{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T17:07:44Z","timestamp":1791220064067,"version":"4.1.0"},"reference-count":70,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2009,11,1]],"date-time":"2009-11-01T00:00:00Z","timestamp":1257033600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2009,11,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>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\u2212 bacteria, respectively. We attempted to determine the role of these TLRs in SLE by creating TLR2- or TLR4-deficient C57BL\/6lpr\/lpr mice. These mice developed a less severe disease and fewer immunological alterations. Indeed, in C57BL\/6lpr\/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\/6lpr\/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.<\/jats:p>","DOI":"10.4049\/jimmunol.0803219","type":"journal-article","created":{"date-parts":[[2009,10,20]],"date-time":"2009-10-20T01:31:56Z","timestamp":1256002316000},"page":"6207-6216","source":"Crossref","is-referenced-by-count":132,"title":["Critical Role of TLR2 and TLR4 in Autoantibody Production and Glomerulonephritis in <i>lpr<\/i> Mutation-Induced Mouse Lupus"],"prefix":"10.1093","volume":"183","author":[{"given":"Aurelia","family":"Lartigue","sequence":"first","affiliation":[{"name":"INSERM , Unit\u00e9 905, Rouen,","place":["France"]},{"name":"Institut F\u00e9d\u00e9ratif de Recherches Multidiciplinaires, Institute for Biomedical Research, University of Rouen , Rouen,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natacha","family":"Colliou","sequence":"additional","affiliation":[{"name":"INSERM , Unit\u00e9 905, Rouen,","place":["France"]},{"name":"Institut F\u00e9d\u00e9ratif de Recherches Multidiciplinaires, Institute for Biomedical Research, University of Rouen , Rouen,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S\u00e9bastien","family":"Calbo","sequence":"additional","affiliation":[{"name":"INSERM , Unit\u00e9 905, Rouen,","place":["France"]},{"name":"Institut F\u00e9d\u00e9ratif de Recherches Multidiciplinaires, Institute for Biomedical Research, University of Rouen , Rouen,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arnault","family":"Fran\u00e7ois","sequence":"additional","affiliation":[{"name":"Pathology Department"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serge","family":"Jacquot","sequence":"additional","affiliation":[{"name":"INSERM , Unit\u00e9 905, Rouen,","place":["France"]},{"name":"Institut F\u00e9d\u00e9ratif de Recherches Multidiciplinaires, Institute for Biomedical Research, University of Rouen , Rouen,","place":["France"]},{"name":"Department of Immunology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christophe","family":"Arnoult","sequence":"additional","affiliation":[{"name":"INSERM , Unit\u00e9 905, Rouen,","place":["France"]},{"name":"Institut F\u00e9d\u00e9ratif de Recherches Multidiciplinaires, Institute for Biomedical Research, University of Rouen , Rouen,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francois","family":"Tron","sequence":"additional","affiliation":[{"name":"INSERM , Unit\u00e9 905, Rouen,","place":["France"]},{"name":"Institut F\u00e9d\u00e9ratif de Recherches Multidiciplinaires, Institute for Biomedical Research, University of Rouen , Rouen,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniele","family":"Gilbert","sequence":"additional","affiliation":[{"name":"INSERM , Unit\u00e9 905, Rouen,","place":["France"]},{"name":"Institut F\u00e9d\u00e9ratif de Recherches Multidiciplinaires, Institute for Biomedical Research, University of Rouen , Rouen,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe","family":"Musette","sequence":"additional","affiliation":[{"name":"INSERM , Unit\u00e9 905, Rouen,","place":["France"]},{"name":"Institut F\u00e9d\u00e9ratif de Recherches Multidiciplinaires, Institute for Biomedical