Indian Journal of Pharmacology Home 

[Download PDF]
Year : 2019  |  Volume : 51  |  Issue : 5  |  Page : 359--365

Novel targets for drug discovery in celiac disease

Rahul Soloman Singh, Ashutosh Singh, Gitika Batra, Hardeep Kaur, Bikash Medhi 
 Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh, India

Correspondence Address:
Dr. Bikash Medhi
Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh - 160 012


Celiac disease is a lifelong, immunological disorder induced by dietary protein-gluten, in a genetically susceptible populations, resulting in different clinical manifestations, the release of antibodies, and damage to the intestinal mucosa. The only recommended therapy for the disease is to strictly follow a gluten-free diet (GFD), which is difficult to comply with. A GFD is found to be ineffective in some active Celiac disease cases. Therefore, there is an unmet need for an alternative nondietary therapeutic approach. The review focuses on the novel drug targets for Celiac disease.

How to cite this article:
Singh RS, Singh A, Batra G, Kaur H, Medhi B. Novel targets for drug discovery in celiac disease.Indian J Pharmacol 2019;51:359-365

How to cite this URL:
Singh RS, Singh A, Batra G, Kaur H, Medhi B. Novel targets for drug discovery in celiac disease. Indian J Pharmacol [serial online] 2019 [cited 2021 Dec 3 ];51:359-365
Available from:

Full Text


Celiac disease is a chronic disease which involves the deregulation of the immune system along with inflammation of the small bowel on exposure to an environmental factor, i.e., dietary protein – gluten, in individuals carrying specific genetic background. Different studies depicted the prevalence of Celiac disease worldwide is 0.7%.[1] The literature reported a prevalence of 1.04% (1 in 96) along with seropositivity of anti-tissue transglutaminase antibody 1.44% (1 in 69) in North India.[2] A gluten-free diet (GFD) is the lone recommended therapy for Celiac disease. To comply with a GFD is challenging because of many reasons, for instance, GFD is not easily available, no proper consensus of available gluten in the GFD, low palatability, and the therapy is not found to be effective in refractory Celiac disease (RCD). Moreover, about 30% experience persistent symptoms with GFD. Therefore, there is an urgent need for an alternative nondietary therapeutic approach. A new understanding of the disease pathophysiology has opened new doors to develop novel therapies.[3]

 Novel Drug Targets for Celiac Disease

Compromised gut permeability – A drug target

Compromised gut permeability is a vital characteristic of Celiac disease. Zonulin, an intestinal enzyme has a structural similarity with growth factors that regulate tight junction integrity. Once Zonulin interacts with specific gliadin peptide, it results in upregulated gut paracellular permeability.[4] Larazotide acetate (AT-1001) is a protein extracted from a cholera toxin found to inhibit the zonulin activity and thereby ameliorate gut permeability.[5],[6] Currently, AT-1001 is in Phase 2 clinical trial [Table 1].{Table 1}

CXCR3, a chemokine receptor and its ligand (specifically CXCL10) overexpress in the disease state. The interaction of CXCR3 with the gliadin peptide regulates Zonulin production and increase gut permeability. MyD88, an adapter protein is also involved during the interaction of chemokine and gliadin. This chemokine could be used as a novel therapeutic target for Celiac disease.[7],[8]

Secretory IgA presents in the apical region of intestinal epithelium forms complexes with gliadin peptide. These complexes, with the help of transferrin receptor CD71 moves into the basal region of lamina propria from the apical region. This way gliadin peptide bypasses the lysosomal degradation. Once these harmful peptides reach the lamina propria, it gets the license to destroy the intestinal cells.[9]

Undigested peptides – A drug target

The human gut lacks prolyl endopeptidase activity which is required to digest the long gliadin peptide. Once these undigested gliadin peptides crosses the tight junction and reaches to lamina propria, it activates different immunological cascades which leads to intestinal damage. One of the approaches is also to introduce enzymes which could break or digest proline and glutamine bond in the immunogenic peptides.[6],[7],[8] ALV003 is an enzyme supplement, the mixture of two recombinant gluten-specific proteases and is in Phase 2b clinical trial as an adjunct therapy with a GFD [Table 1].[10]

Gluten sensitization – A drug target

Apart from targeting a specific cascade which alters in Celiac disease, an alternative approach is vaccination, which aimed to provide gluten tolerance. NexVax 2 is a therapeutic or desensitization vaccine developed by ImmuSanT and is in the Phase 1 clinical trial. The vaccine employed three peptides of gluten to induce tolerogenic in Celiac patients [Table 1].[11]

By encapsulating a component of wheat within a nanoparticle, Cour pharmaceutical is developing a novel treatment that proposes to develop gluten tolerance in Celiac disease. Phase 1 clinical trial is being conducted to characterize the safety and tolerability of a drug called TIMP-GLIA to develop immune tolerance (NCT02679014) [Table 1].

