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Interferon Regulatory Factor-5 Deficiency Ameliorates Disease Severity in the MRL/lpr Mouse Model of Lupus in the Absence of a Mutation in DOCK2

Interferon regulatory factor 5 (IRF5) polymorphisms are strongly associated with an increased risk of developing the autoimmune disease systemic lupus erythematosus. In mouse lupus models, IRF5-deficiency was shown to reduce disease severity consistent with an important role for IRF5 in disease path...

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Autores principales: Yasuda, Kei, Watkins, Amanda A., Kochar, Guneet S., Wilson, Gabriella E., Laskow, Bari, Richez, Christophe, Bonegio, Ramon G., Rifkin, Ian R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4116215/
https://www.ncbi.nlm.nih.gov/pubmed/25076492
http://dx.doi.org/10.1371/journal.pone.0103478
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author Yasuda, Kei
Watkins, Amanda A.
Kochar, Guneet S.
Wilson, Gabriella E.
Laskow, Bari
Richez, Christophe
Bonegio, Ramon G.
Rifkin, Ian R.
author_facet Yasuda, Kei
Watkins, Amanda A.
Kochar, Guneet S.
Wilson, Gabriella E.
Laskow, Bari
Richez, Christophe
Bonegio, Ramon G.
Rifkin, Ian R.
author_sort Yasuda, Kei
collection PubMed
description Interferon regulatory factor 5 (IRF5) polymorphisms are strongly associated with an increased risk of developing the autoimmune disease systemic lupus erythematosus. In mouse lupus models, IRF5-deficiency was shown to reduce disease severity consistent with an important role for IRF5 in disease pathogenesis. However these mouse studies were confounded by the recent demonstration that the IRF5 knockout mouse line contained a loss-of-function mutation in the dedicator of cytokinesis 2 (DOCK2) gene. As DOCK2 regulates lymphocyte trafficking and Toll-like receptor signaling, this raised the possibility that some of the protective effects attributed to IRF5 deficiency in the mouse lupus models may instead have been due to DOCK2 deficiency. We have therefore here evaluated the effect of IRF5-deficiency in the MRL/lpr mouse lupus model in the absence of the DOCK2 mutation. We find that IRF5-deficient (IRF5(−/−)) MRL/lpr mice develop much less severe disease than their IRF5-sufficient (IRF5(+/+)) littermates. Despite markedly lower serum levels of anti-nuclear autoantibodies and reduced total splenocyte and CD4(+) T cell numbers, IRF5(−/−) MRL/lpr mice have similar numbers of all splenic B cell subsets compared to IRF5(+/+) MRL/lpr mice, suggesting that IRF5 is not involved in B cell development up to the mature B cell stage. However, IRF5(−/−) MRL/lpr mice have greatly reduced numbers of spleen plasmablasts and bone marrow plasma cells. Serum levels of B lymphocyte stimulator (BLyS) were markedly elevated in the MRL/lpr mice but no effect of IRF5 on serum BLyS levels was seen. Overall our data demonstrate that IRF5 contributes to disease pathogenesis in the MRL/lpr lupus model and that this is due, at least in part, to the role of IRF5 in plasma cell formation. Our data also suggest that combined therapy targeting both IRF5 and BLyS might be a particularly effective therapeutic approach in lupus.
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spelling pubmed-41162152014-08-04 Interferon Regulatory Factor-5 Deficiency Ameliorates Disease Severity in the MRL/lpr Mouse Model of Lupus in the Absence of a Mutation in DOCK2 Yasuda, Kei Watkins, Amanda A. Kochar, Guneet S. Wilson, Gabriella E. Laskow, Bari Richez, Christophe Bonegio, Ramon G. Rifkin, Ian R. PLoS One Research Article Interferon regulatory factor 5 (IRF5) polymorphisms are strongly associated with an increased risk of developing the autoimmune disease systemic lupus erythematosus. In mouse lupus models, IRF5-deficiency was shown to reduce disease severity consistent with an important role for IRF5 in disease pathogenesis. However these mouse studies were confounded by the recent demonstration that the IRF5 knockout mouse line contained a loss-of-function mutation in the dedicator of cytokinesis 2 (DOCK2) gene. As DOCK2 regulates lymphocyte trafficking and Toll-like receptor signaling, this raised the possibility that some of the protective effects attributed to IRF5 deficiency in the mouse lupus models may instead have been due to DOCK2 deficiency. We have therefore here evaluated the effect of IRF5-deficiency in the MRL/lpr mouse lupus model in the absence of the DOCK2 mutation. We find that IRF5-deficient (IRF5(−/−)) MRL/lpr mice develop much less severe disease than their IRF5-sufficient (IRF5(+/+)) littermates. Despite markedly lower serum levels of anti-nuclear autoantibodies and reduced total splenocyte and CD4(+) T cell numbers, IRF5(−/−) MRL/lpr mice have similar numbers of all splenic B cell subsets compared to IRF5(+/+) MRL/lpr mice, suggesting that IRF5 is not involved in B cell development up to the mature B cell stage. However, IRF5(−/−) MRL/lpr mice have greatly reduced numbers of spleen plasmablasts and bone marrow plasma cells. Serum levels of B lymphocyte stimulator (BLyS) were markedly elevated in the MRL/lpr mice but no effect of IRF5 on serum BLyS levels was seen. Overall our data demonstrate that IRF5 contributes to disease pathogenesis in the MRL/lpr lupus model and that this is due, at least in part, to the role of IRF5 in plasma cell formation. Our data also suggest that combined therapy targeting both IRF5 and BLyS might be a particularly effective therapeutic approach in lupus. Public Library of Science 2014-07-30 /pmc/articles/PMC4116215/ /pubmed/25076492 http://dx.doi.org/10.1371/journal.pone.0103478 Text en © 2014 Yasuda et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Yasuda, Kei
Watkins, Amanda A.
Kochar, Guneet S.
Wilson, Gabriella E.
Laskow, Bari
Richez, Christophe
Bonegio, Ramon G.
Rifkin, Ian R.
Interferon Regulatory Factor-5 Deficiency Ameliorates Disease Severity in the MRL/lpr Mouse Model of Lupus in the Absence of a Mutation in DOCK2
title Interferon Regulatory Factor-5 Deficiency Ameliorates Disease Severity in the MRL/lpr Mouse Model of Lupus in the Absence of a Mutation in DOCK2
title_full Interferon Regulatory Factor-5 Deficiency Ameliorates Disease Severity in the MRL/lpr Mouse Model of Lupus in the Absence of a Mutation in DOCK2
title_fullStr Interferon Regulatory Factor-5 Deficiency Ameliorates Disease Severity in the MRL/lpr Mouse Model of Lupus in the Absence of a Mutation in DOCK2
title_full_unstemmed Interferon Regulatory Factor-5 Deficiency Ameliorates Disease Severity in the MRL/lpr Mouse Model of Lupus in the Absence of a Mutation in DOCK2
title_short Interferon Regulatory Factor-5 Deficiency Ameliorates Disease Severity in the MRL/lpr Mouse Model of Lupus in the Absence of a Mutation in DOCK2
title_sort interferon regulatory factor-5 deficiency ameliorates disease severity in the mrl/lpr mouse model of lupus in the absence of a mutation in dock2
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4116215/
https://www.ncbi.nlm.nih.gov/pubmed/25076492
http://dx.doi.org/10.1371/journal.pone.0103478
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