Research, University of Rouen , Rouen,","place":["France"]},{"name":"Department of Dermatology, Rouen University Hospital , Rouen,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2009,11,15]]},"reference":[{"key":"2025032603213567000_R1","first-page":"303","article-title":"Systemic lupus erythematosus.","volume-title":"Cell","year":"1996"},{"key":"2025032603213567000_R2","first-page":"538","article-title":"Lupus nephritis.","volume-title":"Kidney Int.","year":"1997"},{"key":"2025032603213567000_R3","first-page":"1249","article-title":"Polyclonal B cell activation in lupus-prone mice precedes and predicts the development of autoimmune disease.","volume-title":"J. Clin. Invest.","year":"1990"},{"key":"2025032603213567000_R4","first-page":"454","article-title":"Genetic dissection of systemic lupus erythematosus pathogenesis: Sle2 on murine chromosome 4 leads to B cell hyperactivity.","volume-title":"J. Immunol.","year":"1997"},{"key":"2025032603213567000_R5","first-page":"1127","article-title":"Spontaneous B cell hyperactivity in autoimmune-prone MRL mice.","volume-title":"Int. Immunol.","year":"2006"},{"key":"2025032603213567000_R6","first-page":"1869","article-title":"T cell hyperactivity in lupus as a consequence of hyperstimulatory antigen-presenting cells.","volume-title":"J. Clin. Invest.","year":"2005"},{"key":"2025032603213567000_R7","first-page":"543","article-title":"TLR-dependent and TLR-independent pathways of type I interferon induction in systemic autoimmunity.","volume-title":"Nat. Med.","year":"2007"},{"key":"2025032603213567000_R8","first-page":"397","article-title":"Delineating the genetic basis of systemic lupus erythematosus.","volume-title":"Immunity","year":"2001"},{"key":"2025032603213567000_R9","first-page":"63","article-title":"Epstein-Barr virus and molecular mimicry in systemic lupus erythematosus.","volume-title":"Autoimmunity","year":"2006"},{"key":"2025032603213567000_R10","first-page":"473","article-title":"Infections and SLE.","volume-title":"Autoimmunity","year":"2005"},{"key":"2025032603213567000_R11","first-page":"515","article-title":"Lipopolysaccharide from Gram-negative bacteria enhances polyclonal B cell activation and exacerbates nephritis in MRL\/lpr mice.","volume-title":"Clin. Exp. Immunol.","year":"1990"},{"key":"2025032603213567000_R12","first-page":"353","article-title":"Genetic analysis of host resistance: Toll-like receptor signaling and immunity at large.","volume-title":"Annu. Rev. Immunol.","year":"2006"},{"key":"2025032603213567000_R13","first-page":"783","article-title":"Pathogen recognition and innate immunity.","volume-title":"Cell","year":"2006"},{"key":"2025032603213567000_R14","first-page":"4531","article-title":"Quantitative expression of Toll-like receptor 1\u201310 mRNA in cellular subsets of human peripheral blood mononuclear cells and sensitivity to CpG oligodeoxynucleotides.","volume-title":"J. Immunol.","year":"2002"},{"key":"2025032603213567000_R15","first-page":"3749","article-title":"Cutting edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product.","volume-title":"J. Immunol.","year":"1999"},{"key":"2025032603213567000_R16","first-page":"403","article-title":"Regulatory T cells selectively express Toll-like receptors and are activated by lipopolysaccharide.","volume-title":"J. Exp. Med.","year":"2003"},{"key":"2025032603213567000_R17","first-page":"485","article-title":"Toll-like receptor 2 controls expansion and function of regulatory T cells.","volume-title":"J. Clin. Invest.","year":"2006"},{"key":"2025032603213567000_R18","first-page":"1033","article-title":"Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells.","volume-title":"Science","year":"2003"},{"key":"2025032603213567000_R19","first-page":"823","article-title":"Toll-like receptors in systemic autoimmune