Adaptive immune response – A drug target

When undigested gliadin peptide breaches the intestinal tight junction, it interacts with tissue transglutaminase enzymes (TG2), which deamidate these peptides. Now, these negatively charged and stable peptide interacts with major histocompatibility complex (MHC) Class-II specifically HLADQ2 or HLA-DQ8 which are present on antigen-presenting cells (APCs).[12],[13] APCs present deamidated peptide to CD4+ T-cells. Once CD4+ T-cells get activated, it releases Th1 cytokines like interferon-γ (IFN-γ), interleukin-18 (IL-18), IL-21. IFN-γ activates the Zonulin enzyme and further increased the tight junction permeability of the intestinal barrier.[13] Secreted IFN-γ also induces metalloproteases production by myofibroblasts lamina propria mononuclear cells, which leads to tissue remodeling.[14]

CD4+ T-cells through Th2 response also increases the population of B-Cells and increase in the release of antibodies for instance, tissue transglutaminase, anti-gliadin, deamidated gliadin peptide, and endomysial antibodies [Figure 1].[15]{Figure 1}

Antibodies deposited on the extracellular surface leads to alteration in the enterocyte cytoskeletal and actin redistribution. This further leads to epithelial damage.[16]

These all cascades also generates Fas/Fas ligand or activation of the NKG2D-MIC and perforin granzyme signaling pathway through IL-15 which leads to the interaction of the natural killer (NK) receptor on CD8+ T-cells and MICA (MHC Class I polypeptide-related sequence A) present on epithelial cells and results in further epithelial damage.[17]

It seems to be a promising strategy to inhibit the human leukocyte antigen (HLA) binding grooves with the gliadin antagonist. The strategy can further inhibit the T-cell activation pathway, which is vital for the destructive signaling cascade.[18] Dimeric and azidoproline analogs of gluten peptide are some HLA blockers that are presently in the preclinical stage [Table 1].[19]

Cathepsin S is a cysteine protease which proteolysis MHC Class II invariant chain for the presentation of antigen. This makes it a redundant target for drug therapies in various disease conditions. The protease inhibitor, RG7625 (Cathepsin S inhibitor) is in the Phase 1 clinical trial since 2016 [Table 1]. The result of the trial is still awaited.[20],[21]

Underin vitro and ex vivo studies using Caco cells and organ culture simultaneously, TG2 inhibitors, i.e., R281 and R283 showed a protective effect against gliadin-induced toxicity.[22] Inhibition of TG2 using TG2 inhibitor cystamine reduced the T-cell population. The results depicted that the inhibition of TG2 can ameliorate the harmful response of gluten-specific T-cells in the intestine.[23]

The introduction of anti-IFN-γ antibodies in gliadin-specific T-cell lines showed to avert the intestinal damage from the secreted inflammatory cytokines.[24]

Innate immune response – A drug target

Immunogenic gliadin peptide activates the release of cytokines such as IL-15, epidermal growth factor and IFN-α, which leads to the proliferation of enterocytes, dendritic cells, and intraepithelial lymphocytes (IELs), important for the pathogenesis of the disease.[25],[26] Increase expression of IL-15 in active Celiac disease upregulates NK receptors, i.e., CD94 and NKG2D by CD3+ IEL, which finally leads to T-cell receptor-independent destruction.[27]

Tumor necrosis factor-alpha (TNF-α) along with IFN-γ is cytotoxic to IELs. Infliximab, antibodies against TNF-α, showed to be efficacious in RCD.[28],[29] In the transgenic mouse model, inhibition of IL-15 demonstrated the reduction of IELs by promoting IELs apoptosis. IL-15 inhibits the apoptosis of cytotoxic IELs, which regulates RCD via the JAK3/STAT5 signaling pathway.[30] AMG-714, a monoclonal antibody for IL-15 is a promising drug strategy and has completed the Phase 2 clinical trial in Celiac disease [Table 1]. The study found no significant difference in villous height and crypt depth ratio between Celiac patients and control.[31]

