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

Clinical and Experimental Rheumatology

Katherine A. Fitzgerald¹  Krishna L. Moody¹  Shruti Sharma¹  Patricia Busto¹  Kerstin Nündel¹  Rebecca Baum¹  Sudesh Pawaria¹  Ann Marshak-Rothstein¹  Ellen M. Gravallese¹ 

关键词: Toll-like receptors;    TLR7;    TLR9;    DNaseII;    arthritis;    autoantibody;    anti-nuclear antibody;    splenomegaly;    extramedullary hematopoiesis;    STING;    bifunctional antibody;   

DOI  :  

学科分类：医学（综合）

来源: Pacini Editore SpA

【 摘 要 】

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.

【 授权许可】

Unknown