Dietary gluten increases natural killer cell cytotoxicity and cytokine secretion

Abstract

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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“…tion in animal studies [80][81][82][83][84]. A comparable trend is seen in human 272 diabetes type 1 [85] and CD [86,87] but the effects are controversial in 273 non-celiac gluten sensitivity [88,89].…”

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“…A recent study also found that a GLF diet could lower NKG2D and ligand (DX5) expression in the intestines of BALB/c and NOD mice [20]. Another recently-reported study by Larsen and colleagues also found that dietary gluten increased murine NK-cell activity against the pancreatic beta-cell line MIN6 cells in vitro and induced the expression of NKG2D and CD71 on NKp46+ cells in all lymphoid organs in BALB/c and NOD mice in vivo, compared to a GLF diet [21]. It is known that NK cells are required for diabetes development [22, 23].…”

Non-celiac gluten sensitivity: A work-in-progress entity in the spectrum of wheat-related disorders

“…For instance, serum levels and mucosal expression of anti-transglutaminase antibodies are not gluten-dependent [31]. In NOD mice, dietary gluten alters the composition of their gut microbiome [32], intestinal regulatory T cells [33], as well as their natural killer cell cytotoxicity [34,35]. The significance of these findings in NOD mice to the human situation needs further investigation.…”