Alfa amylase/trypsin inhibitors used in Wheat crops for pest control increase the TLR4-MD2 cluster of differentiation complex activity. It also upregulates proinflammatory cytokines levels, which further leads to the activation of the innate immune system.[32]

Cell adhesion molecules such as mucosal addressin cell adhesion molecule-1 (MAdCAM-1) and integrin (a4b7) are important for the recruitment of lymphocyte at the site of injury in Celiac patients. Hence, the inhibition of both these molecules found to be a beneficial strategy for celiac patients.[16] Moreover, Natalizumab, a monoclonal antibody of a4b7 observed to be efficacious in Crohn's disease.[33]

Toll-like receptor as a drug target

Previous studies suggested the involvement of toll-like receptors (TLRs) in an innate immune response. TLR's recognize the by-products of gut microbiota[34],[35] and in response activates the release of inflammatory cytokines such as IL-6, TNFα, and IFN-γ.[35],[36],[37],[38] The inflammatory cascade activated results in characteristic pathological changes of the intestine.[27],[39] The alteration in the TLR-4 and TLR-9 in blood and biopsy of Celiac disease patients showed its important role in innate immunity. The previous study also depicted the role of an immunogenic peptide in activating TLR's.[7],[40] Thus, it is a potent drug target for Celiac disease, which further requires validation using large data.

Micro RNA – A drug target

In general, micro RNA (miRNA) acts in cell differentiation and proliferation. miRNA found to alter epithelial cell function and differentiation, increased crypt apoptosis, and alter gut permeability. miRNA alteration found to affect NOTCH1 signaling activity, thereby affecting intestinal cell differentiation in Celiac disease. Studies showed that miRNA such as miR-124a, miR-189, miR-299-5p, miR-379, miR-449a, and miR-34 dysregulated in Celiac disease.[41],[42],[43],[44]

By minute identification of these miRNAs and related targets and mechanisms, specific therapeutics can be developed for suppression of these pathophysiological pathways through miRNAs enhancement or inhibition.[41],[42]

Dysbiosis – A drug target

Previous studies depicted dysbiosis in active Celiac patients. The beneficial microbiota for instance Bifidobacteria level gets decreased, and harmful microbiota levels such as Gram-negative bacteria, such as Proteobacteria genera (Staphylococcus spp. And Bacteroides) increases in the disease state.[45],[46],[47],[48]

Studies suggested that the imbalance in microbiota in active Celiac condition results in altered gut permeability, which could be deleterious for immune activation. Probiotic therapy, along with GFD could be useful to ameliorate the dysbiosis, which ultimately prevents gliadin toxicity and immune activation.

Genetic susceptibility – A drug target

Genome-wide association study (GWAS) and immunochip analyses studies found about 39 important regions which increase the susceptibility toward the disease.[49],[50] These targets are crucial for future drug therapy approaches.

Thymocyte-expressed molecule involved in selection (THEMIS), which leads to T-cell maturation and thymocyte maturation into CD4+ and CD8+ T-cells, leads to a decrease in T-cell receptor signaling.[51] Once THEMIS gets activated, it decreases TCR signaling through the recruitment of SHP1.[52] TCR signaling finally affects the selection of immunological tolerant T-cells or overly self-reactive T-cells. Expression of THEMIS increases in Celiac disease, thereby making it a novel target for drug therapy.

Protein tyrosine phosphatase, receptor type, kappa (PTPRK) gene codes for transmembrane protein tyrosine phosphatase. TGF-β induces expression of PTPRK and modulates T-cell development which involves the progression of Celiac disease.[53] The expression of PTPRK decreases in Celiac disease. In the PTPRK knockout animal, IgG decreases, which ultimately decreases the T-helper function.[54] PTPRK maintain cell-cell adhesion, thereby maintaining the membrane permeability.[55]

Α-1,2-fucosyltransferase (FUT2) catalyzes the transformation of the type-1 precursor into H-antigen type-1 through the addition of α-1,2-linked fucose.[56] Now H-antigen type-1 acts as a precursor of A, B-blood group antigen, which mainly expressed in mucus, gastrointestinal mucosa and served as an anchor for the microbes. It is associated with an increased susceptibility toward Celiac disease.[57]

Polymorphisms of B-cell specific transcriptional repressor (BACH 2) associates with allergies and autoimmune disease. BACH2 in T-cells are important for regulatory T-cells, and naïve T-cells state.[50],[58],[59],[60] BACH2 helps in maintaining immune homeostasis, which is vital for T-cell differentiation.[61] It is interesting to validate its role in Celiac disease.

