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An Interpretable Classification Model Using Gluten-Specific TCR Sequences Shows Diagnostic Potential in Coeliac Disease.

ABSTRACT: Coeliac disease (CeD) is a T-cell mediated enteropathy triggered by dietary gluten which remains substantially under-diagnosed around the world. The diagnostic gold-standard requires histological assessment of intestinal biopsies taken at endoscopy while consuming a gluten-containing diet. However, there is a lack of concordance between pathologists in histological assessment, and both endoscopy and gluten challenge are burdensome and unpleasant for patients. Identification of gluten-specific T-cell receptors (TCRs) in the TCR repertoire could provide a less subjective diagnostic test, and potentially remove the need to consume gluten. We review published gluten-specific TCR sequences, and develop an interpretable machine learning model to investigate their diagnostic potential. To investigate this, we sequenced the TCR repertoires of mucosal CD4⁺ T cells from 20 patients with and without CeD. These data were used as a training dataset to develop the model, then an independently published dataset of 20 patients was used as the testing dataset. We determined that this model has a training accuracy of 100% and testing accuracy of 80% for the diagnosis of CeD, including in patients on a gluten-free diet (GFD). We identified 20 CD4⁺ TCR sequences with the highest diagnostic potential for CeD. The sequences identified here have the potential to provide an objective diagnostic test for CeD, which does not require the consumption of gluten.

SUBMITTER: Fowler A

PROVIDER: S-EPMC10742135 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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An Interpretable Classification Model Using Gluten-Specific TCR Sequences Shows Diagnostic Potential in Coeliac Disease.

Fowler Anna A FitzPatrick Michael M Shanmugarasa Aberami A Ibrahim Amro Sayed Fadel ASF Kockelbergh Hannah H Yang Han-Chieh HC Williams-Walker Amelia A Luu Hoang Kim Ngan KN Evans Shelley S Provine Nicholas N Klenerman Paul P Soilleux Elizabeth J EJ

Biomolecules 20231125 12

Coeliac disease (CeD) is a T-cell mediated enteropathy triggered by dietary gluten which remains substantially under-diagnosed around the world. The diagnostic gold-standard requires histological assessment of intestinal biopsies taken at endoscopy while consuming a gluten-containing diet. However, there is a lack of concordance between pathologists in histological assessment, and both endoscopy and gluten challenge are burdensome and unpleasant for patients. Identification of gluten-specific T- ...[more]

PMID: 38136579

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Project description:Background:Increasing efforts are being put into new treatment options for coeliac disease (CeD), a chronic disorder of the small intestine induced by gluten. Interleukin-2 (IL-2) and gluten-specific CD4 + T cells increase in the blood after four hours and six days, respectively, following a gluten challenge in CeD patients. These responses are unique to CeD and are not seen in controls. We aimed to evaluate different markers reflecting a recall response to gluten exposure that may be used to monitor therapy. Methods:CeD patients on a gluten-free diet underwent a one- (n = 6) or three-day (n = 7) oral gluten challenges. We collected blood samples at several time points between baseline and day 8, and monitored gluten-specific CD4 + T cells for their frequency and CD38 expression using HLA-DQ:gluten tetramers. We assessed the IL-2 concentration in plasma four hours after the first gluten intake. Results:The frequency of gut-homing, tetramer-binding, CD4 + effector memory T (tetramer + β7 + TEM) cells and the IL-2 concentration measured shortly after the first dose of gluten increased significantly after the one- and three-day gluten challenges, but large interindividual differences were exhibited. The frequency of tetramer + β7 + TEM plateaued between days 6 and 8 and was lower after the one-day challenge. We observed a consistent increase in CD38 expression on tetramer + β7 + TEM cells and did not find a significant difference between the one- and three-day challenges. Conclusions:The optimal time points for monitoring therapy response in CeD after a three-day oral gluten challenge is four hours for plasma IL-2 or six to eight days for the frequency of tetramer + β7 + TEM cells, but both these parameters involved large interindividual differences. In contrast, CD38 expression on tetramer + β7 + TEM cells increased uniformly and irrespectively of the length of gluten challenge, suggesting that this parameter is more suited for monitoring drug efficacy in clinical trials for CeD.

