Activation of toll‐like receptor‐9 induces progression of renal disease in MRL‐Fas(lpr) mice

Anders, Hans Joachim; Vielhauer, Volker; Eis, Václav; Linde, Yvonne; Kretzler, Matthias; Lema, Guillermo Pérez de; Strutz, Frank; Bauer, Stefan; Rutz, Mark; Wagner, Hermann; Gröne, Hermann Josef; Schlöndorff, Detlef

doi:10.1096/fj.03-0646fje

Cited by 199 publications

(139 citation statements)

References 44 publications

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“…A role for MyD88-dependent TLR signaling in the development of pathogenic ANA is supported by evidence from murine models and in vitro systems [18,19,[43][44][45]. Our results show that the generation of autoAb in Lyn-deficient mice is also dependent on MyD88-mediated signaling.…”

Section: Discussionsupporting

confidence: 69%

MyD88‐dependent autoimmune disease in Lyn‐deficient mice

et al. 2007

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Recent evidence suggests that systemic autoimmune disease depends on signals from TLR ligands, but little is known about how TLR-dependent pathways lead to the loss of self tolerance in vivo. To address this, we have examined the role of TLR signaling in Lyndeficient mice, which develop an autoimmune disease similar to SLE. We found that absence of the TLR signaling adaptor molecule MyD88 suppresses plasma cell differentiation of switched and unswitched B cells, and prevents the generation of antinuclear IgG antibodies and glomerulonephritis. In mixed chimeras the increased IgM and IgG antibody secretion in Lyn-deficient mice is at least partially due to B cellindependent effects of Lyn. We now show that MyD88 deficiency blocks the expansion and activation of DC in which Lyn is also normally expressed, and prevents the hypersecretion of proinflammatory cytokines IL-6 and IL-12 by Lyn-deficient DC. These findings further highlight the important role of TLR-dependent signals in both lymphocyte activation and autoimmune pathogenesis. IntroductionOur understanding of the pathways leading to autoantibody (autoAb) production in systemic lupus erythematosus (SLE) has been greatly enhanced by studies of murine SLE models, including mice with single targeted mutations to negative regulators of BCR signaling, e.g., the src-family protein tyrosine kinase Lyn [1][2][3], phosphatase SHP-1 [4] and coreceptor CD22 [5, 6]. Lyn deficiency manifests as the hypersecretion of IgM, IgA and IgG autoAb, which, by 17-20 weeks of age, develop specificity to nuclear components such as dsDNA, are deposited as immune complexes (IC) in the kidneys and lead to lethal proliferative glomerulonephritis [1][2][3]. Following BCR stimulation, Lyn-deficient B cells have greater and more prolonged intracellular calcium flux, more MAPK activation and hyperproliferate in comparison to WT B cells [1, 7, 8]. These findings, together with the fact that the expression of Lyn is limited to B, NK and myeloid cells [9], have led to the suggestion that B cell intrinsic effects are the main cause of SLE-like autoimmune disease. Growing support for the central role B cells play in the development of autoimmune disease (reviewed in [10]) and the discovery of lower levels of Lyn in B cells of human SLE patients have helped strengthen this idea [11].However, the development of high-affinity pathogenic autoAb, which are targeted at nuclear antigens and potentially damaging to organs including kidneys, depends on somatic hypermutation in the germinal center and collaboration between cells of the adaptive and innate immune systems. T cells play an important role in this process and autoantigen-specific T cells are required for secretion of IgG autoAb specific for nuclear components and end-organ damage in the spontaneous murine models, MRL-lpr/lpr and (NZBÂNZW)F 1 [18]. Disease in the gp96 transgenic mice is dependent on MyD88, an adaptor molecule required for signaling by all TLR except TLR3, which binds dsRNA, and TLR4, which also signals by a MyD88-independent pa...