Previous studies have observed that SNPs in the RGS1 gene lead to an autoimmune condition such as Celiac disease, type-1 diabetes, and multiple sclerosis.[62],[63],[64] RGS1 encodes for regulator G-protein signaling-1 which modulates chemokine-induced GPCR activity. It also regulates cell chemotaxis.[65],[66] It has been found that the mRNA expression of RGS1 gets increased more in the gut than in peripheral blood during inflammation.[67] In Celiac disease, the SNPs for RGS1 affect its transcriptional regulation.


There is a dearth of drug therapy in Celiac disease. The only recommended therapy for Celiac disease is a GFD throughout life which is difficult to follow. The ideal therapy for the disease would provide the opportunity to the Celiac disease patients to include gluten in their diet. There are many promising therapeutic strategies that are under preclinical and clinical phasesIL-15 inhibitor (AMG 714) has shown to be promising in the Phase 2 clinical trial. Zonulin antagonist (Larazotide Acetate) also proved to be potential therapy. Glutenases for instance ALV003 seem to be more beneficial and is under Phase 2 clinical trials. Many promising molecules are at early stages of research such as TG2 inhibitors, HLA blockers, and probioticsDrug therapies targeting miRNA which alter in Celiac disease are promising while GWAS studies also paved the way to find novel drug targets. For validation these targets require further studies with large sample sizeThe lacuna in the development of drugs for Celiac disease is the unavailability of suitable animal model for the disease which can be used to evaluate therapeutic approaches. Hence, it is the need of the hour to establish and validate suitable animal model for the diseaseWith the increase in understanding of the mechanism of Celiac disease, numerous novel targets for the disease have identified, which provided a scope to develop new drug strategies for Celiac disease. The current and future therapies are targeting to provide an alternate of GFD instead of searching adjuvant therapy.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.


