title: Cutting Edge: DNase II deficiency prevents activation of autoreactive B cells by double-stranded DNA endogenous ligands.
abstract: In mice that fail to express the phagolysosomal endonuclease DNase II and the type I IFN receptor, excessive accrual of undegraded DNA results in a STING-dependent, TLR-independent inflammatory arthritis. These double-knockout (DKO) mice develop additional indications of systemic autoimmunity, including anti-nuclear autoantibodies and splenomegaly, that are not found in Unc93b1(3d/3d) DKO mice and, therefore, are TLR dependent. The DKO autoantibodies predominantly detect RNA-associated autoantigens, which are commonly targeted in TLR7-dominated systemic erythematosus lupus-prone mice. To determine whether an inability of TLR9 to detect endogenous DNA could explain the absence of dsDNA-reactive autoantibodies in DKO mice, we used a novel class of bifunctional autoantibodies, IgM/DNA dual variable domain Ig molecules, to activate B cells through a BCR/TLR9-dependent mechanism. DKO B cells could not respond to the IgM/DNA dual variable domain Ig molecule, despite a normal response to both anti-IgM and CpG ODN 1826. Thus, DKO B cells only respond to RNA-associated ligands because DNase II-mediated degradation of self-DNA is required for TLR9 activation.
authors.affiliation: Department of Medicine, University of Massachusetts School of Medicine, Worcester, MA 01605;
authors.forename: Sudesh
authors.initials: S
authors.lastname: Pawaria
authors.affiliation: Department of Medicine, University of Massachusetts School of Medicine, Worcester, MA 01605; Department of Microbiology, Boston University School of Medicine, Boston, MA 02118; and.
authors.forename: Krishna
authors.initials: K
authors.lastname: Moody
authors.affiliation: Department of Medicine, University of Massachusetts School of Medicine, Worcester, MA 01605;
authors.forename: Patricia
authors.initials: P
authors.lastname: Busto
authors.affiliation: Department of Medicine, University of Massachusetts School of Medicine, Worcester, MA 01605;
authors.forename: Kerstin
authors.initials: K
authors.lastname: Nündel
authors.affiliation: Global Biologics, AbbVie BioResearch Center, Worcester, MA 01605.
authors.forename: Chee-Ho
authors.initials: CH
authors.lastname: Choi
authors.affiliation: Global Biologics, AbbVie BioResearch Center, Worcester, MA 01605.
authors.forename: Tariq
authors.initials: T
authors.lastname: Ghayur
authors.affiliation: Department of Medicine, University of Massachusetts School of Medicine, Worcester, MA 01605; ann.rothstein@umassmed.edu.
authors.forename: Ann
authors.initials: A
authors.lastname: Marshak-Rothstein
mesh_terms: D000818:Animals; D000918:Antibody Specificity / Q000276:immunology; D001323:Autoantibodies / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology*; D015551:Autoimmunity / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D004247:DNA; D004706:Endodeoxyribonucleases / Q000172:deficiency* / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D008024:Ligands; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D011947:Receptors, Antigen, B-Cell / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000276:immunology
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D008024:Ligands; D011947:Receptors, Antigen, B-Cell; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D004247:DNA; D004706:Endodeoxyribonucleases; C019329:deoxyribonuclease II