Celiac Disease: A Review of Current Concepts in Pathogenesis, Prevention, and Novel Therapies

Tye–Din, Jason A.; Galipeau, Heather J.; Agardh, Daniel

doi:10.3389/fped.2018.00350

Cited by 138 publications

(107 citation statements)

References 242 publications

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“…After clustering our cis -eQTL prioritized genes on shared co-regulation, we identified a cluster of genes involved in T cell activation and co-stimulation (cluster 3), highlighting a key role for T cell activation in the pathogenesis of CeD 63 . Within this co-regulation cluster we found the THEMIS , IL2, CD28 , CTLA4 and UBASH3A genes ( Fig.…”

Section: Discussionmentioning

confidence: 99%

Systematic prioritization of candidate genes in disease loci identifies TRAFD1 as a master regulator of IFNγ signalling in celiac disease

Graaf

Zorro

Claringbould

et al. 2020

Preprint

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BackgroundCeliac disease (CeD) is a complex T cell–mediated enteropathy induced by gluten. Although genome-wide association studies have identified numerous genomic regions associated with CeD, it is difficult to accurately pinpoint which genes in these loci are most likely to cause CeD.ResultsWe used four different in silico approaches – Mendelian Randomization inverse variance weighting, COLOC, LD overlap and DEPICT – to integrate information gathered from a large transcriptomics dataset. This identified 118 prioritized genes across 50 CeD-associated regions. Co-expression and pathway analysis of these genes indicated an association with adaptive and innate cytokine signalling and T cell activation pathways. 51 of these genes are targets of known drug compounds and likely druggable genes, suggesting that our methods can be used to pinpoint potential therapeutic targets. In addition, we detected 172 gene-combinations that were affected by our CeD-prioritized genes in trans. Notably, 41 of these trans-mediated genes appear to be under control of one master regulator, TRAFD1, and were found to be involved in IFNγ signalling and MHC I antigen processing/presentation. Finally, we performed in vitro experiments that validated the role of TRAFD1 as an immune regulator acting in trans.ConclusionsOur strategy has confirmed the role of adaptive immunity in CeD and revealed a genetic link between CeD and the IFNγ signalling and MHC I antigen processing pathways, both major players of immune activation and CeD pathogenesis.

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Section: Discussionmentioning

confidence: 99%

Systematic prioritization of candidate genes in disease loci identifies TRAFD1 as a master regulator of IFNγ signalling in celiac disease

Graaf

Zorro

Claringbould

et al. 2020

Preprint

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“…Although, the GFD is efficacious in the great majority of patients, with the restoration of mucosa villous morphology and function, many young patients are poorly compliant, so that the identification of an alternative treatment would be beneficial for those patients for whom the GFD fails or is impracticable (102). Recently, great efforts were made to identify a pharmacological therapy that could be used to replace or support the GFD for treatment of CD patients (103). Currently, several proteolytic enzymes of microbial or plant origins have demonstrated a high efficiency to quickly degrade gluten proteins at very low pH, as occurring in gastric conditions (104)(105)(106)(107).…”

Section: Gluten Degradation As a Treatmentmentioning

confidence: 99%

Recent Progress and Recommendations on Celiac Disease From the Working Group on Prolamin Analysis and Toxicity

et al. 2020

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Celiac disease (CD) affects a growing number of individuals worldwide. To elucidate the causes for this increase, future multidisciplinary collaboration is key to understanding the interactions between immunoreactive components in gluten-containing cereals and the human gastrointestinal tract and immune system and to devise strategies for CD prevention and treatment beyond the gluten-free diet. During the last meetings, the Working Group on Prolamin Analysis and Toxicity (Prolamin Working Group, PWG) discussed recent progress in the field together with key stakeholders from celiac disease societies, academia, industry and regulatory bodies. Based on the current state of knowledge, this perspective from the PWG members provides recommendations regarding clinical, analytical and legal aspects of CD. The selected key topics that require future multidisciplinary collaborative efforts in the clinical field are to collect robust data on the increasing prevalence of CD, to evaluate what is special about gluten-specific T cells, to study their kinetics and transcriptomics and to put some attention to the identification of the environmental agents that facilitate the breaking of tolerance to gluten. In the field of gluten analysis, the key topics are the precise assessment of gluten immunoreactive components in wheat, rye and barley to understand how these are affected by genetic and environmental factors, the comparison of different methods for compliance monitoring of gluten-free products and the development of improved reference materials for gluten analysis.

