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      Toll-like receptors in lupus nephritis

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          Abstract

          The pathogenesis of systemic autoimmune diseases such as systemic lupus erythematosus (SLE) is based on the loss of self-tolerance against ubiquitous autoantigens involving all mechanisms of adaptive immunity. However, data accumulating over the last decade imply an important role also for numerous elements of innate immunity, namely the Toll-like receptors in the pathogenesis of SLE. Here we discuss their role in the most common organ complication of SLE, i.e. lupus nephritis. We summarize experimental and clinical data on the expression and functional contribution of the Toll-like receptors in immune complex glomerulonephritis, and intrarenal inflammation. Based on these discoveries Toll-like receptors are evolving as therapeutic targets for the treatment of SLE and lupus nephritis.

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          Most cited references124

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          RNA-associated autoantigens activate B cells by combined B cell antigen receptor/Toll-like receptor 7 engagement

          Previous studies (Leadbetter, E.A., I.R. Rifkin, A.H. Hohlbaum, B. Beaudette, M.J. Shlomchik, and A. Marshak-Rothstein. 2002. Nature. 416:603–607; Viglianti, G.A., C.M. Lau, T.M. Hanley, B.A. Miko, M.J. Shlomchik, and A. Marshak-Rothstein. 2003. Immunity. 19:837–847) established the unique capacity of DNA and DNA-associated autoantigens to activate autoreactive B cells via sequential engagement of the B cell antigen receptor (BCR) and Toll-like receptor (TLR) 9. We demonstrate that this two-receptor paradigm can be extended to the BCR/TLR7 activation of autoreactive B cells by RNA and RNA-associated autoantigens. These data implicate TLR recognition of endogenous ligands in the response to both DNA- and RNA-associated autoantigens. Importantly, the response to RNA-associated autoantigens was markedly enhanced by IFN-α, a cytokine strongly linked to disease progression in patients with systemic lupus erythematosus (SLE). As further evidence that TLRs play a key role in autoantibody responses in SLE, we found that autoimmune-prone mice, lacking the TLR adaptor protein MyD88, had markedly reduced chromatin, Sm, and rheumatoid factor autoantibody titers.
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            A Tlr7 translocation accelerates systemic autoimmunity in murine lupus.

            The y-linked autoimmune accelerating (yaa) locus is a potent autoimmune disease allele. Transcription profiling of yaa-bearing B cells revealed the overexpression of a cluster of X-linked genes that included Tlr7. FISH analysis demonstrated the translocation of this segment onto the yaa chromosome. The resulting overexpression of Tlr7 increased in vitro responses to Toll-like receptor (TLR) 7 signaling in all yaa-bearing males. B6.yaa mice are not overtly autoimmune, but the addition of Sle1, which contains the autoimmune-predisposing Slam/Cd2 haplotype, causes the development of fatal lupus with numerous immunological aberrations. B6.Sle1yaa CD4 T cells develop the molecular signature for T(FH) cells and also show expression changes in numerous cytokines and chemokines. Disease development and all component autoimmune phenotypes were inhibited by Sles1, a potent suppressor locus. Sles1 had no effect on yaa-enhanced TLR7 signaling in vitro, and these data place Sles1 downstream from the lesion in innate immune responses mediated by TLR7, suggesting that Sles1 modulates the activation of adaptive immunity in response to innate immune signaling.
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              The pathogenesis of lupus nephritis.

              Lupus nephritis is an immune complex GN that develops as a frequent complication of SLE. The pathogenesis of lupus nephritis involves a variety of pathogenic mechanisms. The extrarenal etiology of systemic lupus is based on multiple combinations of genetic variants that compromise those mechanisms normally assuring immune tolerance to nuclear autoantigens. This loss of tolerance becomes clinically detectable by the presence of antinuclear antibodies. In addition, nucleic acids released from netting or apoptotic neutrophils activate innate and adaptive immunity via viral nucleic acid-specific Toll-like receptors. Therefore, many clinical manifestations of systemic lupus resemble those of viral infection. In lupus, endogenous nuclear particles trigger IFN-α signaling just like viral particles during viral infection. As such, dendritic cells, T helper cells, B cells, and plasma cells all contribute to the aberrant polyclonal autoimmunity. The intrarenal etiology of lupus nephritis involves antibody binding to multiple intrarenal autoantigens rather than the deposition of circulating immune complexes. Tertiary lymphoid tissue formation and local antibody production add to intrarenal complement activation as renal immunopathology progresses. Here we provide an update on the pathogenic mechanisms that lead to lupus nephritis and provide the rationale for the latest and novel treatment strategies.
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                Author and article information

                Contributors
                satish.devarapu@med.uni-muenchen.de
                ++49-89-4400-53583 , hjanders@med.uni-muenchen.de
                Journal
                J Biomed Sci
                J. Biomed. Sci
                Journal of Biomedical Science
                BioMed Central (London )
                1021-7770
                1423-0127
                12 April 2018
                12 April 2018
                2018
                : 25
                : 35
                Affiliations
                ISNI 0000 0004 0477 2585, GRID grid.411095.8, Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, , Klinikum der Ludwig Maximilians Universität München, ; Ziemssenstr, 1&Schillerstr, 42, 80336 Munich, Germany
                Author information
                http://orcid.org/0000-0003-2434-2956
                Article
                436
                10.1186/s12929-018-0436-2
                5898010
                29650017
                151ca8d8-fb5d-4bab-aef5-5b6f20790c9d
                © The Author(s). 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 22 December 2017
                : 5 April 2018
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001659, Deutsche Forschungsgemeinschaft;
                Award ID: AN372/24-1
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100010661, Horizon 2020 Framework Programme;
                Award ID: 668036
                Award Recipient :
                Categories
                Review
                Custom metadata
                © The Author(s) 2018

                Molecular medicine
                immune complex,inflammasome,innate immunity,interferon,glomerulonephritis
                Molecular medicine
                immune complex, inflammasome, innate immunity, interferon, glomerulonephritis

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