HLA-DQ2 and -DQ8 genotypes in celiac and healthy Libyan children
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HLA-DQ
Genetic predisposition
Candidate gene
Abstract HLA class II antigen presentation is key for controlling and triggering T cell immune responses. HLA-DQ molecules, which are believed to play a major role in autoimmune diseases, are heterodimers that can be formed as both cis and trans variants depending on whether the α- and β-chains are encoded on the same (cis) or opposite (trans) chromosomes. So far, limited progress has been made for predicting HLA-DQ antigen presentation. In addition, the contribution of trans-only variants (i.e. variants not observed in the population as cis) in shaping the HLA-DQ immunopeptidome remains largely unresolved. Here, we seek to address these issues by integrating state-of-the-art immunoinformatics data mining models with large volumes of high-quality HLA-DQ specific MS-immunopeptidomics data. The analysis demonstrated a highly improved predictive power and molecular coverage for models trained including these novel HLA-DQ data. More importantly, investigating the role of trans-only HLA-DQ variants revealed a limited to no contribution to the overall HLA-DQ immunopeptidome. In conclusion, this study has furthered our understanding of HLA-DQ specificities and has for the first time cast light on the relative role of cis versus trans-only HLA-DQ variants in the HLA class II antigen presentation space. The developed method, NetMHCIIpan-4.2, is available at https://services.healthtech.dtu.dk/services/NetMHCIIpan-4.2 .
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Patients with celiac disease (CD) lacking both human leukocyte antigen (HLA)-DQ2.5 in cis (DQA1*05:01, DQB1*02:01) or trans (DQA1*05:05, DQB1*02:02) configuration and HLA-DQ8 (DQA1*03:01, DQB1*03:02) are considered to be rare. Therefore, absence of these genotypes is commonly used to exclude the diagnosis of CD. To investigate whether this approach is justified, the HLA-distribution in 155 children with CD was studied. A total of 139 (89.7%) patients carried HLA-DQ2.5. Of the remaining patients, 7 (4.5%) carried HLA-DQ8. Interestingly, the 9 (5.8%) patients lacking HLA-DQ2.5 and HLA-DQ8 carried HLA-DQA1*02:01 and -DQB1*02:02 (HLA-DQ2.2). Therefore, HLA-DQ2.2 should be included as an important HLA-type related to CD.
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Abstract Because susceptibility to celiac disease is associated strongly with HLA-DQ2 (DQA1*05/DQB1*02) and weakly with HLA-DQ8 (DQA1*03/DQB1*03), a subset of patients carries both HLA-DQ2 and HLA-DQ8. As a result, these patients may express two types of mixed HLA-DQ2/8 transdimers (encoded by DQA1*05/DQB1*03 and DQA1*03/DQB1*02) in addition to HLA-DQ2 and HLA-DQ8. Using T cells from a celiac disease patient expressing HLA-DQ8trans (encoded by DQA*0501/DQB*0302), but neither HLA-DQ2 nor HLA-DQ8, we demonstrate that this transdimer is expressed on the cell surface and can present multiple gluten peptides to T cell clones isolated from the duodenum of this patient. Furthermore, T cell clones derived from this patient and HLA-DQ2/8 heterozygous celiac disease patients respond to gluten peptides presented by HLA-DQ8trans, as well as HLA-DQ8, in a similar fashion. Finally, one gluten peptide is recognized better when presented by HLA-DQ8trans, which correlates with preferential binding of this peptide to HLA-DQ8trans. These results implicate HLA-DQ8trans in celiac disease pathogenesis and demonstrate extensive T cell cross-reactivity between HLA-DQ8 and HLA-DQ8trans. Because type 1 diabetes is strongly associated with the presence of HLA-DQ8trans, our findings may bear relevance to this disease as well.
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The human leukocyte antigen (HLA) complex is located on the short arm of chromosome 6 at p21.3 (1-4). It encompasses approximately 3,500 kilobases of DNA and contains at least 150 genes. It is the primary region of susceptibility for type 1 diabetes mellitus, as well as other autoimmune disorders. Recent genome screens have designated the class II subregion (i.e., the HLA-DR, HLA-DQ, and HLA-DP loci) IDDM1. The DQ locus, which is the focus of this review, consists of two tightly linked genes (DQA1 and DQB1) that encode a and fj glycoproteins, respectively. These molecules combine noncovalently to form functional a-(J heterodimers. The DQA1 and DQB1 genes are highly polymorphic. Allelic variation is observed primarily in the second exon, which corresponds to the peptide-binding cleft. HLA-DQ and other class II molecules present extracellular antigens to helper T cells and stimulate the body's immune response. They have a restricted tissue distribution and are located mainly on macrophages, B cells, and activated T cells. Transcription of DQA1 and DQB1 is complex and involves cisand frans-acting factors. Critical upstream regulatory sequences have been reported for DQA1 and DQB1. Variation in promoter sequences affects gene expression and may also be involved in the pathogenesis of autoimmune disorders. In addition, posttranscription activities appear to influence disease risk. For example, functional DQa$ heterodimers can be formed from the noncovalent association of products of DQA1 and DQB1 genes in cis (5). Alternatively, the combined a and (3 glycoproteins can represent molecules encoded by genes in trans. Hybrid DQ molecules with DR or DP glycoproteins have also been observed.
