An unexpected role for RNA-sensing toll-like receptors in a murine model of DNA accrual
Authors
Pawaria, SudeshMoody, Krishna L.
Busto, Patricia
Nundel, Kerstin
Baum, Rebecca
Sharma, Shrutie
Gravallese, Ellen M.
Fitzgerald, Katherine A.
Marshak-Rothstein, Ann
UMass Chan Affiliations
Department of Medicine, Division of Infectious Diseases and ImmunologyDepartment of Medicine, Division of Rheumatology
Document Type
Journal ArticlePublication Date
2015-07-01Keywords
AnimalsArthritis
Autoantibodies
*Autoimmunity
DNA
Endodeoxyribonucleases
Endosomes
Genotype
Hematopoiesis, Extramedullary
Ligands
Membrane Glycoproteins
Membrane Transport Proteins
Mice, Knockout
Phenotype
RNA
Receptor, Interferon alpha-beta
Signal Transduction
Splenomegaly
Toll-Like Receptor 7
Toll-Like Receptor 9
Toll-Like Receptors
Immunity
Rheumatology
Metadata
Show full item recordAbstract
OBJECTIVES: The goal of this study was to determine whether endosomal Toll-like receptors (TLRs) contribute to the clinical manifestation of systemic autoimmunity exhibited by mice that lack the lysosomal nuclease DNaseII. METHODS: DNaseII/IFNaR double deficient mice were intercrossed with Unc93b13d/3d mice to generate DNaseII-/-mice with non-functional endosomal TLRs. The resulting triple deficient mice were evaluated for arthritis, autoantibody production, splenomegaly, and extramedullary haematopoiesis. B cells from both strains were evaluated for their capacity to respond to endogenous DNA by using small oligonucleotide based TLR9D ligands and a novel class of bifunctional anti-DNA antibodies. RESULTS: Mice that fail to express DNaseII, IFNaR, and Unc93b1 still develop arthritis but do not make autoantibodies, develop splenomegaly, or exhibit extramedullary haematopoiesis. DNaseII-/- IFNaR-/- B cells can respond to synthetic ODNs, but not to endogenous dsDNA. CONCLUSIONS: RNA-reactive TLRs, presumably TLR7, are required for autoantibody production, splenomegaly, and extramedullary haematopoiesis in the DNaseII-/- model of systemic autoimmunity.Source
Clin Exp Rheumatol. 2015 Jul-Aug;33(4 Suppl 92):S70-3. Epub 2015 Oct 12. Link to article on publisher's websitePermanent Link to this Item
http://hdl.handle.net/20.500.14038/30685PubMed ID
26457825Related Resources
Link to Article in PubMedCollections
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