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

被引:126
作者
Lartigue, Aurelia [2 ]
Colliou, Natacha [2 ]
Calbo, Sebastien [2 ]
Francois, Arnault [3 ]
Jacquot, Serge [2 ,4 ]
Arnoult, Christophe [2 ]
Tron, Francois [2 ]
Gilbert, Daniele [2 ]
Musette, Philippe [1 ,2 ,5 ]
机构
[1] Fac Med & Pharm, INSERM, U905, F-76183 Rouen, France
[2] Univ Rouen, Inst Biomed Res, Inst Federatif Rech Multidiciplinaires, Rouen, France
[3] Rouen Univ Hosp, Dept Pathol, Rouen, France
[4] Rouen Univ Hosp, Dept Immunol, Rouen, France
[5] Rouen Univ Hosp, Dept Dermatol, Rouen, France
关键词
TOLL-LIKE RECEPTOR-4; B-CELL DEVELOPMENT; REGULATORY T-CELLS; MURINE LUPUS; SYSTEMIC AUTOIMMUNITY; DEFICIENT MICE; INDEPENDENT ANTIGENS; GENETIC DISSECTION; IMMUNE-RESPONSE; DENDRITIC CELLS;
D O I
10.4049/jimmunol.0803219
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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 Journal of Immunology, 2009, 183: 6207-6216.
引用
收藏
页码:6207 / 6216
页数:10
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