title: TLR9 Deficiency Leads to Accelerated Renal Disease and Myeloid Lineage Abnormalities in Pristane-Induced Murine Lupus.
abstract: Systemic lupus erythematosus (SLE) is a chronic, life-threatening autoimmune disorder, leading to multiple organ pathologies and kidney destruction. Analyses of numerous murine models of spontaneous SLE have revealed a critical role for endosomal TLRs in the production of autoantibodies and development of other clinical disease manifestations. Nevertheless, the corresponding TLR9-deficient autoimmune-prone strains consistently develop more severe disease pathology. Injection of BALB/c mice with 2,6,10,14-tetramethylpentadecane (TMPD), commonly known as pristane, also results in the development of SLE-like disease. We now show that Tlr9(-/-) BALB/c mice injected i.p. with TMPD develop more severe autoimmunity than do their TLR-sufficient cohorts. Early indications include an increased accumulation of TLR7-expressing Ly6C(hi) inflammatory monocytes at the site of injection, upregulation of IFN-regulated gene expression in the peritoneal cavity, and an increased production of myeloid lineage precursors (common myeloid progenitors and granulocyte myeloid precursors) in the bone marrow. TMPD-injected Tlr9(-/-) BALB/c mice develop higher autoantibody titers against RNA, neutrophil cytoplasmic Ags, and myeloperoxidase than do TMPD-injected wild-type BALB/c mice. The TMP-injected Tlr9(-/-) mice, and not the wild-type mice, also develop a marked increase in glomerular IgG deposition and infiltrating granulocytes, much more severe glomerulonephritis, and a reduced lifespan. Collectively, the data point to a major role for TLR7 in the response to self-antigens in this model of experimental autoimmunity. Therefore, the BALB/c pristane model recapitulates other TLR7-driven spontaneous models of SLE and is negatively regulated by TLR9.
authors.affiliation: Department of Clinical Immunology and Rheumatology, Hannover Medical School, 30625 Hannover, Germany; Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605; ann.rothstein@umassmed.edu lukas.bossaller@uni-greifswald.de.
authors.forename: Lukas
authors.initials: L
authors.lastname: Bossaller
authors.affiliation: Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605; Institute of Innate Immunity, University Hospital Bonn, 53217 Bonn, Germany;
authors.forename: Anette
authors.identifier: 0000-0003-0829-6179
authors.initials: A
authors.lastname: Christ
authors.affiliation: Institute of Innate Immunity, University Hospital Bonn, 53217 Bonn, Germany;
authors.forename: Karin
authors.identifier: 0000-0003-2856-8602
authors.initials: K
authors.lastname: Pelka
authors.affiliation: Division of Rheumatology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605; and.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Nündel
authors.affiliation: Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605;
authors.forename: Ping-I
authors.initials: PI
authors.lastname: Chiang
authors.affiliation: Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605;
authors.forename: Catherine
authors.identifier: 0000-0003-3450-4728
authors.initials: C
authors.lastname: Pang
authors.affiliation: Department of Clinical Immunology and Rheumatology, Hannover Medical School, 30625 Hannover, Germany;
authors.forename: Neha
authors.initials: N
authors.lastname: Mishra
authors.affiliation: Division of Rheumatology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605; and.
authors.forename: Patricia
authors.identifier: 0000-0003-4531-0494
authors.initials: P
authors.lastname: Busto
authors.affiliation: Renal Section, Department of Medicine, Boston University Medical Center, Boston, MA 021184.
authors.forename: Ramon G
authors.identifier: 0000-0002-1286-141X
authors.initials: RG
authors.lastname: Bonegio
authors.affiliation: Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605;
authors.forename: Reinhold Ernst
authors.initials: RE
authors.lastname: Schmidt
authors.affiliation: Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605; Institute of Innate Immunity, University Hospital Bonn, 53217 Bonn, Germany;
authors.forename: Eicke
authors.initials: E
authors.lastname: Latz
authors.affiliation: Division of Rheumatology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605; and ann.rothstein@umassmed.edu lukas.bossaller@uni-greifswald.de.
authors.forename: Ann
authors.initials: A
authors.lastname: Marshak-Rothstein
mesh_terms: D000818:Animals; D019070:Cell Lineage; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D058501:Enzyme-Linked Immunospot Assay; D005434:Flow Cytometry; D007166:Immunosuppressive Agents / Q000633:toxicity; D008181:Lupus Nephritis / Q000276:immunology / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000276:immunology / Q000473:pathology*; D016133:Polymerase Chain Reaction; D013729:Terpenes / Q000633:toxicity; D051217:Toll-Like Receptor 9 / Q000172:deficiency*
chemical_list: D007166:Immunosuppressive Agents; D013729:Terpenes; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; C009042:pristane