disease.","volume-title":"Nat. Rev. Immunol.","year":"2006"},{"key":"2025032603213567000_R20","first-page":"11","article-title":"Regulation of lupus-related autoantibody production and clinical disease by Toll-like receptors.","volume-title":"Semin. Immunol.","year":"2007"},{"key":"2025032603213567000_R21","first-page":"1349","article-title":"Role of TLR9 in anti-nucleosome and anti-DNA antibody production in lpr mutation-induced murine lupus.","volume-title":"J. Immunol.","year":"2006"},{"key":"2025032603213567000_R22","first-page":"6145","article-title":"Toll-like receptor 2 pathway drives streptococcal cell wall-induced joint inflammation: critical role of myeloid differentiation factor 88.","volume-title":"J. Immunol.","year":"2003"},{"key":"2025032603213567000_R23","first-page":"537","article-title":"Interleukin 1 receptor dependence of serum transferred arthritis can be circumvented by Toll-like receptor 4 signaling.","volume-title":"J. Exp. Med.","year":"2003"},{"key":"2025032603213567000_R24","first-page":"558","article-title":"Cutting edge: heat shock protein 60 is a putative endogenous ligand of the Toll-like receptor-4 complex.","volume-title":"J. Immunol.","year":"2000"},{"key":"2025032603213567000_R25","first-page":"3594","article-title":"Heat shock protein 60 activates B cells via the TLR4-MyD88 pathway.","volume-title":"J. Immunol.","year":"2005"},{"key":"2025032603213567000_R26","first-page":"6880","article-title":"TLR4 up-regulation at protein or gene level is pathogenic for lupus-like autoimmune disease.","volume-title":"J. Immunol.","year":"2006"},{"key":"2025032603213567000_R27","first-page":"243","article-title":"lpr and gld: single gene models of systemic autoimmunity and lymphoproliferative disease.","volume-title":"Annu. Rev. Immunol.","year":"1991"},{"key":"2025032603213567000_R28","first-page":"281","article-title":"Genetic dissection of SLE: SLE1 and FAS impact alternate pathways leading to lymphoproliferative autoimmunity.","volume-title":"J. Exp. Med.","year":"2002"},{"key":"2025032603213567000_R29","first-page":"321","article-title":"Toll-like receptor 9 controls anti-DNA autoantibody production in murine lupus.","volume-title":"J. Exp. Med.","year":"2005"},{"key":"2025032603213567000_R30","first-page":"2322","article-title":"lpr gene control of the anti-DNA antibody response.","volume-title":"J. Immunol.","year":"1982"},{"key":"2025032603213567000_R31","first-page":"1644","article-title":"Th1\/Th2 balance of peripheral T helper cells in systemic lupus erythematosus.","volume-title":"Arthritis Rheum.","year":"1999"},{"key":"2025032603213567000_R32","first-page":"443","article-title":"Differential roles of TLR2 and TLR4 in recognition of Gram-negative and Gram-positive bacterial cell wall components.","volume-title":"Immunity","year":"1999"},{"key":"2025032603213567000_R33","first-page":"6639","article-title":"Role of TLR in B cell development: signaling through TLR4 promotes B cell maturation and is inhibited by TLR2.","volume-title":"J. 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Immunol.","year":"2005"},{"key":"2025032603213567000_R47","first-page":"75","article-title":"B cell development in the spleen takes place in discrete steps and is determined by the quality of B cell receptor-derived signals.","volume-title":"J. Exp. Med.","year":"1999"},{"key":"2025032603213567000_R48","first-page":"323","article-title":"Marginal-zone B cells.","volume-title":"Nat. Rev. Immunol.","year":"2002"},{"key":"2025032603213567000_R49","first-page":"1293","article-title":"ADAM10 is a principal \u201csheddase\u201d of the low-affinity immunoglobulin E receptor CD23.","volume-title":"Nat. Immunol.","year":"2006"},{"key":"2025032603213567000_R50","first-page":"7139","article-title":"Defining in vivo transcription factor complexes of the murine CD21 and CD23 genes.","volume-title":"J. 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