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dc.contributor.authorZipris, Danny
dc.contributor.authorLien, Egil
dc.contributor.authorNair, Anjali
dc.contributor.authorXie, Jenny X.
dc.contributor.authorGreiner, Dale L.
dc.contributor.authorMordes, John P.
dc.contributor.authorRossini, Aldo A.
dc.date2022-08-11T08:09:32.000
dc.date.accessioned2022-08-23T16:34:52Z
dc.date.available2022-08-23T16:34:52Z
dc.date.issued2007-01-05
dc.date.submitted2009-03-16
dc.identifier.citation<p>J Immunol. 2007 Jan 15;178(2):693-701.</p>
dc.identifier.issn0022-1767 (Print)
dc.identifier.doi10.4049/jimmunol.178.2.693
dc.identifier.pmid17202329
dc.identifier.urihttp://hdl.handle.net/20.500.14038/38431
dc.description.abstractViral 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.
dc.language.isoen_US
dc.relation<p><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=17202329&dopt=Abstract">Link to Article in PubMed</a></p>
dc.relation.urlhttps://doi.org/10.4049/jimmunol.178.2.693
dc.subjectAnimals
dc.subjectB-Lymphocytes
dc.subjectBreeding
dc.subjectCells, Cultured
dc.subjectChloroquine
dc.subjectDNA, Viral
dc.subjectDiabetes Mellitus, Type 1
dc.subjectDisease Susceptibility
dc.subjectFemale
dc.subjectGenome, Viral
dc.subject*Health
dc.subjectInterleukin-12 Subunit p40
dc.subjectInterleukin-6
dc.subjectMacrophages
dc.subjectMale
dc.subjectMembrane Proteins
dc.subjectNF-kappa B
dc.subjectParvovirus
dc.subjectRats
dc.subject*Signal Transduction
dc.subjectSpleen
dc.subjectToll-Like Receptor 9
dc.subjectTumor Necrosis Factor-alpha
dc.subjectLife Sciences
dc.subjectMedicine and Health Sciences
dc.titleTLR9-signaling pathways are involved in Kilham rat virus-induced autoimmune diabetes in the biobreeding diabetes-resistant rat
dc.typeJournal Article
dc.source.journaltitleJournal of immunology (Baltimore, Md. : 1950)
dc.source.volume178
dc.source.issue2
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/oapubs/1299
dc.identifier.contextkey782970
html.description.abstract<p>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.</p>
dc.identifier.submissionpathoapubs/1299
dc.contributor.departmentDepartment of Medicine, Division of Endocrinology and Metabolism
dc.contributor.departmentDepartment of Medicine, Division of Diabetes
dc.contributor.departmentDepartment of Medicine, Division of Infectious Diseases and Immunology
dc.source.pages693-701


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