Dataset Information

A molecular basis for the T cell response in HLA-DQ2.2 mediated celiac disease.

ABSTRACT: The highly homologous human leukocyte antigen (HLA)-DQ2 molecules, HLA-DQ2.5 and HLA-DQ2.2, are implicated in the pathogenesis of celiac disease (CeD) by presenting gluten peptides to CD4+ T cells. However, while HLA-DQ2.5 is strongly associated with disease, HLA-DQ2.2 is not, and the molecular basis underpinning this differential disease association is unresolved. We here provide structural evidence for how the single polymorphic residue (HLA-DQ2.5-Tyr22? and HLA-DQ2.2-Phe22?) accounts for HLA-DQ2.2 additionally requiring gluten epitopes possessing a serine at the P3 position of the peptide. In marked contrast to the biased T cell receptor (TCR) usage associated with HLA-DQ2.5-mediated CeD, we demonstrate with extensive single-cell sequencing that a diverse TCR repertoire enables recognition of the immunodominant HLA-DQ2.2-glut-L1 epitope. The crystal structure of two CeD patient-derived TCR in complex with HLA-DQ2.2 and DQ2.2-glut-L1 (PFSEQEQPV) revealed a docking strategy, and associated interatomic contacts, which was notably distinct from the structures of the TCR:HLA-DQ2.5:gliadin epitope complexes. Accordingly, while the molecular surfaces of the antigen-binding clefts of HLA-DQ2.5 and HLA-DQ2.2 are very similar, differences in the nature of the peptides presented translates to differences in responding T cell repertoires and the nature of engagement of the respective antigen-presenting molecules, which ultimately is associated with differing disease penetrance.

SUBMITTER: Ting YT

PROVIDER: S-EPMC7022145 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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A molecular basis for the T cell response in HLA-DQ2.2 mediated celiac disease.

Ting Yi Tian YT Dahal-Koirala Shiva S Kim Hui Shi Keshia HSK Qiao Shuo-Wang SW Neumann Ralf S RS Lundin Knut E A KEA Petersen Jan J Reid Hugh H HH Sollid Ludvig M LM Rossjohn Jamie J

Proceedings of the National Academy of Sciences of the United States of America 20200123 6

The highly homologous human leukocyte antigen (HLA)-DQ2 molecules, HLA-DQ2.5 and HLA-DQ2.2, are implicated in the pathogenesis of celiac disease (CeD) by presenting gluten peptides to CD4<sup>+</sup> T cells. However, while HLA-DQ2.5 is strongly associated with disease, HLA-DQ2.2 is not, and the molecular basis underpinning this differential disease association is unresolved. We here provide structural evidence for how the single polymorphic residue (HLA-DQ2.5-Tyr22α and HLA-DQ2.2-Phe22α) accoun ...[more]

PMID: 31974305

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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.

Project description:BACKGROUND:The presence of HLA haplotype DR3-DQ2 or DR4-DQ8 is associated with an increased risk of celiac disease. In addition, nearly all children with celiac disease have serum antibodies against tissue transglutaminase (tTG). METHODS:We studied 6403 children with HLA haplotype DR3-DQ2 or DR4-DQ8 prospectively from birth in the United States, Finland, Germany, and Sweden. The primary end point was the development of celiac disease autoimmunity, which was defined as the presence of tTG antibodies on two consecutive tests at least 3 months apart. The secondary end point was the development of celiac disease, which was defined for the purpose of this study as either a diagnosis on biopsy or persistently high levels of tTG antibodies. RESULTS:The median follow-up was 60 months (interquartile range, 46 to 77). Celiac disease autoimmunity developed in 786 children (12%). Of the 350 children who underwent biopsy, 291 had confirmed celiac disease; an additional 21 children who did not undergo biopsy had persistently high levels of tTG antibodies. The risks of celiac disease autoimmunity and celiac disease by the age of 5 years were 11% and 3%, respectively, among children with a single DR3-DQ2 haplotype, and 26% and 11%, respectively, among those with two copies (DR3-DQ2 homozygosity). In the adjusted model, the hazard ratios for celiac disease autoimmunity were 2.09 (95% confidence interval [CI], 1.70 to 2.56) among heterozygotes and 5.70 (95% CI, 4.66 to 6.97) among homozygotes, as compared with children who had the lowest-risk genotypes (DR4-DQ8 heterozygotes or homozygotes). Residence in Sweden was also independently associated with an increased risk of celiac disease autoimmunity (hazard ratio, 1.90; 95% CI, 1.61 to 2.25). CONCLUSIONS:Children with the HLA haplotype DR3-DQ2, especially homozygotes, were found to be at high risk for celiac disease autoimmunity and celiac disease early in childhood. The higher risk in Sweden than in other countries highlights the importance of studying environmental factors associated with celiac disease. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others.).

Dataset Information

A molecular basis for the T cell response in HLA-DQ2.2 mediated celiac disease.

Publications

A molecular basis for the T cell response in HLA-DQ2.2 mediated celiac disease.

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