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J Immunol. 2016 Aug 15;197(4):1044-53. doi: 10.4049/jimmunol.1501943. Epub 2016 Jun 27.

TLR9 Deficiency Leads to Accelerated Renal Disease and Myeloid Lineage Abnormalities in Pristane-Induced Murine Lupus.

Author information

1
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.
2
Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605; Institute of Innate Immunity, University Hospital Bonn, 53217 Bonn, Germany;
3
Institute of Innate Immunity, University Hospital Bonn, 53217 Bonn, Germany;
4
Division of Rheumatology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605; and.
5
Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605;
6
Department of Clinical Immunology and Rheumatology, Hannover Medical School, 30625 Hannover, Germany;
7
Renal Section, Department of Medicine, Boston University Medical Center, Boston, MA 021184.
8
Division of Rheumatology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605; and ann.rothstein@umassmed.edu lukas.bossaller@uni-greifswald.de.

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.

PMID:
27354219
PMCID:
PMC5266544
DOI:
10.4049/jimmunol.1501943
[Indexed for MEDLINE]
Free PMC Article

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