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Siglec-H protects from virus-triggered severe systemic autoimmunity

It is controversial whether virus infections can contribute to the development of autoimmune diseases. Type I interferons (IFNs) are critical antiviral cytokines during virus infections and have also been implicated in the pathogenesis of systemic lupus erythematosus. Type I IFN is mainly produced b...

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Autores principales: Schmitt, Heike, Sell, Sabrina, Koch, Julia, Seefried, Martina, Sonnewald, Sophia, Daniel, Christoph, Winkler, Thomas H., Nitschke, Lars
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4986536/
https://www.ncbi.nlm.nih.gov/pubmed/27377589
http://dx.doi.org/10.1084/jem.20160189
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author Schmitt, Heike
Sell, Sabrina
Koch, Julia
Seefried, Martina
Sonnewald, Sophia
Daniel, Christoph
Winkler, Thomas H.
Nitschke, Lars
author_facet Schmitt, Heike
Sell, Sabrina
Koch, Julia
Seefried, Martina
Sonnewald, Sophia
Daniel, Christoph
Winkler, Thomas H.
Nitschke, Lars
author_sort Schmitt, Heike
collection PubMed
description It is controversial whether virus infections can contribute to the development of autoimmune diseases. Type I interferons (IFNs) are critical antiviral cytokines during virus infections and have also been implicated in the pathogenesis of systemic lupus erythematosus. Type I IFN is mainly produced by plasmacytoid dendritic cells (pDCs). The secretion of type I IFN of pDCs is modulated by Siglec-H, a DAP12-associated receptor on pDCs. In this study, we show that Siglec-H–deficient pDCs produce more of the type I IFN, IFN-α, in vitro and that Siglec-H knockout (KO) mice produce more IFN-α after murine cytomegalovirus (mCMV) infection in vivo. This did not impact control of viral replication. Remarkably, several weeks after a single mCMV infection, Siglec-H KO mice developed a severe form of systemic lupus–like autoimmune disease with strong kidney nephritis. In contrast, uninfected aging Siglec-H KO mice developed a mild form of systemic autoimmunity. The induction of systemic autoimmune disease after virus infection in Siglec-H KO mice was accompanied by a type I IFN signature and fully dependent on type I IFN signaling. These results show that Siglec-H normally serves as a modulator of type I IFN responses after infection with a persistent virus and thereby prevents induction of autoimmune disease.
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spelling pubmed-49865362017-01-25 Siglec-H protects from virus-triggered severe systemic autoimmunity Schmitt, Heike Sell, Sabrina Koch, Julia Seefried, Martina Sonnewald, Sophia Daniel, Christoph Winkler, Thomas H. Nitschke, Lars J Exp Med Research Articles It is controversial whether virus infections can contribute to the development of autoimmune diseases. Type I interferons (IFNs) are critical antiviral cytokines during virus infections and have also been implicated in the pathogenesis of systemic lupus erythematosus. Type I IFN is mainly produced by plasmacytoid dendritic cells (pDCs). The secretion of type I IFN of pDCs is modulated by Siglec-H, a DAP12-associated receptor on pDCs. In this study, we show that Siglec-H–deficient pDCs produce more of the type I IFN, IFN-α, in vitro and that Siglec-H knockout (KO) mice produce more IFN-α after murine cytomegalovirus (mCMV) infection in vivo. This did not impact control of viral replication. Remarkably, several weeks after a single mCMV infection, Siglec-H KO mice developed a severe form of systemic lupus–like autoimmune disease with strong kidney nephritis. In contrast, uninfected aging Siglec-H KO mice developed a mild form of systemic autoimmunity. The induction of systemic autoimmune disease after virus infection in Siglec-H KO mice was accompanied by a type I IFN signature and fully dependent on type I IFN signaling. These results show that Siglec-H normally serves as a modulator of type I IFN responses after infection with a persistent virus and thereby prevents induction of autoimmune disease. The Rockefeller University Press 2016-07-25 /pmc/articles/PMC4986536/ /pubmed/27377589 http://dx.doi.org/10.1084/jem.20160189 Text en © 2016 Schmitt et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Research Articles
Schmitt, Heike
Sell, Sabrina
Koch, Julia
Seefried, Martina
Sonnewald, Sophia
Daniel, Christoph
Winkler, Thomas H.
Nitschke, Lars
Siglec-H protects from virus-triggered severe systemic autoimmunity
title Siglec-H protects from virus-triggered severe systemic autoimmunity
title_full Siglec-H protects from virus-triggered severe systemic autoimmunity
title_fullStr Siglec-H protects from virus-triggered severe systemic autoimmunity
title_full_unstemmed Siglec-H protects from virus-triggered severe systemic autoimmunity
title_short Siglec-H protects from virus-triggered severe systemic autoimmunity
title_sort siglec-h protects from virus-triggered severe systemic autoimmunity
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4986536/
https://www.ncbi.nlm.nih.gov/pubmed/27377589
http://dx.doi.org/10.1084/jem.20160189
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