1Singh P, Arora A, Strand TA, Leffler DA, Catassi C, Green PH, et al. Global prevalence of celiac disease: Systematic review and meta-analysis. Clin Gastroenterol Hepatol 2018;16:823-3600.
2Makharia GK, Verma AK, Amarchand R, Bhatnagar S, Das P, Goswami A, et al. Prevalence of celiac disease in the northern part of India: A community based study. J Gastroenterol Hepatol 2011;26:894-900.
3Bakshi A, Stephen S, Borum ML, Doman DB. Emerging therapeutic options for celiac disease: Potential alternatives to a gluten-free diet. Gastroenterol Hepatol (N Y) 2012;8:582-8.
4Fasano A. Zonulin and its regulation of intestinal barrier function: The biological door to inflammation, autoimmunity, and cancer. Physiol Rev 2011;91:151-75.
5Paterson BM, Lammers KM, Arrieta MC, Fasano A, Meddings JB. The safety, tolerance, pharmacokinetic and pharmacodynamic effects of single doses of AT-1001 in coeliac disease subjects: A proof of concept study. Aliment Pharmacol Ther 2007;26:757-66.
6Fasano A, Uzzau S. Modulation of intestinal tight junctions by Zonula occludens toxin permits enteral administration of insulin and other macromolecules in an animal model. J Clin Invest 1997;99:1158-64.
7Fasano A. Zonulin, regulation of tight junctions, and autoimmune diseases. Ann N Y Acad Sci 2012;1258:25-33.
8Haghbin M, Rostami-Nejad M, Forouzesh F, Sadeghi A, Rostami K, Aghamohammadi E, et al. The role of CXCR3 and its ligands CXCL10 and CXCL11 in the pathogenesis of celiac disease. Medicine (Baltimore) 2019;98:e15949.
9Matysiak-Budnik T, Moura IC, Arcos-Fajardo M, Lebreton C, Ménard S, Candalh C, et al. Secretory IgA mediates retrotranscytosis of intact gliadin peptides via the transferrin receptor in celiac disease. J Exp Med 2008;205:143-54.
10Lähdeaho ML, Kaukinen K, Laurila K, Vuotikka P, Koivurova OP, Kärjä-Lahdensuu T, et al. Glutenase ALV003 attenuates gluten-induced mucosal injury in patients with celiac disease. Gastroenterology 2014;146:1649-58.
11Di Sabatino A, Lenti MV, Corazza GR, Gianfrani C. Vaccine immunotherapy for celiac disease. Front Med (Lausanne) 2018;5:187.
12Stamnaes J, Sollid LM. Celiac disease: Autoimmunity in response to food antigen. Semin Immunol 2015;27:343-52.
13van de Wal Y, Kooy Y, van Veelen P, Peña S, Mearin L, Papadopoulos G, et al. Selective deamidation by tissue transglutaminase strongly enhances gliadin-specific T cell reactivity. J Immunol 1998;161:1585-8.
14Prehn JL, Landers CJ, Targan SR. A soluble factor produced by lamina propria mononuclear cells is required for TNF-alpha enhancement of IFN-gamma production by T cells. J Immunol 1999;163:4277-83.
15De Re V, Magris R, Cannizzaro R. New insights into the pathogenesis of celiac disease. Front Med (Lausanne) 2017;4:137.
16Di Sabatino A, Corazza GR. Coeliac disease. Lancet 2009;373:1480-93.
17Jabri B, Sollid LM. Tissue-mediated control of immunopathology in coeliac disease. Nat Rev Immunol 2009;9:858-70.
18Rashtak S, Murray JA. Review article: Coeliac disease, new approaches to therapy. Aliment Pharmacol Ther 2012;35:768-81.
19Xia J, Bergseng E, Fleckenstein B, Siegel M, Kim CY, Khosla C, et al. Cyclic and dimeric gluten peptide analogues inhibiting DQ2-mediated antigen presentation in celiac disease. Bioorg Med Chem 2007;15:6565-73.
20Nakagawa TY, Brissette WH, Lira PD, Griffiths RJ, Petrushova N, Stock J, et al. Impaired invariant chain degradation and antigen presentation and diminished collagen-induced arthritis in Cathepsin S null mice. Immunity 1999;10:207-17.
21Theron M, Bentley D, Nagel S, Manchester M, Gerg M, Schindler T, et al. Pharmacodynamic monitoring of ro5459072, a small molecule inhibitor of Cathepsin S. Front Immunol 2017;8:806.
22Rauhavirta T, Oittinen M, Kivistö R, Männistö PT, Garcia-Horsman JA, Wang Z, et al. Are transglutaminase 2 inhibitors able to reduce gliadin-induced toxicity related to celiac disease? A proof-of-concept study. J Clin Immunol 2013;33:134-42.
23McConoughey SJ, Basso M, Niatsetskaya ZV, Sleiman SF, Smirnova NA, Langley BC, et al. Inhibition of transglutaminase 2 mitigates transcriptional dysregulation in models of Huntington disease. EMBO Mol Med 2010;2:349-70.
