An unexpected role for RNA-sensing toll-like receptors in a murine model of DNA accrual

作者：Pawaria S; Moody K L; Busto P; Nuendel K; Baum R; Sharma S; Gravallese E M; Fitzgerald K A; Marshak Rothstein A^*

来源：Clinical and Experimental Rheumatology, 2015, 33(4): S70-S73.

• TLR7
• TLR9
• DNaseII
• arthritis
• autoantibody
• anti-nuclear antibody
• splenomegaly
• STING
• extramedullary haematopoiesis
• bifunctional antibody

Objective. 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 Unc93b1(3d/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 TLR9 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.
Conclusion. RNA-reactive TLRs, presumably TLR7, are required for auto-antibody production, splenomegaly, and extramedullary haematopoiesis in the DNaseII(-/-) model of systemic autoimmunity.

• 出版日期2015-8