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TLR9-signaling pathways are involved in Kilham rat virus-induced autoimmune diabetes in the biobreeding diabetes-resistant rat
Authors
Zipris, DannyLien, Egil
Nair, Anjali
Xie, Jenny X.
Greiner, Dale L.
Mordes, John P.
Rossini, Aldo A.
UMass Chan Affiliations
Department of Medicine, Division of Endocrinology and MetabolismDepartment of Medicine, Division of Diabetes
Department of Medicine, Division of Infectious Diseases and Immunology
Document Type
Journal ArticlePublication Date
2007-01-05Keywords
AnimalsB-Lymphocytes
Breeding
Cells, Cultured
Chloroquine
DNA, Viral
Diabetes Mellitus, Type 1
Disease Susceptibility
Female
Genome, Viral
*Health
Interleukin-12 Subunit p40
Interleukin-6
Macrophages
Male
Membrane Proteins
NF-kappa B
Parvovirus
Rats
*Signal Transduction
Spleen
Toll-Like Receptor 9
Tumor Necrosis Factor-alpha
Life Sciences
Medicine and Health Sciences
Metadata
Show full item recordAbstract
Viral infections are associated epidemiologically with the expression of type 1 diabetes in humans, but the mechanisms underlying this putative association are unknown. To investigate the role of viruses in diabetes, we used a model of viral induction of autoimmune diabetes in genetically susceptible biobreeding diabetes-resistant (BBDR) rats. BBDR rats do not develop diabetes in viral-Ab-free environments, but approximately 25% of animals infected with the parvovirus Kilham rat virus (KRV) develop autoimmune diabetes via a mechanism that does not involve beta cell infection. Using this model, we recently documented that TLR agonists synergize with KRV infection and increase disease penetrance. We now report that KRV itself activates innate immunity through TLR ligation. We show that KRV infection strongly stimulates BBDR splenocytes to produce the proinflammatory cytokines IL-6 and IL-12p40 but not TNF-alpha. KRV infection induces high levels of IL-12p40 by splenic B cells and Flt-3-ligand-induced bone marrow-derived dendritic cells (DCs) but only low levels of IL-12p40 production by thioglycolate-elicited peritoneal macrophages or GM-CSF plus IL-4-induced bone marrow-derived DCs. KRV-induced cytokine production is blocked by pharmacological inhibitors of protein kinase R and NF-kappaB. Genomic KRV DNA also induces BBDR splenocytes and Flt-3L-induced DCs from wild-type but not TLR9-deficient mice to produce IL-12p40; KRV-induced up-regulation of B lymphocytes can be blocked by TLR9 antagonists including inhibitory CpG and chloroquine. Administration of chloroquine to virus-infected BBDR rats decreases the incidence of diabetes and decreases blood levels of IL-12p40. Our data implicate the TLR9-signaling pathway in KRV-induced innate immune activation and autoimmune diabetes in the BBDR rat.Source
J Immunol. 2007 Jan 15;178(2):693-701.
DOI
10.4049/jimmunol.178.2.693Permanent Link to this Item
http://hdl.handle.net/20.500.14038/38431PubMed ID
17202329Related Resources
ae974a485f413a2113503eed53cd6c53
10.4049/jimmunol.178.2.693