Journal
DIABETES
Volume 60, Issue 8, Pages 2112-2119Publisher
AMER DIABETES ASSOC
DOI: 10.2337/db10-1643
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Funding
- Novo Nordisk
- U.K. Department of Health via the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre
- Juvenile Diabetes Research Foundation [7-2005-877, 1-2007-1803, 5-2007-269]
- European Union
- Communaute Francaisede Belgique-Actions de Recherche Concertees (ARC)
- Fonds National de la Recherche Scientifique (FNRS) Belgium
- Belgium Program on Interuniversity Poles of Attraction [IUAP P6/40]
- FNRS
- Spanish Ministry of Science and Innovation [PS09/00253]
- Instituto de Salud Carlos III
- Health Department of the Catalan Government
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OBJECTIVE-CD4 T-cells secreting interleukin (M)-17 are implicated in several human autoimmune diseases, but their role in type 1 diabetes has not been defined. To address the relevance of such cells, we examined IL-17 secretion in response to beta-cell autoantigens, IL-17A gene expression in islets, and the potential functional consequences of IL-17 release for beta-cells. RESEARCH DESIGN AND METHODS-Peripheral blood CD4 T-cell responses to beta-cell autoantigens (proinsulin, insulinoma-associated protein, and GAD65 peptides) were measured by IL-17 enzyme-linked inununospot assay in patients with new-onset type 1 diabetes (n = 50). mRNA expression of IL-17A and IFNG pathway genes was studied by qRT-PCR using islets obtained from subjects who died 5 days and 10 years after diagnosis of disease, respectively, and from matched control subjects. IL-17 effects on the function of human islets, rat beta-cells, and the rat insulinoma cell line INS-1E were examined. RESULTS-A total of 27 patients (54%) showed IL-17 reactivity to one or more beta-cell peptides versus 3 of 30 (10%) control subjects (P = 0.0001). In a single case examined close to diagnosis, islet expression of IL17A, RORC, and IL22 was detected. It is noteworthy that we show that IL-17 mediates significant and reproducible enhancement of IL-1 beta/interferon (IFN)-gamma-induced and tumor necrosis factor (TNF)-alpha/IFN-gamma-induced apoptosis in human islets, rat beta-cells, and INS-1E cells, in association with significant upregulation of beta-cell IL17RA expression via activation of the transcription factors STAT1 and nuclear factor (NF)-kappa B. CONCLUSIONS-Circulating IL-17(+) beta-cell-specific autoreactive CD4 T-cells are a feature of type 1 diabetes diagnosis. We disclose a novel pathway to beta-cell death involving IL-17 and STAT1 and NF-kappa B, rendering this cytokine a novel disease biomarker and potential therapeutic target. Diabetes 60:2112-2119, 2011
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