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“…This therefore renders at least onethird of the patients without the possibility of benefiting from this therapeutic approach. Hence, it is necessary to identify the specific epitopes that are recognized by all patients and that allow the safe reintroduction of gluten in the diet [54], regardless of the HLA haplotype. [119,120].…”

Section: C) Vaccination: Nexvax2mentioning

confidence: 99%

Challenges to drug discovery for celiac disease and approaches to overcome them

Vaquero

Bernardo

León

et al. 2019

Expert Opinion on Drug Discovery

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Introduction: The only available effective treatment for celiac disease is strict and long-term compliance with a gluten-free diet. Dietary gluten restriction must be strict and long term, but is difficult to achieve in many cases and alternative dietary strategies have been investigated in the past few years.Areas covered: This review highlights the progress that has been made in the development of new therapeutics for CD. Detailed information of the evidence about the targets of the drugs related to their mechanisms of action is covered. The therapies are classified in five mechanisms: modification of gluten, intraluminal therapies, immunomodulation, intestinal permeability and modulation of adaptative response. The actual development phase and future approach are also described and discussed.Expert opinion: There are several limitations in each of the treatment targets related to their complications or the lack of complete response to normal gluten containing diet. The most desired therapy for celiac patients is the induction of gluten tolerance that would be curative.Therefore, it is expected that shortly, alternative or complementary tools for the treatment of gluten-free diet will be available to patients with celiac disease and will improve their quality of life.Gluten is a protein that is insoluble in both water and diluted salt solutions [9]. This protein triggers intestinal inflammation mediated by the human leucocyte antigen (HLA) system via HLA-DQ2 or DQ8 molecules. Intestinal inflammation may lead to the malabsorption of nutrients, as well as secondary iron deficiency (anemia) and osteoporosis.The only available effective treatment for CD is strict and long-term compliance with a glutenfree diet (GFD). Nonetheless, it has been shown that mucosal recovery can be lengthy.Moreover, 30%-50% of patients have persistent lesions in the intestinal mucosa and recurrent symptoms despite dietary gluten restriction (GFD-resistant CD or non-responsive CD) [10, 11].Gluten restriction requires extensive personal effort, which has psychological and social consequences and may limit full compliance [12,13]. Unintentional or deliberate noncompliance with GFD occurs in up to 50% of cases [14, 15]. In addition, approximately 1% of patients with celiac disease do not respond to GFD (refractory CD [RCD]). These patients are diagnosed mainly in adulthood after long-term exposure to gluten and are at risk of developing complications such as RCD type II (an intestinal lymphoma) or its more severe complication, enteropathy-associated T-cell lymphoma (EATL) [16, 17]. PATHOGENESIS OF CDCD develops in genetically predisposed individuals as an immune response to gluten present in certain grains (wheat, barley, and rye [18]). Although oats are considered safe for patients with CD, different oat varieties have distinct immunogenic potentials in patients with celiac disease based on the presence of toxic prolamines [19]. The immune system involves innate responses (caused by the direct toxic effects of gluten on the epithelium) and ...

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Celiac Disease: A Review of Current Concepts in Pathogenesis, Prevention, and Novel Therapies

Cited by 138 publications

References 242 publications

Systematic prioritization of candidate genes in disease loci identifies TRAFD1 as a master regulator of IFNγ signalling in celiac disease

Systematic prioritization of candidate genes in disease loci identifies TRAFD1 as a master regulator of IFNγ signalling in celiac disease

Recent Progress and Recommendations on Celiac Disease From the Working Group on Prolamin Analysis and Toxicity

Challenges to drug discovery for celiac disease and approaches to overcome them

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