Divergent Motifs but Overlapping Binding Repertoires of Six HLA-DQ Molecules Frequently Expressed in the Worldwide Human Population

Abstract

Knowledge of the binding repertoires and specificities of HLA-DQ molecules is somewhat limited and contradictory, partly because of the scarcity of reports addressing some of the most common molecules and possibly because of the diversity of the techniques used. In this paper, we report the development of high-throughput binding assays for the six most common DQ molecules in the general worldwide population. Using comprehensive panels of single substitution analogs of specific ligands, we derived detailed binding motifs for DQA1*0501/DQB1*0301, DQA1*0401/DQB1*0402, and DQA1*0101/DQB1*0501 and more detailed motifs for DQA1*0501/DQB1*0201, DQA1*0301/DQB1*0302, and DQA1*0102/DQB1*0602, previously characterized on the basis of sets of eluted ligands and/or limited sets of substituted peptides. In contrast to what has previously been observed for DR and DP molecules, DQ motifs were generally less clearly defined in terms of chemical specificity and, strikingly, had little overlap with each other. However, testing a panel of peptides spanning a set of Phleum pratense Ags, and panels of known DQ epitopes, revealed a surprisingly significant and substantial overlap in the repertoire of peptides bound by these DQ molecules. Although the mechanism underlying these apparently contradictory findings is not clear, it likely reflects the peculiar mode of interaction between DQ (and not DR or DP) molecules and their peptide ligands. Because the DQ molecules studied are found in >85% of the general human population, these findings have important implications for epitope identification studies and monitoring of DQ-restricted immune responses.

Associations of human leukocyte antigens with autoimmune diseases: challenges in identifying the mechanism

“…[35][36][37] The HLA-peptide binding studies revealed that the selfpeptides derived from these autoantigens bound promiscuously to the susceptible, neutral and protective DR and DQ allele products, [38][39][40] which may reflect the facts that the peptide-binding spectrum of DR and DQ allele products partially overlaps across alleles. 41,42 It has remained unknown whether the HLA associations with T1D can be explained by the selective presentation of certain pancreatic self-peptides on the susceptible HLA allele products. Potential contributions of other functional variations among the alleles, such as the promoter activity 43 and the dependency of HLA proteins to invariant chain and HLA-DM, [44][45][46] to T1D risk have also been reported.…”

T cells from hemophilia A subjects recognize the same HLA-restricted FVIII epitope with a narrow TCR repertoire

“…FVIII 508-527 binding to DRB1*01:01 and DRB1*10:01 was tested experimentally yielding 50% inhibitory concentration values .20 mM, which is considerably higher than the 1000 nM affinity threshold defined for MHCII binding, [47][48][49] whereas FVIII 2194-2213 bound to DRB1*01:01 with an 50% inhibitory concentration of 0.33 mM (supplemental Figure 3). The ProPred and Immune Epitope Database programs predicted that 28 and 15 core FVIII sequences, respectively, could bind DRB1*01:01 (supplemental Tables 2-3).…”

Distribution of HLA-DQB1 alleles in patients with Kleine-Levin syndrome

“…Specific HLA class II alleles, including DQB1⁄0201 and DQB1⁄0602, may affect the risk of human diseases due to the presence of HLA-DQ-restricted immune responses. 13,14 To our knowledge, this is the first report discussing HLA class II DQB1 typing in patients with KLS in a Taiwanese population. An immunoresponsive HLA-DQB1 allele, DQB1⁄0602, is detected in significant quantities in patients with KLS, which is helpful in identifying the genomic susceptibility of KLS and determining immunospecific targeted therapies for patients with this genetic disorder.…”