Project description:Non-coeliac gluten sensitivity (NCGS) refers to patients with primarily gastrointestinal symptoms without enteropathy that symptomatically benefit from gluten-free diet (GFD). Little is known about its pathophysiology, propensity to neurological manifestations, and if these differ from patients with coeliac disease (CD). We investigated the clinical and immunological characteristics of patients presenting with neurological manifestations with CD and those with NCGS.We compared clinical, neurophysiological, and imaging data of patients with CD and NCGS presenting with neurological dysfunction assessed and followed up regularly over a period of 20 years.Out of 700 patients, 562 were included. Exclusion criteria included no bowel biopsy to confirm CD, no HLA type available, and failure to adhere to GFD. All patients presented with neurological dysfunction and had circulating anti-gliadin antibodies. Out of 562 patients, 228 (41%) had evidence of enteropathy (Group 1, CD) and 334 (59%) did not (Group 2, NCGS). The most common neurological manifestations were cerebellar ataxia, peripheral neuropathy, and encephalopathy. There was a greater proportion of patients with encephalopathy in Group 1 and with a greater proportion of neuropathy in Group 2. The severity of ataxia did not differ between the two groups. Patients in Group 1 had more severe neuropathy. All patients from both groups responded to gluten-free diet. Anti-tissue transglutaminase (TG2) antibodies were found in 91% of patients in Group 1 and in 29% of patients in Group 2. Comparison between those patients in Group 2 with HLA-DQ2/DQ8 and those without as well as those with positive TG2 compared with those with negative TG2 antibodies identified no differences within these subgroups. Serological positivity for TG6 antibodies was similar in the two groups (67 and 60%).The neurological manifestations of CD and NCGS are similar and equally responsive to a GFD suggestive of common pathophysiological mechanisms.

Project description:IntroductionCoeliac disease (CD) is a systemic immune-mediated disorder triggered by gluten in genetically predisposed individuals. CD is diagnosed using a combination of serology tests and endoscopic biopsy of the small intestine. However, because of non-specific symptoms and heterogeneous clinical presentation, diagnosing CD is challenging. Early detection of CD through improved case-finding strategies can improve the response to a gluten-free diet, patients' quality of life and potentially reduce the risk of complications. However, there is a lack of consensus in which groups may benefit from active case-finding.Methods and analysisWe will perform a systematic review to determine the accuracy of diagnostic indicators (such as symptoms and risk factors) for CD in adults and children, and thus can help identify patients who should be offered CD testing. MEDLINE, Embase, Cochrane Library and Web of Science will be searched from 1997 until 2020. Screening will be performed in duplicate. Data extraction will be performed by one and checked by a second reviewer. Disagreements will be resolved through discussion or referral to a third reviewer. We will produce a narrative summary of identified prediction models. Studies, where 2×2 data can be extracted or reconstructed, will be treated as diagnostic accuracy studies, that is, the diagnostic indicators are the index tests and CD serology and/or biopsy is the reference standard. For each diagnostic indicator, we will perform a bivariate random-effects meta-analysis of the sensitivity and specificity.Ethics and disseminationResults will be reported in peer-reviewed journals, academic and public presentations and social media. We will convene an implementation panel to advise on the optimum strategy for enhanced dissemination. We will discuss findings with Coeliac UK to help with dissemination to patients. Ethical approval is not applicable, as this is a systematic review and no research participants will be involved.Prospero registration numberCRD42020170766.

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An Interpretable Classification Model Using Gluten-Specific TCR Sequences Shows Diagnostic Potential in Coeliac Disease.

Publications

An Interpretable Classification Model Using Gluten-Specific TCR Sequences Shows Diagnostic Potential in Coeliac Disease.

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