Deficiency of Antigen-Presenting Cell Invariant Chain Reduces Atherosclerosis in Mice
| Autor: | Dror Harats, Karsten Hartvigsen, Hidde Ploegh, Galina K. Sukhova, Peter Libby, Guo-Ping Shi, Jacob George, Joseph L. Witztum, Yadong Zhang, Jiusong Sun, Meng-Yun Chou, Cody J. Diehl, Jie Zhang, Marco Lopez-Ilasaca, Niva Yakov |
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| Přispěvatelé: | Massachusetts Institute of Technology. Department of Biology, Whitehead Institute for Biomedical Research, Ploegh, Hidde |
| Rok vydání: | 2010 |
| Předmět: |
CD4-Positive T-Lymphocytes
Male medicine.medical_specialty CD74 Antigen presentation Antigen-Presenting Cells Article Mice Bacterial Proteins Antigen Malondialdehyde Physiology (medical) Internal medicine medicine Animals IL-2 receptor Antigen-presenting cell Autoantibodies biology Histocompatibility Antigens Class II Chaperonin 60 Atherosclerosis Acquired immune system Immunity Innate Antigens Differentiation B-Lymphocyte Immunoglobulin Isotypes Lipoproteins LDL Mice Inbred C57BL Endocrinology Receptors LDL biology.protein Immunization Antibody Cardiology and Cardiovascular Medicine Lipoprotein |
| Zdroj: | PMC |
| ISSN: | 1524-4539 0009-7322 |
| DOI: | 10.1161/circulationaha.109.891887 |
| Popis: | August 25, 2010 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. |
| Databáze: | OpenAIRE |
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