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Section: Discussionsupporting

confidence: 69%

MyD88‐dependent autoimmune disease in Lyn‐deficient mice

et al. 2007

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“…In models of chronic glomerular disease, viral doublestranded RNA, a known TLR3 ligand, and bacterial DNA, a TLR9 ligand, have been shown to aggravate lupus nephritis (37,38). Bacterial DNA also has been shown to aggravate horse apoferritin-induced glomerulonephritis.…”

Section: Discussionmentioning

confidence: 99%

Toll-Like Receptor 2 Agonists Exacerbate Accelerated Nephrotoxic Nephritis

Brown

Sacks

Robson

2006

Journal of the American Society of Nephrology

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Glomerulonephritis can be exacerbated by infection. This study investigated the effect of N-palmitoyl-S-(2,3-bis(palmitoyloxy)-(2R,S)-propyl)-(R)-cysteinyl-seryl-(lysyl)3-lysine (Pam 3 CysSK 4 ), a synthetic Toll-like receptor 2 (TLR2) ligand, that was given at immunization on disease severity in accelerated nephrotoxic nephritis. Stimulation of TLR by microbial constituents is known to influence the development of the adaptive immunity. It was hypothesized that the TLR2 ligand Pam 3 CysSK 4 can modulate the development of disease in accelerated nephrotoxic nephritis by influencing the development of adaptive immunity. It is shown that Pam 3 CysSK 4 , when given at immunization, can increase profoundly the severity of disease, and with the use of TLR2-deficient mice, it is shown that this disease exacerbation depends on the presence of TLR2. Wild-type mice that were given Pam 3 CysSK 4 at immunization and had more severe disease also had a greater amount of antigen-specific IgG1, IgG2b, and IgG3 in the serum and more IgG2b and IgG3 deposited within the glomerulus. They also had increased numbers of glomerular CD4-positive T cells. Therefore, the more severe disease that was seen in the group that was immunized with lipopeptide can be attributed to an influence on the adaptive immune response.

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“…52 Recently, it was shown that the TLR 9 pathway is activated in SLE patients, and the activation could induce disease progression in a mouse model. 53,54 A systematic study on the TLR profile in SLE, with the same approach used in this paper, might shed light on its relation to HNL.…”

Section: Discussionmentioning

confidence: 97%

Oligoclonal T cells in histiocytic necrotizing lymphadenopathy are associated with TLR9+ plasmacytoid dendritic cells

Lin

Liu

Lin

et al. 2005

Laboratory Investigation

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Histiocytic necrotizing lymphadenopathy (HNL), a disease of unknown cause, is characterized pathologically by the presence of plasmacytoid dendritic cells (pDCs), which are frequently mixed with oligoclonal T cells (OTCs) and myeloid cells. Toll-like receptors (TLRs 1-10) are a family of pattern recognition receptors of DCs. To investigate the interactions between pDCs and T cells, and to look for an etiology of HNL, we studied 24 HNLs for the profile of TLRs. Transcripts of TLR7, a receptor on pDCs for single-stranded RNA, were found in every case, confirming the universal presence of pDCs. Transcripts of TLR9, another receptor on pDCs for microbial unmethylated CpG-rich DNA, were correlated with OTCs, implying T-cell expansion stimulated by TLR9 þ pDCs in response to a microbe. Because PCRs for bacterial 16S rDNAs were negative in the lymph nodes, a bacterial origin seems unlikely, but a virus remains a possible candidate. The pDCs lacked the maturation marker CD83, which suggested ineffective stimulation of T cells and might account for the usually benign course of HNL. Taken together, these data illustrate a novel approach, based upon TLR transcript analysis, for the integration of pathology, immunology, and clinical findings of HNL.

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Activation of toll‐like receptor‐9 induces progression of renal disease in MRL‐Fas(lpr) mice

Cited by 199 publications

References 44 publications

MyD88‐dependent autoimmune disease in Lyn‐deficient mice

MyD88‐dependent autoimmune disease in Lyn‐deficient mice

Toll-Like Receptor 2 Agonists Exacerbate Accelerated Nephrotoxic Nephritis

Oligoclonal T cells in histiocytic necrotizing lymphadenopathy are associated with TLR9+ plasmacytoid dendritic cells

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