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Critical Role of TLR2 and TLR4 in Autoantibody Production and Glomerulonephritis in lpr Mutation-Induced Mouse Lupus¹

Aurelia Lartigue,^2* Natacha Colliou,^2* Sébastien Calbo,^* Arnault François, Serge Jacquot,^* Christophe Arnoult,^* Francois Tron,^* Daniele Gilbert,^* and Philippe Musette^3*

^*INSERM, Unité 905, Rouen, France; and Institut Fédératif de Recherches Multidiciplinaires, Institute for Biomedical Research, University of Rouen, Rouen, France; and Pathology Department, Department of Immunology, and Department of Dermatology, Rouen University Hospital, Rouen, France

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by pathogenic autoantibodies directed against nuclear Ags and immune complex deposits in damaged organs. Environmental factors have been thought to play a role in the onset of the disease. The recognition of these factors is mediated by TLRs, in particular TLR2 and TLR4 which bind pathogen-associated molecular patterns of Gram⁺ and Gram^– bacteria, respectively. We attempted to determine the role of these TLRs in SLE by creating TLR2- or TLR4-deficient C57BL/6^lpr/lpr mice. These mice developed a less severe disease and fewer immunological alterations. Indeed, in C57BL/6^lpr/lpr-TLR2 or -TLR4-deficient mice, glomerular IgG deposits and mesangial cell proliferation were dramatically decreased and antinuclear, anti-dsDNA, and anti-cardiolipin autoantibody titers were significantly reduced. However, the response against nucleosome remained unaffected, indicating a role of TLR2 and TLR4 in the production of Abs directed against only certain categories of SLE-related autoantigens. Analysis of B cell phenotype showed a significant reduction of marginal zone B cells, particularly in C57BL/6^lpr/lpr-TLR4-deficient mice, suggesting an important role of TLR4 in the sustained activation of these cells likely involved in autoantibody production. Interestingly, the lack of TLR4 also affected the production of cytokines involved in the development of lupus disease.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by INSERM.

² A.L. and N.C. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Philippe Musette, INSERM Unité 905, Faculté de Médecine et Pharmacie, 22, bd Gambetta, 76183 Rouen, Cedex, France. E-mail address: Philippe.Musette{at}chu-rouen.fr

⁴ Abbreviations used in this paper: SLE, systemic lupus erythematosus; MZ, marginal zone; TI, T cell independent; Treg, regulatory T cell; HSP, heat shock protein; WT, wild type; RF, rheumatoid factor; MZ, marginal zone; BLyS, B lymphocyte stimulator; TACI, transmembrane activator calcium modulator and cyclophilin ligand; ANA, antinuclear Ab; CL, cardiolipin.