Cytotoxic activity in children with insulin-dependent diabetes mellitus

Lorini, Renata; Moretta, Antonia; Valtorta, A.; d’Annunzio, Giuseppe; Cortona, L.; Vitali, Letizia; Bozzola, Mauro; Severi, F

doi:10.1016/0168-8227(94)90125-2

Cited by 34 publications

(34 citation statements)

References 19 publications

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“…Conversely, another study has shown that the onset period is characterized by unusually active IFN-γ-secreting NK cells in some patients [20]. Furthermore, reduced NK-cell activation and cytotoxicity is only seen in longstanding patients, implying that it might only be a consequence of the disease [20,55], and the NKG2D ligand RAE-1 is expressed in the prediabetic NOD mouse pancreas [56]. Activated NK cells could also affect pathology indirectly by NK-mediated DC death [57].…”

Section: Discussionmentioning

confidence: 99%

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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Section: Discussionmentioning

confidence: 99%

Dietary gluten increases natural killer cell cytotoxicity and cytokine secretion

et al. 2014

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“…4B), but was still higher than in the spleen (data not shown). Pancreatic NK cells from NOD mice are hyporesponsive upon stimulation, but display higher spontaneous ex vivo IFN-g production NK cells from the spleen of NOD mice and the blood of diabetic humans are known to be impaired in function (3,10,30). Given their phenotype and high proliferation rate, we speculated that pancreatic NK cells would instead display an enhanced responsiveness, perhaps reflecting a pathogenic role in diabetes pathogenesis.…”

Section: Activated and Proliferating Nk Cells Are Present In The Earlmentioning

confidence: 97%

Distinct Phenotype and Function of NK Cells in the Pancreas of Nonobese Diabetic Mice

Brauner¹,

Elemans²,

Lemos³

et al. 2010

The Journal of Immunology

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“…Increased NK cell activity has been reported in the periphery of individuals with type 1 diabetes [1][2][3][4][5][6], but a role for these innate immune cells in the pathogenesis of type 1 diabetes has not, however, been elucidated. NK cells act by either activating or inhibiting cytolysis [7] and their activity is controlled by the balance of inhibitory and activating receptors on the cell surface [8].…”

Section: Introductionmentioning

confidence: 99%

An increased frequency of NK cell receptor and HLA-C group 1 combinations in early-onset type 1 diabetes

Mehers

Long

Slik³

et al. 2011

Diabetologia

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Aims/hypothesis Natural killer (NK) cells serve as primary immune surveillance and are partially regulated by combinations of killer immunoglobulin-like receptor (KIR) genes and their HLA class I ligands. Alterations in NK cell activity have been associated with type 1 diabetes. The aim of this study was to determine whether KIR-HLA class I gene frequency: (1) is altered in a current population with type 1 diabetes compared with healthy controls; and (2) has changed over the half century in which the incidence of type 1 diabetes has increased rapidly.Methods KIR-HLA class I gene frequencies were compared in 551 individuals diagnosed with type 1 diabetes ≤15 years of age (394 in a current cohort and 157 from the historical 'Golden Years' cohort) and 168 healthy controls. The overall balance of activation and inhibition was analysed using KIR-HLA genotype models. Results Children with type 1 diabetes who were positive for KIR2DS2/KIR2DL2 and KIR2DL3 were more often homozygous for HLA-C group 1 and this effect was strongest in children diagnosed with diabetes before the age of 5 years (p=0.003, corrected p [p corr ]=0.012) and (p=0.001, p corr = 0.004), respectively. Children with type 1 diabetes have fewer inhibitory KIRs with their corresponding ligands compared with healthy controls (p=1.9×10 −4 ). This pattern of NK activation has not changed significantly in individuals with type 1 diabetes over the last half century. Conclusions/interpretation Activating combinations of KIR-HLA genes are more frequent in young children with type 1 diabetes diagnosed in the first 5 years of life, suggesting that NK cell responses may be altered in this group.

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Cytotoxic activity in children with insulin-dependent diabetes mellitus

Cited by 34 publications

References 19 publications

Dietary gluten increases natural killer cell cytotoxicity and cytokine secretion

Dietary gluten increases natural killer cell cytotoxicity and cytokine secretion

Distinct Phenotype and Function of NK Cells in the Pancreas of Nonobese Diabetic Mice

An increased frequency of NK cell receptor and HLA-C group 1 combinations in early-onset type 1 diabetes

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