gene. These DQB1 genes code for the shared amino acids (aa) GVY in position 45-47 of the DQ beta chain. DQ1+4+8+9 specific (IIB3) and DQ3 specific (IVD12) reference mAbs inhibited binding of all three mAbs. Testing 13B6, 17F8 and 19A1 with cells made using aa substitutions in various positions of DQ beta 1*0302 indicated involvement of aa 45 in the epitopes of all three mAbs. The last mAb (12G6) bound to all B-LCLs and all DP transfected cells. However, only some DR transfectants and a single DQ transfectant (carrying DQA1*0201 and DQB1*0202) bound mAb 12G6. This reactivity pattern correlates with a shared sequence of aa (RFDSDVGE) in position 39-46 of DR- and DQ- and 37-44 of DP beta chains.

Amino Acid Sequence↗
PubMed1995

Distribution of HLA class II molecules in epidermal Langerhans cells in situ.

We performed immunoelectron microscopic studies to investigate the expression of HLA class II molecules in Langerhans cells (LC). In the epidermis, LC expressed class II molecules on the plasma membrane of the dendrites, resulting in a class II positive reticulo-epithelial network, but not on the surface of the cell body. In contrast, isolated LC as well as activated LC in situ displayed an even and strong expression of class II molecules on their entire cell surface. Therefore, isolation and/or activation results in redistribution and up-regulation of class II molecules on the cell surface. In addition, double-labeling experiments were carried out with monoclonal antibodies to class II antigens and to LAMP-1, CD63 and alpha-glucosidase, specific markers for organelles of the endosomal/lysosomal system. The results show expression of class II molecules on intracellular, electron-dense vesicular structures, and co-localization of class II molecules and the markers for late endosomes and early lysosomes in human LC in situ. Expression of these markers was not found on Birbeck granules, an LC-specific organelle.

Animals↗
PubMed1992

Induction of HLA class II antigen and interleukin 2 receptor expression in acute vascular rejection of human kidney allografts.

The induction of HLA class II antigens on graft tubular cells and IL-2 receptor expression on the infiltrating lymphoid cells was studied in 245 prospective aspiration biopsies taken during the first posttransplant month from 20 human renal allografts with histologically verified acute vascular rejection (AVR). Based on the histological findings, the specimens were categorized into two main groups: biopsies from grafts with features of AVR only, and biopsies with a combination of AVR and acute cellular rejection (ACR). Also in the second group the AVR findings were predominant. Biopsies were further divided into two subgroups, depending on whether the rejection was reversible or irreversible. Evaluation of class II and IL-2R expression was done by indirect immunoperoxidase staining using monoclonal antibodies. The initial posttransplant tubular cell class II expression was low in all 20 grafts, with 5-15% positive tubular cells, and IL-2R expression was negative. All 13 grafts with a combination of AVR and ACR displayed class II induction, closely correlating to the blast response, with 50% positive tubular cells on days 2-7 after the onset of rejection, and declining thereafter back to prerejection level in grafts with reversible rejection. In grafts with irreversible rejection, tubular cell class II expression remained elevated. A similar pattern was observed with regard to IL-2R expression: the IL-2R positive cells disappeared from the grafts with reversible rejection, but they persisted in the irreversible rejections. The same pattern of class II and IL-2R expression was observed in grafts with pure AVR and reversible rejection. Instead, completely different findings were seen in grafts with pure AVR and irreversible rejection: there was neither class II induction on tubular cells nor IL-2R expression on lymphoid cells. The persistant inflammation was dominated by mononuclear phagocytes, and no blast response could be detected during the entire follow-up. These findings demonstrate a close relationship between IL-2R expression and tubular cell class II induction also in AVR, in the majority of cases. On the other hand, the findings in grafts with pure AVR in histology and irreversible rejection suggest that AVR is a heterogenous group of rejections, where different cellular and molecular mechanisms are operating.

Graft Rejection↗