24Przemioslo RT, Lundin KE, Sollid LM, Nelufer J, Ciclitira PJ. Histological changes in small bowel mucosa induced by gliadin sensitive T lymphocytes can be blocked by anti-interferon gamma antibody. Gut 1995;36:874-9.
25Kim SM, Mayassi T, Jabri B. Innate immunity: Actuating the gears of celiac disease pathogenesis. Best Pract Res Clin Gastroenterol 2015;29:425-35.
26Barone MV, Troncone R, Auricchio S. Gliadin peptides as triggers of the proliferative and stress/innate immune response of the celiac small intestinal mucosa. Int J Mol Sci 2014;15:20518-37.
27Jelínková L, Tucková L, Cinová J, Flegelová Z, Tlaskalová-Hogenová H. Gliadin stimulates human monocytes to production of IL-8 and TNF-alpha through a mechanism involving NF-kappaB. FEBS Lett 2004;571:81-5.
28Gillett HR, Arnott ID, McIntyre M, Campbell S, Dahele A, Priest M, et al. Successful infliximab treatment for steroid-refractory celiac disease: A case report. Gastroenterology 2002;122:800-5.
29Costantino G, della Torre A, Lo Presti MA, Caruso R, Mazzon E, Fries W. Treatment of life-threatening type I refractory coeliac disease with long-term infliximab. Dig Liver Dis 2008;40:74-7.
30Malamut G, Meresse B, Cellier C, Cerf-Bensussan N. Celiac disease in 2009: A future without gluten-free diet?. Gastroenterol Clin Biol 2009;33:635-47.
31Lähdeaho ML, Scheinin M, Vuotikka P, Taavela J, Popp A, Laukkarinen J, et al. Safety and efficacy of AMG 714 in adults with coeliac disease exposed to gluten challenge: A phase 2a, randomised, double-blind, placebo-controlled study. Lancet Gastroenterol Hepatol 2019;4:948-59.
32Reig-Otero Y, Mañes J, Manyes L. Amylase-trypsin inhibitors in wheat and other cereals as potential activators of the effects of nonceliac gluten sensitivity. J Med Food 2018;21:207-14.
33Nelson SM, Nguyen TM, McDonald JW, MacDonald JK. Natalizumab for induction of remission in Crohn's disease. Cochrane Database Syst Rev 2018;8:CD006097.
34Marasco G, Di Biase AR, Schiumerini R, Eusebi LH, Iughetti L, Ravaioli F, et al. Gut microbiota and celiac disease. Dig Dis Sci 2016;61:1461-72.
35Kalliomäki M, Satokari R, Lähteenoja H, Vähämiko S, Grönlund J, Routi T, et al. Expression of microbiota, toll-like receptors, and their regulators in the small intestinal mucosa in celiac disease. J Pediatr Gastroenterol Nutr 2012;54:727-32.
36Kamada N, Seo SU, Chen GY, Núñez G. Role of the gut microbiota in immunity and inflammatory disease. Nat Rev Immunol 2013;13:321-35.
37Kumar H, Kawai T, Akira S. Pathogen recognition by the innate immune system. Int Rev Immunol 2011;30:16-34.
38Camilleri M, Madsen K, Spiller R, Greenwood-Van Meerveld B, Verne GN. Intestinal barrier function in health and gastrointestinal disease. Neurogastroenterol Motil 2012;24:503-12.
39Bao F, Green PH, Bhagat G. An update on celiac disease histopathology and the road ahead. Arch Pathol Lab Med 2012;136:735-45.
40Ghasiyari H, Rostami-Nejad M, Amani D, Rostami K, Pourhoseingholi MA, Asadzadeh-Aghdaei H, et al. Diverse profiles of toll-like receptors 2, 4, 7, and 9 mRNA in peripheral blood and biopsy specimens of patients with celiac disease. J Immunol Res 2018;2018:7587095.
41Wu F, Zikusoka M, Trindade A, Dassopoulos T, Harris ML, Bayless TM, et al. MicroRNAs are differentially expressed in ulcerative colitis and alter expression of macrophage inflammatory peptide-2 alpha. Gastroenterology 2008;135:1624-.635E+27.
42Capuano M, Iaffaldano L, Tinto N, Montanaro D, Capobianco V, Izzo V, et al. MicroRNA-449a overexpression, reduced NOTCH1 signals and scarce goblet cells characterize the small intestine of celiac patients. PLoS One 2011;6:e29094.
43Wang JL, Hu Y, Kong X, Wang ZH, Chen HY, Xu J, et al. Candidate microRNA biomarkers in human gastric cancer: A systematic review and validation study. PLoS One 2013;8:e73683.
44Vaira V, Roncoroni L, Barisani D, Gaudioso G, Bosari S, Bulfamante G, et al. microRNA profiles in coeliac patients distinguish different clinical phenotypes and are modulated by gliadin peptides in primary duodenal fibroblasts. Clin Sci (Lond) 2014;126:417-23.
45Collado MC, Donat E, Ribes-Koninckx C, Calabuig M, Sanz Y. Specific duodenal and faecal bacterial groups associated with paediatric coeliac disease. J Clin Pathol 2009;62:264-9.
46Nadal I, Donat E, Ribes-Koninckx C, Calabuig M, Sanz Y. Imbalance in the composition of the duodenal microbiota of children with coeliac disease. J Med Microbiol 2007;56:1669-74.
