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. CONCLUSION: 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.
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 murinepristane-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. CONCLUSION:TLR-2 is required for the production of prototypical lupus autoantibodies and the development of renal disease in pristane-induced murinelupus. Interference with TLR-2 signaling may be a promising novel strategy for the treatment of SLE.
Authors: Deborah Kienhöfer; Jonas Hahn; Julia Stoof; Janka Zsófia Csepregi; Christiane Reinwald; Vilma Urbonaviciute; Caroline Johnsson; Christian Maueröder; Malgorzata J Podolska; Mona H Biermann; Moritz Leppkes; Thomas Harrer; Malin Hultqvist; Peter Olofsson; Luis E Munoz; Attila Mocsai; Martin Herrmann; Georg Schett; Rikard Holmdahl; Markus H Hoffmann Journal: JCI Insight Date: 2017-05-18
Authors: S A Summers; D Odobasic; M B Khouri; O M Steinmetz; Y Yang; S R Holdsworth; A R Kitching Journal: Clin Exp Immunol Date: 2014-06 Impact factor: 4.330
Authors: Consuelo P C Marques; Vandilson P Rodrigues; Larissa C de Carvalho; Louise P Nichilatti; Mayra M Franco; Fernando José B Patrício; Marcelo Magalhães; Marcelo S de Andrade; Bruno B Benatti Journal: Clin Rheumatol Date: 2021-02-11 Impact factor: 2.980