Exhausted cytotoxic control of Epstein-Barr virus in human lupus.

Systemic Lupus Erythematosus (SLE) pathology has long been associated with an increased Epstein-Barr Virus (EBV) seropositivity, viremia and cross-reactive serum antibodies specific for both virus and self. It has therefore been postulated that EBV triggers SLE immunopathology, although the mechanis...

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Autores principales:	Martin Larsen, Delphine Sauce, Claire Deback, Laurent Arnaud, Alexis Mathian, Makoto Miyara, David Boutolleau, Christophe Parizot, Karim Dorgham, Laura Papagno, Victor Appay, Zahir Amoura, Guy Gorochov
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/d72206bdd62d4f47a4cf46c56cffe186
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spelling	oai:doaj.org-article:d72206bdd62d4f47a4cf46c56cffe1862021-11-18T06:05:13ZExhausted cytotoxic control of Epstein-Barr virus in human lupus.1553-73661553-737410.1371/journal.ppat.1002328https://doaj.org/article/d72206bdd62d4f47a4cf46c56cffe1862011-10-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22028659/pdf/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Systemic Lupus Erythematosus (SLE) pathology has long been associated with an increased Epstein-Barr Virus (EBV) seropositivity, viremia and cross-reactive serum antibodies specific for both virus and self. It has therefore been postulated that EBV triggers SLE immunopathology, although the mechanism remains elusive. Here, we investigate whether frequent peaks of EBV viral load in SLE patients are a consequence of dysfunctional anti-EBV CD8+ T cell responses. Both inactive and active SLE patients (n = 76 and 42, respectively), have significantly elevated EBV viral loads (P = 0.003 and 0.002, respectively) compared to age- and sex-matched healthy controls (n = 29). Interestingly, less EBV-specific CD8+ T cells are able to secrete multiple cytokines (IFN-γ, TNF-α, IL-2 and MIP-1β) in inactive and active SLE patients compared to controls (P = 0.0003 and 0.0084, respectively). Moreover, EBV-specific CD8+ T cells are also less cytotoxic in SLE patients than in controls (CD107a expression: P = 0.0009, Granzyme B release: P = 0.0001). Importantly, cytomegalovirus (CMV)-specific responses were not found significantly altered in SLE patients. Furthermore, we demonstrate that EBV-specific CD8+ T cell impairment is a consequence of their Programmed Death 1 (PD-1) receptor up-regulation, as blocking this pathway reverses the dysfunctional phenotype. Finally, prospective monitoring of lupus patients revealed that disease flares precede EBV reactivation. In conclusion, EBV-specific CD8+ T cell responses in SLE patients are functionally impaired, but EBV reactivation appears to be an aggravating consequence rather than a cause of SLE immunopathology. We therefore propose that autoimmune B cell activation during flares drives frequent EBV reactivation, which contributes in a vicious circle to the perpetuation of immune activation in SLE patients.Martin LarsenDelphine SauceClaire DebackLaurent ArnaudAlexis MathianMakoto MiyaraDavid BoutolleauChristophe ParizotKarim DorghamLaura PapagnoVictor AppayZahir AmouraGuy GorochovPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 7, Iss 10, p e1002328 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
spellingShingle	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Martin Larsen Delphine Sauce Claire Deback Laurent Arnaud Alexis Mathian Makoto Miyara David Boutolleau Christophe Parizot Karim Dorgham Laura Papagno Victor Appay Zahir Amoura Guy Gorochov Exhausted cytotoxic control of Epstein-Barr virus in human lupus.
description	Systemic Lupus Erythematosus (SLE) pathology has long been associated with an increased Epstein-Barr Virus (EBV) seropositivity, viremia and cross-reactive serum antibodies specific for both virus and self. It has therefore been postulated that EBV triggers SLE immunopathology, although the mechanism remains elusive. Here, we investigate whether frequent peaks of EBV viral load in SLE patients are a consequence of dysfunctional anti-EBV CD8+ T cell responses. Both inactive and active SLE patients (n = 76 and 42, respectively), have significantly elevated EBV viral loads (P = 0.003 and 0.002, respectively) compared to age- and sex-matched healthy controls (n = 29). Interestingly, less EBV-specific CD8+ T cells are able to secrete multiple cytokines (IFN-γ, TNF-α, IL-2 and MIP-1β) in inactive and active SLE patients compared to controls (P = 0.0003 and 0.0084, respectively). Moreover, EBV-specific CD8+ T cells are also less cytotoxic in SLE patients than in controls (CD107a expression: P = 0.0009, Granzyme B release: P = 0.0001). Importantly, cytomegalovirus (CMV)-specific responses were not found significantly altered in SLE patients. Furthermore, we demonstrate that EBV-specific CD8+ T cell impairment is a consequence of their Programmed Death 1 (PD-1) receptor up-regulation, as blocking this pathway reverses the dysfunctional phenotype. Finally, prospective monitoring of lupus patients revealed that disease flares precede EBV reactivation. In conclusion, EBV-specific CD8+ T cell responses in SLE patients are functionally impaired, but EBV reactivation appears to be an aggravating consequence rather than a cause of SLE immunopathology. We therefore propose that autoimmune B cell activation during flares drives frequent EBV reactivation, which contributes in a vicious circle to the perpetuation of immune activation in SLE patients.
format	article
author	Martin Larsen Delphine Sauce Claire Deback Laurent Arnaud Alexis Mathian Makoto Miyara David Boutolleau Christophe Parizot Karim Dorgham Laura Papagno Victor Appay Zahir Amoura Guy Gorochov
author_facet	Martin Larsen Delphine Sauce Claire Deback Laurent Arnaud Alexis Mathian Makoto Miyara David Boutolleau Christophe Parizot Karim Dorgham Laura Papagno Victor Appay Zahir Amoura Guy Gorochov
author_sort	Martin Larsen
title	Exhausted cytotoxic control of Epstein-Barr virus in human lupus.
title_short	Exhausted cytotoxic control of Epstein-Barr virus in human lupus.
title_full	Exhausted cytotoxic control of Epstein-Barr virus in human lupus.
title_fullStr	Exhausted cytotoxic control of Epstein-Barr virus in human lupus.
title_full_unstemmed	Exhausted cytotoxic control of Epstein-Barr virus in human lupus.
title_sort	exhausted cytotoxic control of epstein-barr virus in human lupus.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/d72206bdd62d4f47a4cf46c56cffe186
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Exhausted cytotoxic control of Epstein-Barr virus in human lupus.

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