47Sánchez E, Donat E, Ribes-Koninckx C, Calabuig M, Sanz Y. Intestinal Bacteroides species associated with coeliac disease. J Clin Pathol 2010;63:1105-11.
48Sánchez E, Donat E, Ribes-Koninckx C, Fernández-Murga ML, Sanz Y. Duodenal-mucosal bacteria associated with celiac disease in children. Appl Environ Microbiol 2013;79:5472-9.
49Einarsdottir E, Koskinen LL, de Kauwe AL, Dukes E, Mustalahti K, Balogh M, et al. Genome-wide analysis of extended pedigrees confirms IL2-IL21 linkage and shows additional regions of interest potentially influencing coeliac disease risk. Tissue Antigens 2011;78:428-37.
50Dubois PC, Trynka G, Franke L, Hunt KA, Romanos J, Curtotti A, et al. Multiple common variants for celiac disease influencing immune gene expression. Nat Genet 2010;42:295-302.
51Lesourne R, Uehara S, Lee J, Song KD, Li L, Pinkhasov J, et al. Themis, a T cell-specific protein important for late thymocyte development. Nat Immunol 2009;10:840-7.
52Fu G, Casas J, Rigaud S, Rybakin V, Lambolez F, Brzostek J, et al. Themis sets the signal threshold for positive and negative selection in T-cell development. Nature 2013;504:441-5.
53Wang SE, Wu FY, Shin I, Qu S, Arteaga CL. Transforming growth factor {beta} (TGF-{beta})-Smad target gene protein tyrosine phosphatase receptor type kappa is required for TGF-{beta} function. Mol Cell Biol 2005;25:4703-15.
54Asano A, Tsubomatsu K, Jung CG, Sasaki N, Agui T. A deletion mutation of the protein tyrosine phosphatase kappa (Ptprk) gene is responsible for T-helper immunodeficiency (thid) in the LEC rat. Mamm Genome 2007;18:779-86.
55Sap J, Jiang YP, Friedlander D, Grumet M, Schlessinger J. Receptor tyrosine phosphatase R-PTP-kappa mediates homophilic binding. Mol Cell Biol 1994;14:1-9.
56Kelly RJ, Rouquier S, Giorgi D, Lennon GG, Lowe JB. Sequence and expression of a candidate for the human secretor blood group alpha (1,2) fucosyltransferase gene (FUT2). Homozygosity for an enzyme-inactivating nonsense mutation commonly correlates with the non-secretor phenotype. J Biol Chem 1995;270:4640-9.
57Plugis NM, Khosla C. Therapeutic approaches for celiac disease. Best Pract Res Clin Gastroenterol 2015;29:503-21.
58International Multiple Sclerosis Genetics Consortium, Wellcome Trust Case Control Consortium 2, Sawcer S, Hellenthal G, Pirinen M, Spencer CC, et al. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 2011;476:214-9.
59Ferreira MA, Matheson MC, Duffy DL, Marks GB, Hui J, Le Souëf P, et al. Identification of IL6R and chromosome 11q13.5 as risk loci for asthma. Lancet 2011;378:1006-14.
60Franke A, McGovern DP, Barrett JC, Wang K, Radford-Smith GL, Ahmad T, et al. Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci. Nat Genet 2010;42:1118-25.
61Roychoudhuri R, Hirahara K, Mousavi K, Clever D, Klebanoff CA, Bonelli M, et al. BACH2 represses effector programs to stabilize T(reg)-mediated immune homeostasis. Nature 2013;498:506-10.
62Smyth DJ, Plagnol V, Walker NM, Cooper JD, Downes K, Yang JH, et al. Shared and distinct genetic variants in type 1 diabetes and celiac disease. N Engl J Med 2008;359:2767-77.
63International Multiple Sclerosis Genetics Consortium (IMSGC), Bush WS, Sawcer SJ, de Jager PL, Oksenberg JR, McCauley JL, et al. Evidence for polygenic susceptibility to multiple sclerosis-the shape of things to come. Am J Hum Genet 2010;86:621-5.
64Hunt KA, Zhernakova A, Turner G, Heap GA, Franke L, Bruinenberg M, et al. Newly identified genetic risk variants for celiac disease related to the immune response. Nat Genet 2008;40:395-402.
65Moratz C, Kang VH, Druey KM, Shi CS, Scheschonka A, Murphy PM, et al. Regulator of G protein signaling 1 (RGS1) markedly impairs Gi alpha signaling responses of B lymphocytes. J Immunol 2000;164:1829-38.
66Moratz C, Hayman JR, Gu H, Kehrl JH. Abnormal B-cell responses to chemokines, disturbed plasma cell localization, and distorted immune tissue architecture in Rgs1-/- mice. Mol Cell Biol 2004;24:5767-75.
67Gibbons DL, Abeler-Dörner L, Raine T, Hwang IY, Jandke A, Wencker M, et al. Cutting Edge: Regulator of G protein signaling-1 selectively regulates gut T cell trafficking and colitic potential. J Immunol 2011;187:2067-71.