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

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

Journal of immunology (Baltimore, Md. : 1950) (2016-06-30)
Lukas Bossaller, Anette Christ, Karin Pelka, Kerstin Nündel, Ping-I Chiang, Catherine Pang, Neha Mishra, Patricia Busto, Ramon G Bonegio, Reinhold Ernst Schmidt, Eicke Latz, Ann Marshak-Rothstein

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.

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Anti-Mouse IgG (whole molecule)–Peroxidase antibody produced in goat, affinity isolated antibody, buffered aqueous solution
Ribonucleic acid from baker's yeast (S. cerevisiae)