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Humoral graft-specific alloreactivity was investigated in 110 renal transplant (RTx) recipients (group A) starting immediately postTx and in 32 RTx candidates sensitized against a failed graft (group B) using an enzyme-linked immunosorbent assay (ELISA) assay. All patients received a human leukocyte antigen (HLA) class I and II incompatible graft. Donor-specific (DS) antibodies were detected in 11 of 110 (90.9%) group-A patients, predominately during the first 6 months postTx. In all 11 cases, only HLA class II antibodies were detected. Ten of 11 antibody-positive patients received an HLA-DR, HLA-DQ incompatible graft, and all patients had HLA-DQ DS antibodies, either alone (n=8) or with HLA-DR antibodies (n=2). HLA-DQ antibodies were also detected in 80.9% of group-B patients. The presence of HLA-DQ DS antibodies in the early postTx period does not identify patients with rejection or deterioration of graft function. Whether these patients are at high risk for graft loss remains to be clarified.
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In human type 1 diabetes (T1D), both genetic and environmental factors are involved in the pathogenesis of the disease. The strongest genetic contribution has been mapped to the major histocompatibility complex (MHC) on the short arm of chromosome 6, which encodes the human leukocyte antigens (HLA). It is estimated that HLA class II gene polymorphisms account for 20 to 50% of familial aggregation of type 1 diabetes. Several studies have clearly demonstrated that there are susceptibility and protective markers at HLA-DR and -DQ.
In this study, HLA class II antigens were investigated using a serological method in 210 T1D patients from the central region of Algeria, and compared to 140 healthy controls. Marker frequencies were compared between three groups of diabetics : children, juveniles and adults with latent autoimmune diabetes (LADA), and the control group.
The frequency was calculated for HLA-DR and -DQ. Significant differences were detected between T1D patient and the control groups for the frequencies of HLA-DR3, -DR4, -DQ2 and -DQ8 (DQ3) but there were no significant differences in these antigen frequencies between the three T1D groups versus the controls, with the respective frequencies of HLA-DR3 (71.76, 66.67, 70% vs 31.43%), HLA-DR4 (64.71, 48.89, 52.50% vs 26.43%), HLA-DQ2 (76.47, 66.67, 75% vs 39.29%) and HLA-DQ8 (3) (64.71, 46.67, 47.50% vs 19.29%).
Mantel-Haenszel tests were used to calculate the odds ratio for the presence of type 1 diabetes in association with HLA-DR3, -DR4, -DQ2 and -DQ8 (3). The values for each respective HLA antigen were as follows : for the T1D children (OR: 5.54; 5.1; 5.02; 7.67) for the juveniles (OR: 4.36; 2.66; 3.09; 3.66) and for LADA (OR: 5.09; 3.08; 4.64; 3.79). The heterozygous phenotype HLA-DR3/DR4 increased the risk (conferred the highest susceptibility) (OR: 8.79, 2.68, 4.23 for children, juveniles and the LADA group, respectively).
These results confirm the positive association between T1D and HLA class II antigens, as previously reported in other populations in the central region of Algeria.
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Association of human leukocyte antigen DP and DQ with postpartum thyroiditis:an analysis of 52 cases
Objective To study the genetic susceptibility in patients with postpartum thyroiditis(PPT)by genotyping their human leukocyte antigen(HLA)-DP and -DQ alleles.Methods The polymerase chain reaction-sequence based typing(PCR-SBP)method was used to analyze the distribution of HLA-DPA1,HLA-DPB1,HLA-DQA1 and HLA-DQB1 alleles among 52 PPT patients(31 clinical patients,21 subclinical patients)and 82 healthy controls.Compare the allele frequencies between various patient groups and the control population.Results There was no significant difference between patient group and control group.Conclusion Perhaps PPT is not associated with HLA-DP and HLA-DQ alleles.
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Background: The risk for type 1 diabetes mellitus (T1DM) and celiac disease (CD) is related to human leukocyte antigen (HLA) DQA1, DQB1 and DRB1 loci. Unfortunately, HLA typing has been too difficult and costly for frequent use. Automated genotyping focused on risk alleles could provide access to HLA typing in diagnostic evaluations, epidemiological screening and contribute to preventive strategies.
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