Wheat amylase trypsin inhibitors drive intestinal inflammation via activation of toll-like receptor 4

Junker, Yvonne; Zeißig, Sebastian; Kim, Seong-Jun; Barisani, Donatella; Wieser, Herbert; Leffler, Daniel A.; Zevallos, Victor F.; Libermann, Towia A.; Dillon, Simon T.; Freitag, Tobias; Kelly, Ciarán P.; Schuppan, Detlef

doi:10.1084/jem.20102660

Cited by 557 publications

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“…Both CXCR3 and TLR4 are expressed on beta cells [46,47] and subsets of NK cells [45,48], and gliadin is known to interact with both receptors [47,49]. Interestingly, a recent study has shown that amylase/trypsin inhibitor family members present in the ω-gliadin fraction are able to induce strong innate responses in human and murine macrophages, monocytes, and DCs via TLR4 [49], through a mechanism that could potentially induce IFN-γ secretion from NK cells [45].We also investigated the effect of gliadins directly on beta cells. C57BL/6 islets incubated with gliadin increase production of insulin, IL-6, and the chemokine CCL2.…”

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confidence: 99%

“…Both T1D and CD are multifactorial diseases, where genetic predisposition and the mode, timing, and dose of gluten introduction are important for the development [58]. Most people thus tolerate gluten even if several immune stimulating effects have been described in healthy BALB/c and C57BL/6 mice [11,49,59]. Interestingly, a disorder called nonceliac gluten sensitivity has been described, reporting about a growing number of cases of self-diagnosed patients who observe improvements in several parameters after reducing gluten intake [60].…”

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Dietary gluten increases natural killer cell cytotoxicity and cytokine secretion

et al. 2014

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Dietary gluten influences the development of type 1 diabetes in nonobese diabetic (NOD) mice and biobreeding rats, and has been shown to influence a wide range of immunological factors in the pancreas and gut. In the present study, the effects of gluten on NK cells were studied in vitro and in vivo. We demonstrated that gliadin increased direct cytotoxicity and IFN-γ secretion from murine splenocytes and NK cells toward the pancreatic beta-cell line MIN6 cells. Additionally, stimulation of MIN6 cells led to a significantly increased proportion of degranulating C57BL/6 CD107a + NK cells. Stimulation of C57BL/6 pancreatic islets with gliadin significantly increased secretion of IL-6 more than ninefold. In vivo, the gluten-containing diet led to a higher expression of NKG2D and CD71 on NKp46 + cells in all lymphoid organs in BALB/c and NOD mice compared with the gluten-free diet. Collectively, our data suggest that dietary gluten increases murine NK-cell activity against pancreatic beta cells. This mechanism may contribute to development of type 1 diabetes and explain the higher disease incidence associated with gluten intake in NOD mice.Keywords: C56BL/6 mice r Gliadin r Gluten r NK cells r NOD mice r Type 1 diabetes Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionDietary gluten is the initiating factor in the development of celiac disease (CD), however, an association between CD and type 1 diabetes (T1D) has been established. A gluten-free (GF) diet has been shown to have a protective effect against the development of T1D. It has been demonstrated that a GF diet in nonobese diabetic (NOD) mice reduces diabetes incidence from 64 to 15% [1], and similar results have been obtained with biobreeding rats [2]. Increased intestinal permeability occurs prior to the onset of T1D in both spontaneous animal models and human disease [3,4]. Patients with both CD and T1D diseases carry high-risk HLA alleles [5], and approximately 10% of T1D patients have anCorrespondence: Jesper Larsen e-mail: jelars@gmail.com increased prevalence of CD [6]. Moreover, T1D rarely develops after diagnosed CD, which may be because of the protective effect of a GF diet [7]. A recently published case report describes a boy with T1D who was able to maintain a low fasting blood glucose level without insulin therapy for more than 20 months after the time of diagnosis by adhering to a GF diet [8]. Lately, it has also been suggested that a family of gluten proteins known as gliadins may contribute directly to beta-cell hyperactivity, as enzymatically digested gliadin and a 33-mer gliadin fragment increase insulin secretion from beta cells by affecting the K ATP channel current [9]. This process could induce increased Ag expression of the beta-cell surface and prevent beta-cell rest [10]. Gliadin has been shown to stimulate several components of the adaptive immune system, such as Treg cells, Th17 cells, and DCs [11,12]. Gliadin fragments have also been shown to stimulate TLR4 a...

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Dietary gluten increases natural killer cell cytotoxicity and cytokine secretion

et al. 2014

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“…In NCGS patients, gliadin fractions do not provoke a clear picture of inflammation upon contact with the duodenal mucosa or with peripheral basophils [20]. In vitro studies suggest that wheat ATIs could play a major role as triggers of the innate immune response in GS [21].…”

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confidence: 99%

Gluten Sensitivity in Pediatrics: A Clinical Conundrum

et al. 2014

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“…In this respect, it would be interesting to know whether CLE findings correlate with the eosinophil cationic protein concentrations in the stools or with the flow cytometric allergen stimulation assay results, biomarkers that showed a good concordance with the DBPC challenge results in IBS patients. 6,7 …”

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Nonceliac Wheat Sensitivity in the Context of Multiple Food Hypersensitivity: New Data From Confocal Endomicroscopy

2015

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Wheat amylase trypsin inhibitors drive intestinal inflammation via activation of toll-like receptor 4

Abstract: Pest resistance molecules, α-amylase/trypsin inhibitors from wheat, activate innate immune cells through engagement of TLR4 to elicit inflammatory responses in the intestine.

Cited by 557 publications

References 48 publications

Dietary gluten increases natural killer cell cytotoxicity and cytokine secretion

Dietary gluten increases natural killer cell cytotoxicity and cytokine secretion

Gluten Sensitivity in Pediatrics: A Clinical Conundrum

Nonceliac Wheat Sensitivity in the Context of Multiple Food Hypersensitivity: New Data From Confocal Endomicroscopy

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