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Deficiency of Antigen Presenting Cell Invariant Chain Reduces Atherosclerosis in Mice

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dc.contributor.author Ploegh, Hidde
dc.contributor.author Sun, Jiusong
dc.contributor.author Hartvigsen, Karsten
dc.contributor.author Chou, Meng-Yun
dc.contributor.author Zhang, Yadong
dc.contributor.author Sukhova, Galina K.
dc.contributor.author Zhang, Jie
dc.contributor.author Lopez-Ilasaca, Marco
dc.contributor.author Diehl, Cody J.
dc.contributor.author Yakov, Niva
dc.contributor.author Harats, Dror
dc.contributor.author George, Jacob
dc.contributor.author Witztum, Joseph L.
dc.contributor.author Libby, Peter
dc.contributor.author Shi, Guo-Ping
dc.date.accessioned 2012-10-25T20:54:32Z
dc.date.available 2012-10-25T20:54:32Z
dc.date.issued 2010-08
dc.date.submitted 2009-07
dc.identifier.issn 0009-7322
dc.identifier.issn 1524-4539
dc.identifier.uri http://hdl.handle.net/1721.1/74265
dc.description August 25, 2010 en_US
dc.description.abstract Background: Adaptive immunity and innate immunity play important roles in atherogenesis. Invariant chain (CD74) mediates antigen-presenting cell antigen presentation and T-cell activation. This study tested the hypothesis that CD74-deficient mice have reduced numbers of active T cells and resist atherogenesis. Methods and Results: In low-density lipoprotein receptor–deficient (Ldlr[superscript −/−]) mice, CD74 deficiency (Ldlr[superscript −/−]Cd74[superscript −/−]) significantly reduced atherosclerosis and CD25+-activated T cells in the atheromata. Although Ldlr[superscript −/−]Cd74[superscript −/−] mice had decreased levels of plasma immunoglobulin (Ig) G1, IgG2b, and IgG2c against malondialdehyde-modified LDL (MDA-LDL), presumably as a result of impaired antigen-presenting cell function, Ldlr[superscript −/−]Cd74[superscript −/−] mice showed higher levels of anti–MDA-LDL IgM and IgG3. After immunization with MDA-LDL, Ldlr[superscript −/−]Cd74[superscript −/−] mice had lower levels of all anti–MDA-LDL Ig isotypes compared with Ldlr[superscript −/−] mice. As anticipated, only Ldlr[superscript −/−] splenocytes responded to in vitro stimulation with MDA-LDL, producing Th1/Th2 cytokines. Heat shock protein-65 immunization enhanced atherogenesis in Ldlr[superscript −/−] mice, but Ldlr[superscript −/−] Cd74[superscript −/−] mice remained protected. Compared with Ldlr[superscript −/−] mice, Ldlr[superscript −/−]Cd74[superscript −/−] mice had higher anti–MDA-LDL autoantibody titers, fewer lesion CD25+-activated T cells, impaired release of Th1/Th2 cytokines from antigen-presenting cells after heat shock protein-65 stimulation, and reduced levels of all plasma anti–heat shock protein-65 Ig isotypes. Cytofluorimetry of splenocytes and peritoneal cavity cells of MDA-LDL– or heat shock protein-65–immunized mice showed increased percentages of autoantibody-producing marginal zone B and B-1 cells in Ldlr[superscript −/−]Cd74[superscript −/−] mice compared with Ldlr[superscript −/−] mice. Conclusions: Invariant chain deficiency in Ldlr[superscript −/−] mice reduced atherosclerosis. This finding was associated with an impaired adaptive immune response to disease-specific antigens. Concomitantly, an unexpected increase in the number of innate-like peripheral B-1 cell populations occurred, resulting in increased IgM/IgG3 titers to the oxidation-specific epitopes. en_US
dc.language.iso en_US
dc.publisher Ovid Technologies (Wolters Kluwer) -American Heart Association en_US
dc.relation.isversionof http://dx.doi.org/10.1161/circulationaha.109.891887 en_US
dc.rights Creative Commons Attribution-Noncommercial-Share Alike 3.0 en_US
dc.rights.uri http://creativecommons.org/licenses/by-nc-sa/3.0/ en_US
dc.source PMC en_US
dc.title Deficiency of Antigen Presenting Cell Invariant Chain Reduces Atherosclerosis in Mice en_US
dc.type Article en_US
dc.identifier.citation Sun, J. et al. “Deficiency of Antigen-Presenting Cell Invariant Chain Reduces Atherosclerosis in Mice.” Circulation 122.8 (2010): 808–820. en_US
dc.contributor.department Massachusetts Institute of Technology. Department of Biology en_US
dc.contributor.department Whitehead Institute for Biomedical Research en_US
dc.contributor.mitauthor Ploegh, Hidde
dc.relation.journal Circulation en_US
dc.identifier.mitlicense OPEN_ACCESS_POLICY en_US
dc.eprint.version Author's final manuscript en_US
dc.type.uri http://purl.org/eprint/type/JournalArticle en_US
eprint.status http://purl.org/eprint/status/PeerReviewed en_US
dspace.orderedauthors Sun, J.; Hartvigsen, K.; Chou, M.-Y.; Zhang, Y.; Sukhova, G. K.; Zhang, J.; Lopez-Ilasaca, M.; Diehl, C. J.; Yakov, N.; Harats, D.; George, J.; Witztum, J. L.; Libby, P.; Ploegh, H.; Shi, G.-P. en


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