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 S, Moody KL, Busto P, Nundel K, Baum R, Sharma S, Gravallese EM, Fitzgerald KA, Marshak-Rothstein A. (2015). An unexpected role for RNA-sensing toll-like receptors in a murine model of DNA accrual. UMass Chan Medical School Faculty Publications. Retrieved from https://escholarship.umassmed.edu/faculty_pubs/963