Type 1 Diabetes Mellitus Caused by Treatment with Interferon-.BETA..

Kado, Shigenobu; Miyamoto, Jiro; Komatsu, Norie; Iwaki, Yoshiki; Ozaki, Hirofumi; Taguchi, Hirohisa; Kure, Masahiko; Sarashina, Gen; Watanabe, Toshiya; Katsura, Yoshiya; Nemoto, Yuta; Noritake, Masayuki; Matsuoka, Takeshi

doi:10.2169/internalmedicine.39.146

Cited by 22 publications

(19 citation statements)

References 17 publications

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“…1b, c, f), similar to previous observations for other CVB serotypes [41][42][43]. We have also found that CVB1 infection is accompanied by an upregulated expression of type I IFNs in pancreases early after infection (P. G. Larsson, E. Domsgen and M. Flodström-Tullberg, unpublished observations), indicating that immune responses previously implicated in type 1 diabetes are activated during CVB1 infection [45][46][47][48]. In contrast, the vaccine, which was based on formalininactivated CVB1 virus, failed to accelerate diabetes onset (Fig.…”

Section: Discussionsupporting

confidence: 89%

A preclinical study on the efficacy and safety of a new vaccine against Coxsackievirus B1 reveals no risk for accelerated diabetes development in mouse models

et al. 2014

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Section: Discussionsupporting

confidence: 89%

A preclinical study on the efficacy and safety of a new vaccine against Coxsackievirus B1 reveals no risk for accelerated diabetes development in mouse models

et al. 2014

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“…NOD. Ncf1 m1J BM-Mϕ exhibited significant decreases in TNF-α and IFN-β expression, key cytokines linking innate and adaptive immune responses in T1D [35] and T1D development in NOD mice [69, 70]. Interestingly, we did not observe significant differences in Ifna2 or IFN-α expression between poly(I:C)-stimulated NOD and NOD.…”

Section: Discussionmentioning

confidence: 60%

Dysregulated TLR3-dependent signaling and innate immune activation in superoxide-deficient macrophages from nonobese diabetic mice

Seleme

Lei

Burg

et al. 2012

Free Radical Biology and Medicine

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In Type 1 diabetes (T1D), reactive oxygen species (ROS) and pro-inflammatory cytokines produced by macrophages and other innate immune cells destroy pancreatic β-cells while promoting autoreactive T cell maturation. Superoxide-deficient Non-Obese Diabetic mice (NOD.Ncf1m1J) are resistant to spontaneous diabetes, revealing the integral role of ROS-signaling in T1D. Here, we evaluate the innate immune activation state of bone marrow-derived macrophages (BM-Mϕ) from NOD and NOD.Ncf1m1J mice after poly(I:C)-induced Toll-like receptor 3 (TLR3) signaling. We show that ROS synthesis is required for efficient activation of the NF-κB signaling pathway and concomitant expression of TLR3 and the cognate adaptor molecule, TRIF. Poly(I:C)-stimulated NOD.Ncf1m1J BM-Mϕ exhibited a 2- and 10-fold decrease in TNF-α and IFN-β pro-inflammatory cytokine synthesis, respectively, in contrast to NOD BM-Mϕ. Optimal expression of IFN-α/β is not solely dependent on superoxide synthesis, but requires p47phox to function in a NOX-independent manner to mediate Type I interferon synthesis. Interestingly, MHC-II I-Ag7 expression necessary for CD4 T cell activation is increased 2-fold relative to NOD, implicating a role for superoxide in I-Ag7 down-regulation. These findings suggest that defective innate immune pattern-recognition receptor activation and subsequent decrease in TNF-α and IFN-β pro-inflammatory cytokine synthesis necessary for autoreactive T cell maturation, may contribute to the T1D protection observed in NOD.Ncf1m1J mice.

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“…Furthermore, during the treatment with type I IFNs a small but significant proportion of patients develop autoimmune diabetes (27,28). Apart from antiviral activities, type I IFNs are also potent immunomodulators: they are involved in the increase of the expression of MHC class I, in the enhancement of T and NK cell cytotoxicity, in the production of proinflammatory cytokines, and other activities (29,30).…”

Section: Discussionmentioning

confidence: 99%

IFNβ Accelerates Autoimmune Type 1 Diabetes in Nonobese Diabetic Mice and Breaks the Tolerance to β Cells in Nondiabetes-Prone Mice

Alba

Puertas

Carrillo

et al. 2004

The Journal of Immunology

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Genetic and environmental factors are decisive in the etiology of type 1 diabetes. Viruses have been proposed as a triggering environmental event and some evidences have been reported: type I IFNs exist in the pancreata of diabetic patients and transgenic mice expressing these cytokines in β cells develop diabetes. To determine the role of IFNβ in diabetes, we studied transgenic mice expressing human IFNβ in the β cells. Autoimmune features were found: MHC class I islet hyperexpression, T and B cells infiltrating the islets and transfer of the disease by lymphocytes. Moreover, the expression of β2-microglobulin, preproinsulin, and glucagon in the thymus was not altered by IFNβ, thus suggesting that the disease is caused by a local effect of IFNβ, strong enough to break the peripheral tolerance to β cells. This is the first report of the generation of NOD (a model of spontaneous autoimmune diabetes) and nonobese-resistant (its homologous resistant) transgenic mice expressing a type I IFN in the islets: transgenic NOD and nonobese-resistant mice developed accelerated autoimmune diabetes with a high incidence of the disease. These results indicate that the antiviral cytokine IFNβ breaks peripheral tolerance to β cells, influences the insulitis progression and contributes to autoimmunity in diabetes and nondiabetes- prone mice.

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Type 1 Diabetes Mellitus Caused by Treatment with Interferon-.BETA..

Cited by 22 publications

References 17 publications

A preclinical study on the efficacy and safety of a new vaccine against Coxsackievirus B1 reveals no risk for accelerated diabetes development in mouse models

A preclinical study on the efficacy and safety of a new vaccine against Coxsackievirus B1 reveals no risk for accelerated diabetes development in mouse models

Dysregulated TLR3-dependent signaling and innate immune activation in superoxide-deficient macrophages from nonobese diabetic mice

IFNβ Accelerates Autoimmune Type 1 Diabetes in Nonobese Diabetic Mice and Breaks the Tolerance to β Cells in Nondiabetes-Prone Mice

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