HLA class II peptide-binding-region analysis reveals funneling of polymorphism in action

Sarri, Constantina A.; Giannoulis, Themistoklis; Moutou, Katerina A.; Mamuris, Zissis

doi:10.1016/j.imlet.2021.07.005

Cited by 5 publications

(6 citation statements)

References 648 publications

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Section: Introductionmentioning

confidence: 99%

“…The HLA class I molecules exhibit six HLA PBP, namely A to F. Interestingly, the specificity of pockets B and F has been used to classify HLA into supertypes, a useful approach to predict peptide binding to a given HLA motif. 10,11 On the other hand, HLA class II molecules have five pockets, designated P1, P4, P6, P7 and P9. 12,13 Associations between specific amino acid positions and/ or pockets within peptide-binding regions and several diseases were previously demonstrated, [13][14][15][16][17][18] highlighting the role of P4, P6 and P9 of HLA-DRB1 and P4 and P9 of HLA-DQB1 in the selectivity and stability of antigenic peptides.…”

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confidence: 99%

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Comparative analysis of the variability of the human leukocyte antigen peptide‐binding pockets in patients with acute leukaemia

et al. 2022

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Summary The association between acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML) and the human leukocyte antigens (HLA) has rarely been studied in terms of diversity of peptide‐binding pockets. The objective of this study was to analyse whether motifs of HLA class I and class II peptide‐binding pockets and/or their amino acid positions were differentially associated with ALL and AML. We included 849 patients from the Eurocord/European Blood and Marrow Transplant registry. The HLA peptide‐binding pockets whose amino acid variability was analysed were B and F for HLA class I, P4, P6, and P9 for HLA‐DRB1, and P4 and P9 for HLA‐DQB1. The motif RFDRAY in P4 of HLA‐DRB1*16:01/02/03/05 alleles and the motif YYVSY in P9 of HLA‐DQB1*05:02/04/05 alleles, were statistically associated with ALL (corrected p value [pc] = 0.001 and pc = 0.035 respectively). The frequency of serine 57 in the P9 of HLA‐DQB1 was higher in ALL (odds ratio 2.09, 95% confidence interval: 1.27–3.44; pc = 0.037). Our analysis suggests that specific motifs in terms of HLA class II pockets and amino acids might be unique to ALL. The associations identified in this study encourage further investigation oF the role of HLA peptide‐binding pockets and their amino acids in immune processes underpinning acute leukaemia and ultimately in immunotherapy settings.

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Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

Comparative analysis of the variability of the human leukocyte antigen peptide‐binding pockets in patients with acute leukaemia

et al. 2022

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“…Amino acid residues located in the nine peptide-binding grooves (referred to as pockets) were previously described ( 17 , 18 ). Amino acids at positions 9 and 57 of HLA-DRβ1 compose P9, and the amino acid at position 86 composes P1 as well ( Figures 1A, B, C , 4 , 5A ).…”

Section: Resultsmentioning

confidence: 99%

Amino acid polymorphisms in human histocompatibility leukocyte antigen class II and proinsulin epitope have impacts on type 1 diabetes mellitus induced by immune-checkpoint inhibitors

et al. 2023

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IntroductionImmune-checkpoint inhibitors are effective in various advanced cancers. Type 1 diabetes mellitus induced by them (ICI-T1DM) is a serious complication requiring prompt insulin treatment, but the immunological mechanism behind it is unclear.MethodsWe examined amino acid polymorphisms in human histocompatibility leukocyte antigen (HLA) molecules and investigated proinsulin epitope binding affinities to HLA molecules.Results and DiscussionTwelve patients with ICI-T1DM and 35 patients in a control group without ICI-T1DM were enrolled in the study. Allele and haplotype frequencies of HLA-DRB1*04:05, DQB1*04:01, and most importantly DPB1*05:01 were significantly increased in patients with ICI-T1DM. In addition, novel amino acid polymorphisms in HLA-DR (4 polymorphisms), in DQ (12 polymorphisms), and in DP molecules (9 polymorphisms) were identified. These amino acid polymorphisms might be associated with the development of ICI-T1DM. Moreover, novel human proinsulin epitope clusters in insulin A and B chains were discovered in silico and in vitro peptide binding assays to HLA-DP5. In conclusion, significant amino acid polymorphisms in HLA-class II molecules, and conformational alterations in the peptide-binding groove of the HLA-DP molecules were considered likely to influence the immunogenicity of proinsulin epitopes in ICI-T1DM. These amino acid polymorphisms and HLA-DP5 may be predictive genetic factors for ICI-T1DM.

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“…Identification of the DRB1*07:01–DQB1*02:02–DQA1*02:01 risk haplotype is a novel finding, whereas DRB1*03:01–DQB1*02:01–DQA1*05:01 has also been suggested to be a risk haplotype in an extended analyses of a prior GWAS [5, 9]. The association between this haplotype, known as the autoimmune haplotype [16], and ADAb formation, may indicate a common vulnerability due to an overactive or unregulated immune system. The strong association between the two HLA‐DQ2 haplotypes and ADAb formation was robust across diseases, suggesting that the molecular mechanisms of immunogenicity are not disease specific.…”

Section: Discussionmentioning

confidence: 99%

HLA‐DQ2 is associated with anti‐drug antibody formation to infliximab in patients with immune‐mediated inflammatory diseases

et al. 2023

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Background Immunogenicity to tumour necrosis factor inhibitors is a significant clinical problem leading to treatment failure and adverse events. The study aimed to assess human leukocyte antigen (HLA) associations with anti‐drug antibody (ADAb) formation to infliximab. Methods Immune‐mediated inflammatory disease patients on infliximab therapy (n = 612) were included. Neutralising ADAb were assessed with a drug‐sensitive assay. Next generation sequencing‐based HLA typing was performed. Results Overall, 147 (24%) patients developed ADAb. Conditional analyses indicated HLA‐DQB1 (p = 1.4 × 10−6) as a primary risk locus. Highest risk of ADAb was seen when carrying at least one of the HLA‐DQ2 haplotypes; DQB1*02:01–DQA1*05:01 or DQB1*02:02–DQA1*02:01 (OR 3.18, 95% CI 2.15–4.69 and p = 5.9 × 10−9). Results were consistent across diseases and when adjusting for concomitant immunomodulator. Computational predictions indicated that these HLA‐DQ2 haplotypes bind to peptide motifs from infliximab light chain. Conclusion A genome‐wide significant association between two HLA‐DQ2 haplotypes and the risk of ADAb formation to infliximab was identified, suggesting that HLA‐DQ2 testing may facilitate personalised treatment decisions.

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HLA class II peptide-binding-region analysis reveals funneling of polymorphism in action

Cited by 5 publications

References 648 publications

Comparative analysis of the variability of the human leukocyte antigen peptide‐binding pockets in patients with acute leukaemia

Comparative analysis of the variability of the human leukocyte antigen peptide‐binding pockets in patients with acute leukaemia

Amino acid polymorphisms in human histocompatibility leukocyte antigen class II and proinsulin epitope have impacts on type 1 diabetes mellitus induced by immune-checkpoint inhibitors

HLA‐DQ2 is associated with anti‐drug antibody formation to infliximab in patients with immune‐mediated inflammatory diseases

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