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Epitope Selection for HLA-DQ2 Presentation: Implications for Celiac Disease and Viral Defense.

ABSTRACT: We have reported that the major histocompatibility molecule HLA-DQ2 (DQA1*05:01/DQB1*02:01) (DQ2) is relatively resistant to HLA-DM (DM), a peptide exchange catalyst for MHC class II. In this study, we analyzed the role of DQ2/DM interaction in the generation of DQ2-restricted gliadin epitopes, relevant to celiac disease, or DQ2-restricted viral epitopes, relevant to host defense. We used paired human APC, differing in DM expression (DMnull versus DMhigh) or differing by expression of wild-type DQ2, versus a DM-susceptible, DQ2 point mutant DQ2?+53G. The APC pairs were compared for their ability to stimulate human CD4+ T cell clones. Despite higher DQ2 levels, DMhigh APC attenuated T cell responses compared with DMnull APC after intracellular generation of four tested gliadin epitopes. DMhigh APC expressing the DQ2?+53G mutant further suppressed these gliadin-mediated responses. The gliadin epitopes were found to have moderate affinity for DQ2, and even lower affinity for the DQ2 mutant, consistent with DM suppression of their presentation. In contrast, DMhigh APC significantly promoted the presentation of DQ2-restricted epitopes derived intracellularly from inactivated HSV type 2, influenza hemagglutinin, and human papillomavirus E7 protein. When extracellular peptide epitopes were used as Ag, the DQ2 surface levels and peptide affinity were the major regulators of T cell responses. The differential effect of DM on stimulation of the two groups of T cell clones implies differences in DQ2 presentation pathways associated with nonpathogen- and pathogen-derived Ags in vivo.

SUBMITTER: Hung SC

PROVIDER: S-EPMC6494460 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Epitope Selection for HLA-DQ2 Presentation: Implications for Celiac Disease and Viral Defense.

Hung Shu-Chen SC Hou Tieying T Jiang Wei W Wang Nan N Qiao Shuo-Wang SW Chow I-Ting IT Liu Xiaodan X van der Burg Sjoerd H SH Koelle David M DM Kwok William W WW Sollid Ludvig M LM Mellins Elizabeth D ED

Journal of immunology (Baltimore, Md. : 1950) 20190329 9

We have reported that the major histocompatibility molecule HLA-DQ2 (DQA1*05:01/DQB1*02:01) (DQ2) is relatively resistant to HLA-DM (DM), a peptide exchange catalyst for MHC class II. In this study, we analyzed the role of DQ2/DM interaction in the generation of DQ2-restricted gliadin epitopes, relevant to celiac disease, or DQ2-restricted viral epitopes, relevant to host defense. We used paired human APC, differing in DM expression (DM<sup>null</sup> versus DM<sup>high</sup>) or differing by ex ...[more]

PMID: 30926644

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Project description:The use of pure oats (oats cultivated with special care to avoid gluten contamination from wheat, rye, and barley) in the gluten-free diet (GFD) represents important nutritional benefits for the celiac consumer. However, emerging evidence suggests that some oat cultivars may contain wheat gliadin analog polypeptides. Consequently, it is necessary to screen oats in terms of protein and epitope composition to be able to select safe varieties for gluten-free applications. The overall aim of our study is to investigate the variability of oat protein composition directly related to health-related and techno-functional properties. Elements of an oat sample population representing 162 cultivated varieties from 20 countries and the protein composition of resulting samples have been characterized. Size distribution of the total protein extracts has been analyzed by size exclusion-high performance liquid chromatography (SE-HPLC) while the 70% ethanol-extracted proteins were analyzed by RP-HPLC. Protein extracts separated into three main groups of fractions on the SE-HPLC column: polymeric proteins, avenins (both containing three subgroups based on their size), and soluble proteins, representing respectively 68.79-86.60, 8.86-27.72, and 2.89-11.85% of the total protein content. The ratio of polymeric to monomeric proteins varied between 1.37 and 3.73. Seventy-six reversed phase-HPLC-separated peaks have been differentiated from the ethanol extractable proteins of the entire population. Their distribution among the cultivars varied significantly, 6-23 peaks per cultivar. The number of appearances of peaks also showed large variation: one peak has been found in 107 samples, while 15 peaks have been identified, which appeared in less than five cultivars. An estimation method for ranking the avenin-epitope content of the samples has been developed by using MS spectrometric data of collected RP-HPLC peaks and bioinformatics methods. Using ELISA methodology with the R5 antibody, a high number of the investigated samples were found to be contaminated with wheat, barley, or rye.

Project description:BackgroundGenomic prediction aims to leverage genome-wide genetic data towards better disease diagnostics and risk scores. We have previously published a genomic risk score (GRS) for celiac disease (CD), a common and highly heritable autoimmune disease, which differentiates between CD cases and population-based controls at a clinically-relevant predictive level, improving upon other gene-based approaches. HLA risk haplotypes, particularly HLA-DQ2.5, are necessary but not sufficient for CD, with at least one HLA risk haplotype present in up to half of most Caucasian populations. Here, we assess a genomic prediction strategy that specifically targets this common genetic susceptibility subtype, utilizing a supervised learning procedure for CD that leverages known HLA-DQ2.5 risk.MethodsUsing L1/L2-regularized support-vector machines trained on large European case-control datasets, we constructed novel CD GRSs specific to individuals with HLA-DQ2.5 risk haplotypes (GRS-DQ2.5) and compared them with the predictive power of the existing CD GRS (GRS14) as well as two haplotype-based approaches, externally validating the results in a North American case-control study.ResultsConsistent with previous observations, both the existing GRS14 and the GRS-DQ2.5 had better predictive performance than the HLA haplotype approaches. GRS-DQ2.5 models, based on directly genotyped or imputed markers, achieved similar levels of predictive performance (AUC = 0.718-0.73), which were substantially higher than those obtained from the DQ2.5 zygosity alone (AUC = 0.558), the HLA risk haplotype method (AUC = 0.634), or the generic GRS14 (AUC = 0.679). In a screening model of at-risk individuals, the GRS-DQ2.5 lowered the number of unnecessary follow-up tests for CD across most sensitivity levels. Relative to a baseline implicating all DQ2.5-positive individuals for follow-up, the GRS-DQ2.5 resulted in a net saving of 2.2 unnecessary follow-up tests for each justified test while still capturing 90 % of DQ2.5-positive CD cases.ConclusionsGenomic risk scores for CD that target genetically at-risk sub-groups improve predictive performance beyond traditional approaches and may represent a useful strategy for prioritizing individuals at increased risk of disease, thus potentially reducing unnecessary follow-up diagnostic tests.

Dataset Information

Epitope Selection for HLA-DQ2 Presentation: Implications for Celiac Disease and Viral Defense.

Publications

Epitope Selection for HLA-DQ2 Presentation: Implications for Celiac Disease and Viral Defense.

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