An unexpected role for RNA-sensing toll-like receptors in a murine model of DNA accrual
Department of Medicine, Division of Rheumatology; Department of Medicine, Division of Infectious Diseases and Immunology
Animals; Arthritis; 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
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.
Clin Exp Rheumatol. 2015 Jul-Aug;33(4 Suppl 92):S70-3. Epub 2015 Oct 12. Link to article on publisher's website
Clinical and experimental rheumatology
Pawaria, Sudesh; Moody, Krishna L.; Busto, Patricia; Nundel, Kerstin; Baum, Rebecca; Sharma, Shrutie; Gravallese, Ellen M.; Fitzgerald, Katherine A.; and Marshak-Rothstein, Ann, "An unexpected role for RNA-sensing toll-like receptors in a murine model of DNA accrual" (2015). University of Massachusetts Medical School Faculty Publications. 963.