Special Lecture
An unexpected role for RNA-sensing toll-like receptors in a murine model of DNA accrual
S. Pawaria1, K.L. Moody2, P. Busto3, K. Nündel4, R. Baum5, S. Sharma6, E.M. Gravallese7, K.A. Fitzgerald8, A. Marshak-Rothstein9
- Department of Medicine, University of Massachusetts School of Medicine, Worcester, MA, USA.
- Department of Medicine, University of Massachusetts School of Medicine, Worcester, and Department of Microbiology, Boston University School of Medicine, Boston, USA.
- Department of Medicine, University of Massachusetts School of Medicine, Worcester, MA, USA.
- Department of Medicine, University of Massachusetts School of Medicine, Worcester, MA, USA.
- Department of Medicine, University of Massachusetts School of Medicine, Worcester, MA, USA.
- Department of Medicine, University of Massachusetts School of Medicine, Worcester, MA, USA.
- Department of Medicine, University of Massachusetts School of Medicine, Worcester, MA, USA.
- Department of Medicine, University of Massachusetts School of Medicine, Worcester, MA, USA.
- Department of Medicine, University of Massachusetts School of Medicine, Worcester, MA, USA. ann.rothstein@umassmed.edu
CER8908
2015 Vol.33, N°4 ,Suppl.92
PI 0070, PF 0073
Special Lecture
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PMID: 26457825 [PubMed]
Received: 28/08/2015
Accepted : 01/09/2015
In Press: 12/10/2015
Published: 14/10/2015
Abstract
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.
