title: Toll-like receptor 2 is required for autoantibody production and development of renal disease in pristane-induced lupus.
abstract: OBJECTIVE
  The mechanisms involved in breaking immunologic tolerance against nuclear autoantigens in systemic lupus erythematosus (SLE) are not fully understood. Our recent studies in nonautoimmune mice provided evidence of an important role of Toll-like receptor 2 (TLR-2) in antichromatin autoantibody induction by high mobility group box chromosomal protein 1-nucleosome complexes derived from apoptotic cells. The objective of this study was to investigate whether TLR-2 signaling is required for the induction of autoantibodies and the development of SLE-like disease in murine pristane-induced lupus.
  
  
  METHODS
  Lupus-like disease in C57BL/6 and TLR-2(-/-) mice was induced by pristane injection. The numbers of immune cells and serum cytokine concentrations were determined by flow cytometry. Renal disease was assessed by quantification of proteinuria, histologic analyses, and enzyme-linked immunospot assay.
  
  
  RESULTS
  Pristane-injected TLR-2(-/-) mice generated reduced numbers of splenic CD138+/cytoplasmic κL/λL chain-positive plasma cells and displayed diminished IgG responses against double-stranded DNA, histones, nucleosomes, some extractable nuclear autoantigens, and cardiolipin when compared with wild- type controls. TLR-2 deficiency prevented the pristane-induced systemic release of interleukin-6 (IL-6) and IL-10. The absence of TLR-2 attenuated peritoneal recruitment of CD11c+ cells and formation of lipogranulomas. Importantly, the renal disease that developed in pristane-treated TLR-2(-/-) mice was less severe than that in control mice, as reflected by milder proteinuria, reduced glomerular deposition of IgG and complement, and decreased renal infiltration of autoantibody-secreting cells.
  
  
  CONCLUSIONS
  TLR-2 is required for the production of prototypical lupus autoantibodies and the development of renal disease in pristane-induced murine lupus. Interference with TLR-2 signaling may be a promising novel strategy for the treatment of SLE.
authors: University Hospital Erlangen and University of Erlangen-Nuremberg, Erlangen, Germany; Karolinska Institute, Stockholm, Sweden.
authors: Vilma
authors: V
authors: Urbonaviciute
authors: Charlotte
authors: C
authors: Starke
authors: Wiebke
authors: W
authors: Pirschel
authors: Sandy
authors: S
authors: Pohle
authors: Silke
authors: S
authors: Frey
authors: Christoph
authors: C
authors: Daniel
authors: Kerstin
authors: K
authors: Amann
authors: Georg
authors: G
authors: Schett
authors: Martin
authors: M
authors: Herrmann
authors: Reinhard E
authors: RE
authors: Voll
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000276:immunology* / Q000378:metabolism; D016207:Cytokines / Q000097:blood*; D004797:Enzyme-Linked Immunosorbent Assay; D058501:Enzyme-Linked Immunospot Assay; D005434:Flow Cytometry; D024243:HMGB1 Protein / Q000378:metabolism*; D007674:Kidney Diseases / Q000276:immunology*; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008181:Lupus Nephritis / Q000139:chemically induced / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D011507:Proteinuria; D013729:Terpenes / Q000494:pharmacology*; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000276:immunology*
chemical_list: D001323:Autoantibodies; D016207:Cytokines; D024243:HMGB1 Protein; D013729:Terpenes; D051195:Toll-Like Receptor 2; C009042:pristane