title: An unexpected role for RNA-sensing toll-like receptors in a murine model of DNA accrual.
abstract: 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 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.
authors.affiliation: Department of Medicine, University of Massachusetts School of Medicine, Worcester, MA, USA.
authors.forename: Sudesh
authors.initials: S
authors.lastname: Pawaria
authors.affiliation: Department of Medicine, University of Massachusetts School of Medicine, Worcester, and Department of Microbiology, Boston University School of Medicine, Boston, USA.
authors.forename: Krishna L
authors.initials: KL
authors.lastname: Moody
authors.affiliation: Department of Medicine, University of Massachusetts School of Medicine, Worcester, MA, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: Busto
authors.affiliation: Department of Medicine, University of Massachusetts School of Medicine, Worcester, MA, USA.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Nündel
authors.affiliation: Department of Medicine, University of Massachusetts School of Medicine, Worcester, MA, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Baum
authors.affiliation: Department of Medicine, University of Massachusetts School of Medicine, Worcester, MA, USA.
authors.forename: Shruti
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Department of Medicine, University of Massachusetts School of Medicine, Worcester, MA, USA.
authors.forename: Ellen M
authors.initials: EM
authors.lastname: Gravallese
authors.affiliation: Department of Medicine, University of Massachusetts School of Medicine, Worcester, MA, USA.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Fitzgerald
authors.affiliation: Department of Medicine, University of Massachusetts School of Medicine, Worcester, MA, USA. ann.rothstein@umassmed.edu.
authors.forename: Ann
authors.initials: A
authors.lastname: Marshak-Rothstein
mesh_terms: D000818:Animals; D001168:Arthritis / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D001323:Autoantibodies / Q000276:immunology / Q000378:metabolism; D015551:Autoimmunity; D004247:DNA / Q000276:immunology / Q000378:metabolism*; D004706:Endodeoxyribonucleases / Q000172:deficiency / Q000235:genetics; D011992:Endosomes / Q000276:immunology / Q000378:metabolism*; D005838:Genotype; D006411:Hematopoiesis, Extramedullary; D008024:Ligands; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000172:deficiency / Q000235:genetics; D018345:Mice, Knockout; D010641:Phenotype; D012313:RNA / Q000276:immunology / Q000378:metabolism*; D053633:Receptor, Interferon alpha-beta / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction; D013163:Splenomegaly; D051199:Toll-Like Receptor 7 / Q000276:immunology / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000276:immunology / Q000378:metabolism; D051193:Toll-Like Receptors / Q000276:immunology / Q000378:metabolism*
chemical_list: D001323:Autoantibodies; C508032:Ifnar1 protein, mouse; D008024:Ligands; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; C477038:Tlr7 protein, mouse; C495370:Tlr9 protein, mouse; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors; C512254:UNC93B1 protein, mouse; D053633:Receptor, Interferon alpha-beta; D012313:RNA; D004247:DNA; D004706:Endodeoxyribonucleases; C019329:deoxyribonuclease II