Molecular mimicry in innate immunity? The viral RNA recognition receptor TLR7 accelerates murine lupus

Anders, Hans‐Joachim; Krug, Anne; Pawar, Rahul D.

doi:10.1002/eji.200838478

Cited by 22 publications

(17 citation statements)

References 22 publications

(37 reference statements)

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“…The immunostimulatory effects of endogenous nucleic acids are known to drive SLE via TLR7 35 36. We therefore speculated that Irak-m deficiency aggravated murine lupus mainly by uncoupling TLR7 signalling.…”

Section: Resultsmentioning

confidence: 99%

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Interleukin-1 receptor-associated kinase-M suppresses systemic lupus erythematosus

Lech

Kantner

Kulkarni

et al. 2011

Annals of the Rheumatic Diseases

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Objectives Interleukin-1 receptor-associated kinase (IRAK)-M suppresses Toll-like receptor (TLR)-mediated activation of innate immunity during infection. A similar role was hypothesised for IRAK-M in autoimmunity. Methods Irak-m-defi cient mice were crossed with autoimmune C57BL/6-lpr/lpr mice and detailed phenotype analysis was performed. Results Irak-m defi ciency converted the mild autoimmune phenotype of C57BL/6-lpr/lpr mice into a massive lymphoproliferative syndrome with lethal autoimmune lung disease and lupus nephritis. Irak-m defi ciency induced a number of interferon-related genes, cytokines and plasma cell survival factors in spleen cells of these mice. Irak-m-defi cient C57BL/6-lpr/lpr mice showed expansion of autoreactive T cells, dysfunctional regulatory T cells and plasma cells which was associated with increased lupus autoantibody production. TLR7 antagonism almost completely abrogated this phenotype consistent with IRAK-M-mediated suppression of TLR7 signalling in vitro. Conclusions These data identify a previously unknown function of IRAK-M-namely, suppression of TLR7-mediated autoimmunity-and mutant IRAK-M as a previously unknown genetic risk for murine SLE.

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Section: Resultsmentioning

confidence: 99%

“…TLR7 signalling contributes to autoimmunity6 35 and IRAK-M suppresses TLR signalling,21 so we hypothesised that IRAK-M might suppress autoimmunity. Our data support the latter by two lines of evidence.…”

Section: Discussionmentioning

confidence: 98%

Interleukin-1 receptor-associated kinase-M suppresses systemic lupus erythematosus

Lech

Kantner

Kulkarni

et al. 2011

Annals of the Rheumatic Diseases

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“…9 IRF3 and IRF7 mediate type I IFN production upon immune recognition of viral and endogenous nucleic acids in DCs, 10 including TLR7 signaling, which was shown to be an essential pathway in SLE. 7,[11][12][13] IRF5 is required for immune cell maturation and for TLR signaling, two mechanisms that contribute to SLE and lupus nephritis of Fc␥RIIBϪ/ϪYaa or Fc␥RIIBϪ/Ϫ mice 14 and in lupus secondary to pristane injection. 15 Unlike other IRFs, IRF4 is not regulated by IFNs and its expression is restricted to immune cells.…”

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confidence: 99%

IRF4 Deficiency Abrogates Lupus Nephritis Despite Enhancing Systemic Cytokine Production

Lech¹,

Weidenbusch²,

Kulkarni³

et al. 2011

Journal of the American Society of Nephrology

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The IFN-regulatory factors IRF1, IRF3, IRF5, and IRF7 modulate processes involved in the pathogenesis of systemic lupus and lupus nephritis, but the contribution of IRF4, which has multiple roles in innate and adaptive immunity, is unknown. To determine a putative pathogenic role of IRF4 in lupus, we crossed Irf4-deficient mice with autoimmune C57BL/6-(Fas)lpr mice. IRF4 deficiency associated with increased activation of antigen-presenting cells in C57BL/6-(Fas)lpr mice, resulting in a massive increase in plasma levels of TNF and IL-12p40, suggesting that IRF4 suppresses cytokine release in these mice. Nevertheless, IRF4 deficiency completely protected these mice from glomerulonephritis and lung disease. The mice were hypogammaglobulinemic and lacked antinuclear and anti-dsDNA autoantibodies, revealing the requirement of IRF4 for the maturation of plasma cells. As a consequence, Irf4-deficient C57BL/6-(Fas)lpr mice neither developed immune complex disease nor glomerular activation of complement. In addition, lack of IRF4 impaired the maturation of Th17 effector T cells and reduced plasma levels of IL-17 and IL-21, which are cytokines known to contribute to autoimmune tissue injury. In summary, IRF4 deficiency enhances systemic inflammation and the activation of antigen-presenting cells but also prevents the maturation of plasma cells and effector T cells. Because these adaptive immune effectors are essential for the evolution of lupus nephritis, we conclude that IRF4 promotes the development of lupus nephritis despite suppressing antigen-presenting cells.

