Induction of Type I Diabetes by Interferon-α in Transgenic Mice

Stewart, Timothy A.; Hultgren, Bruce; Huang, Xiaojian; Pitts-Meek, Sharon; Hully, James R.; Maclachlan, Nigel J

doi:10.1126/science.8100367

Cited by 246 publications

(151 citation statements)

References 52 publications

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“…Type I IFNs have been associated with T1D because they have been detected in the islets of diabetic patients (8,9,12), thus suggesting that a viral infection and its consequences may be related to the development of the disease. Furthermore, during the treatment with type I IFNs a small but significant proportion of patients develop autoimmune diabetes (27,28).…”

Section: Discussionmentioning

confidence: 99%

“…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). Transgenic mice expressing IFN␣, ␤, and (12)(13)(14) in ␤ cells developed type 1 diabetes, with T and B cells infiltrating the islets. These data suggest a local proinflammatory role for these type I IFNs and their ability to induce T1D.…”

Section: Discussionmentioning

confidence: 99%

“…In previous studies, other scientists and we have detected type I IFNs in the pancreata of patients with a recent onset of diabetes (9 -11). The expression of type I IFNs, IFN␣ and IFN , by the ␤ cells induces autoimmune diabetes in nondiabetes-prone transgenic mice (12,13). These mice developed insulitis and hypoinsulinemic diabetes with a cumulative incidence of ϳ50%.…”

Section: Ifn␤ Accelerates Autoimmune Type 1 Diabetes In Nonobese Diabmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Ifn␤ Accelerates Autoimmune Type 1 Diabetes In Nonobese Diabmentioning

confidence: 99%

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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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“…Laser-captured islets obtained from living donors with recent onset type 1 diabetes showed a significant increase in nearly 50% of the IFN-stimulated genes (ISGs) evaluated [18]. Neutralisation of the IFNα/β receptor (IFNAR1) with monoclonal antibodies prevents diabetes in NOD mice [13,19] and self-reactive antibodies targeting type I IFNs-particularly IFNα-are associated with protection against type 1 diabetes in patients with mutations in the thymus transcription factor autoimmune regulator (AIRE) [20]. It is surprising that very few studies have investigated the direct effects of this cytokine in pancreatic beta cells [21][22][23].…”

Section: Introductionmentioning

confidence: 99%

Interferon-α mediates human beta cell HLA class I overexpression, endoplasmic reticulum stress and apoptosis, three hallmarks of early human type 1 diabetes

et al. 2017

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Aims/hypothesis Three hallmarks of the pancreatic islets in early human type 1 diabetes are overexpression of HLA class I, endoplasmic reticulum (ER) stress and beta cell apoptosis. The mediators of these phenomena remain to be defined. The type I interferon IFNα is expressed in human islets from type 1 diabetes patients and mediates HLA class I overexpression. We presently evaluated the mechanisms involved in IFNα-induced HLA class I expression in human beta cells and determined whether this cytokine contributes to ER stress and apoptosis. Methods IFNα-induced inflammation, ER stress and apoptosis were evaluated by RT-PCR, western blot, immunofluorescence and nuclear dyes, and proteins involved in type I interferon signalling were inhibited by small interfering RNAs. All experiments were performed in human islets or human EndoC-βH1 cells.Results IFNα upregulates HLA class I, inflammation and ER stress markers in human beta cells via activation of the candidate gene TYK2, and the transcription factors signal transducer and activator of transcription 2 and IFN regulatory factor 9. Furthermore, it acts synergistically with IL-1β to induce beta cell apoptosis. Conclusions/interpretation The innate immune effects induced by IFNα may induce and amplify the adaptive immune response against human beta cells, indicating that IFNα has a central role in the early phases of diabetes.

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“…Huang et al [5] reported that IFNα was significantly overexpressed in the pancreases of patients with T1D. Stewart et al [6] reported that transgenic mice in which β cells overexpressed IFNα developed hypoinsulinemic diabetes, and a neutralizing antibody against IFNα prevented its development.…”

Section: Discussionmentioning

confidence: 99%

Diabetic Ketoacidosis Due to Type 1 Diabetes Mellitus Induced by Interferon Therapy for Chronic Hepatitis C During the Course of Hashimoto’s Thyroiditis: Case Report

Jo¹,

Iwase²,

Nishizawa³

et al. 2017

Diabetes Case Rep

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Interferon α (IFNα) has been reported to induce several autoimmune diseases, including autoimmune thyroiditis (AITD) and type 1 diabetes (T1D). In addition, co-occurrence of T1D and AITD is well known as one of the variants of the autoimmune polyglandular syndrome type 3. Meanwhile, there are no reports about the risk of development of IFN treatment-related T1D in patients with previously diagnosed AITD. We present a single case report about a 61-yearold Japanese woman with Diabetic Ketoacidosis (DKA) three months after the initiation of the combination therapy with peginterferon α-2b and ribavirin for chronic hepatitis C. She was diagnosed with T1D owing to severely impaired insulin secretion along with DKA and presence of positive GAD antibody. Her T1D was supposed to be induced by IFN therapy. She had received the replacement therapy for hypothyroidism resulting from Hashimoto's thyroiditis for 30 years. The patient had human leukocyte antigens (HLA), DRB1*04:05 and DQB1*04:01, which are associated with a genetic predisposition for T1D and AITD. Patients with previously diagnosed AITD are assumed to be at high risk for IFN treatment-related T1D because most patients with T1D triggered by IFN were reported to have genetic susceptibilities similar to those with classical T1D and AITD. In conclusion, patients with known AITD should be carefully monitored for their glycemic condition to avoid life-threatening events such as DKA when they receive IFN therapy.

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Induction of Type I Diabetes by Interferon-α in Transgenic Mice

Cited by 246 publications

References 52 publications

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

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

Interferon-α mediates human beta cell HLA class I overexpression, endoplasmic reticulum stress and apoptosis, three hallmarks of early human type 1 diabetes

Diabetic Ketoacidosis Due to Type 1 Diabetes Mellitus Induced by Interferon Therapy for Chronic Hepatitis C During the Course of Hashimoto’s Thyroiditis: Case Report

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