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dc.contributor.authorTsiantoulas, Dimitriosen
dc.contributor.authorSage, Andrewen
dc.contributor.authorGöderle, Lauraen
dc.contributor.authorOzsvar-Kozma, Mariaen
dc.contributor.authorMurphy, Deirdreen
dc.contributor.authorPorsch, Florentinaen
dc.contributor.authorPasterkamp, Gerarden
dc.contributor.authorMenche, Jörgen
dc.contributor.authorSchneider, Pascalen
dc.contributor.authorMallat, Ziaden
dc.contributor.authorBinder, Christoph Jen
dc.date.accessioned2018-10-10T05:15:16Z
dc.date.available2018-10-10T05:15:16Z
dc.date.issued2018-11en
dc.identifier.issn0009-7322
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/283298
dc.description.abstractBackground: Atherosclerotic cardiovascular disease (heart attacks and strokes) is the major cause of death globally and is caused by the buildup of a plaque in the arterial wall. Genomic data showed that the B cell activating factor receptor (BAFFR) pathway, which is specifically essential for the survival of conventional B lymphocytes (B-2 cells), is a key driver of coronary heart disease. Deletion or antibody-mediated blockade of BAFFR ablates B-2 cells and decreases experimental atherosclerosis. Anti-BAFF immunotherapy is approved for treatment of autoimmune systemic lupus erythematosus and can therefore be expected to limit their associated cardiovascular risk. However, direct effects of anti-BAFF immunotherapy on atherosclerosis remain unknown. Methods and Results: We demonstrate here that treatment with a well-characterized blocking antibody against BAFF increased atherosclerosis in mice, despite efficient depletion of mature B-2 cells, suggesting a unique mechanism of action. Indeed, myeloid cell specific deletion of an alternative receptor for BAFF, transmembrane activator and CAML interactor receptor (TACI), also results in increased atherosclerosis, while B cell-specific TACI deletion had no effect. Mechanistically, BAFF-TACI signaling represses macrophage IRF7-dependent (but not NF-kB dependent) TLR9 responses including proatherogenic CXCL10 production. Conclusions: These data identify a novel B cell independent anti-inflammatory role for BAFF in atherosclerosis and may have important clinical implications.
dc.description.sponsorshipThis work was supported by grants of the Austrian Science Fund (SFB F54), the European Union (FP7 VIA), the British Heart Foundation, and the European Research Council (ERC). PS is supported by grants from the Swiss National Science Foundation.
dc.format.mediumPrinten
dc.languageengen
dc.publisherWolters Kluwer Health
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectAortaen
dc.subjectBone Marrow Cellsen
dc.subjectMacrophagesen
dc.subjectAnimalsen
dc.subjectMice, Inbred C57BLen
dc.subjectMice, Knockouten
dc.subjectMiceen
dc.subjectCholesterolen
dc.subjectAntibodiesen
dc.subjectImmunotherapyen
dc.subjectAtherosclerosisen
dc.subjectInterferon Regulatory Factor-7en
dc.subjectToll-Like Receptor 9en
dc.subjectChemokine CCL2en
dc.subjectB-Cell Activating Factoren
dc.subjectTransmembrane Activator and CAML Interactor Proteinen
dc.subjectChemokine CXCL10en
dc.titleB Cell-Activating Factor Neutralization Aggravates Atherosclerosis.en
dc.typeArticle
prism.endingPage2273
prism.issueIdentifier20en
prism.publicationDate2018en
prism.publicationNameCirculationen
prism.startingPage2263
prism.volume138en
dc.identifier.doi10.17863/CAM.30666
dcterms.dateAccepted2018-05-18en
rioxxterms.versionofrecord10.1161/circulationaha.117.032790en
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2018-11en
dc.contributor.orcidTsiantoulas, Dimitrios [0000-0002-7743-3192]
dc.contributor.orcidSage, Andrew [0000-0001-7255-3497]
dc.contributor.orcidMenche, Jörg [0000-0002-1583-6404]
dc.contributor.orcidSchneider, Pascal [0000-0003-0677-9409]
dc.contributor.orcidMallat, Ziad [0000-0003-0443-7878]
dc.identifier.eissn1524-4539
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idBritish Heart Foundation (RG/10/001/27643)
pubs.funder-project-idBritish Heart Foundation (CH/10/001/27642)
pubs.funder-project-idBritish Heart Foundation (FS/15/57/31557)
pubs.funder-project-idEuropean Research Council (281164)
pubs.funder-project-idEC FP7 CP (603131)
pubs.funder-project-idBritish Heart Foundation (RG/15/11/31593)


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International