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“…This process would be similar to the molecular mimicry of self and viral nucleic acids at the level of the Toll-like receptors by which nuclear particles induce those autoadjuvant effects that drive the presentation of lupus autoantigens. 5,6,36 In addition, it might be possible that persistent DNA virus replication, e.g., Epstein-Barr virus, serves as a second source of mitogenic DNA driving lymphoproliferation in lupus as it has been proven for Epstein-Barr virus-induced lymphomas. 19,36 Furthermore, it is intriguing to speculate that Mdm2 induction is also responsible for the recently described phenomenon of TLR7/9-mediated expansion and steroid resistance of plasmacytoid dendritic cells in lupus.…”

Section: Basic Research Wwwjasnorgmentioning

confidence: 99%

“…4,5 For example, certain endogenous RNA or DNA particles activate Toll-like receptor (TLR)-7 and TLR9 in dendritic cells and B cells, which promotes lymphoproliferation and immune complex disease as well as intrarenal inflamma-tion. 5,6 Vice versa, neutralizing TLR7 and/or TLR9 prevents and suppresses lupus nephritis. [7][8][9] Although RNA and DNA seem to have identical immunostimulatory effects on systemic and intrarenal inflammation, some observations suggest that RNA and DNA immune recognition differ in terms of their mitogenic effects.…”

mentioning

confidence: 99%

Mdm2 Promotes Systemic Lupus Erythematosus and Lupus Nephritis

Allam

Sayyed

Kulkarni

et al. 2011

Journal of the American Society of Nephrology

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Systemic lupus erythematosus (SLE) is a polyclonal autoimmune syndrome directed against multiple nuclear autoantigens. Although RNA and DNA seem to have identical immunostimulatory effects on systemic and intrarenal inflammation, each seems to differ with regard to the propensity to induce mitogenic effects such as lymphoproliferation. To identify potential mechanisms by which DNA specifically contributes to the pathogenesis of lupus nephritis, we stimulated cells with immunostimulatory DNA or RNA in vitro and used microarray to compare the transcriptomes of RNA-and DNA-induced genes. Immunostimulatory DNA, but not RNA, induced Mdm2, which is a negative regulator of p53. In vivo, we observed greater expression and activation of Mdm2 in the spleen and kidneys in a mouse model of lupus (MRL-Fas lpr mice) than healthy controls. Treatment of MRL-Fas lpr mice with the Mdm2 inhibitor nutlin-3a prevented nephritis and lung disease and significantly prolonged survival. Inhibition of Mdm2 reduced systemic inflammation and abrogated immune complex disease by suppressing plasma cells and the production of lupus autoantibodies. In addition, nutlin-3a suppressed the abnormal expansion of all T cell subsets, including CD3 ϩ CD4 Ϫ CD8 Ϫ T cells, which associated with attenuated systemic inflammation. However, inhibiting Mdm2 did not cause myelosuppression or affect splenic regulatory T cells, neutrophils, dendritic cells, or monocytes. Taken together, these data suggest that the induction of Mdm2 promotes the expansion of plasma cells and CD3 ϩ CD4 Ϫ CD8 Ϫ T cells, which cause autoantibody production and immune complex disease in MRL-Fas lpr mice. Antagonizing Mdm2 may have therapeutic potential in lupus nephritis. 22: 201622: -202722: , 201122: . doi: 10.1681 Lupus nephritis is an immune complex glomerulonephritis that develops secondary to systemic lupus erythematosus (SLE), a polyclonal autoimmune syndrome directed against multiple nuclear autoantigens. 1,2 It is becoming increasingly obvious that SLE and lupus nephritis develop from combinations of genetic variants that impair proper apoptotic cell death and rapid clearance of apoptotic cells as a central homeostatic avenue to avoid the exposure of nuclear autoantigens to the immune system. 3 The observation that antinuclear antibodies are directed against double-stranded (ds)DNA in the majority of SLE patients and in almost all lupus nephritis patients first documented dsDNA as an important lupus autoantigen. The traditional view of nuclear particles as lupus autoantigens was recently broadened by the observation that nuclear particles promote lupus nephritis also by acting as autoadjuvants. 4,5 For example, certain endogenous RNA or DNA particles activate Toll-like receptor (TLR)-7 and TLR9 in dendritic cells and B cells, which promotes lymphoproliferation and immune complex disease as well as intrarenal inflamma- J Am Soc Nephrol

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Molecular mimicry in innate immunity? The viral RNA recognition receptor TLR7 accelerates murine lupus

Cited by 22 publications

References 22 publications

Interleukin-1 receptor-associated kinase-M suppresses systemic lupus erythematosus

Interleukin-1 receptor-associated kinase-M suppresses systemic lupus erythematosus

IRF4 Deficiency Abrogates Lupus Nephritis Despite Enhancing Systemic Cytokine Production

Mdm2 Promotes Systemic Lupus Erythematosus and Lupus Nephritis

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