title: Deficiency of antigen-presenting cell invariant chain reduces atherosclerosis in mice.
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.
  
  
  RESULTS
  In low-density lipoprotein receptor-deficient (Ldlr(-/-)) mice, CD74 deficiency (Ldlr(-/-)Cd74(-/-)) significantly reduced atherosclerosis and CD25(+)-activated T cells in the atheromata. Although Ldlr(-/-)Cd74(-/-) 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(-/-)Cd74(-/-) mice showed higher levels of anti-MDA-LDL IgM and IgG3. After immunization with MDA-LDL, Ldlr(-/-)Cd74(-/-) mice had lower levels of all anti-MDA-LDL Ig isotypes compared with Ldlr(-/-) mice. As anticipated, only Ldlr(-/-) splenocytes responded to in vitro stimulation with MDA-LDL, producing Th1/Th2 cytokines. Heat shock protein-65 immunization enhanced atherogenesis in Ldlr(-/-) mice, but Ldlr(-/-) Cd74(-/-) mice remained protected. Compared with Ldlr(-/-) mice, Ldlr(-/-)Cd74(-/-) 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(-/-)Cd74(-/-) mice compared with Ldlr(-/-) mice.
  
  
  CONCLUSIONS
  Invariant chain deficiency in Ldlr(-/-) 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.
authors.affiliation: Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Mass., USA.
authors.forename: Jiusong
authors.initials: J
authors.lastname: Sun
authors.forename: Karsten
authors.initials: K
authors.lastname: Hartvigsen
authors.forename: Meng-Yun
authors.initials: MY
authors.lastname: Chou
authors.forename: Yadong
authors.initials: Y
authors.lastname: Zhang
authors.forename: Galina K
authors.initials: GK
authors.lastname: Sukhova
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.forename: Marco
authors.initials: M
authors.lastname: Lopez-Ilasaca
authors.forename: Cody J
authors.initials: CJ
authors.lastname: Diehl
authors.forename: Niva
authors.initials: N
authors.lastname: Yakov
authors.forename: Dror
authors.initials: D
authors.lastname: Harats
authors.forename: Jacob
authors.initials: J
authors.lastname: George
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Witztum
authors.forename: Peter
authors.initials: P
authors.lastname: Libby
authors.forename: Hidde
authors.initials: H
authors.lastname: Ploegh
authors.forename: Guo-Ping
authors.initials: GP
authors.lastname: Shi
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000502:physiology*; D000944:Antigens, Differentiation, B-Lymphocyte / Q000502:physiology*; D050197:Atherosclerosis / Q000517:prevention & control*; D001323:Autoantibodies / Q000096:biosynthesis; D001426:Bacterial Proteins / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology; D018834:Chaperonin 60 / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000502:physiology*; D007113:Immunity, Innate; D007114:Immunization; D007132:Immunoglobulin Isotypes / Q000097:blood; D008077:Lipoproteins, LDL / Q000276:immunology; D008297:Male; D008315:Malondialdehyde / Q000031:analogs & derivatives / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D011973:Receptors, LDL / Q000502:physiology
chemical_list: D000944:Antigens, Differentiation, B-Lymphocyte; D001323:Autoantibodies; D001426:Bacterial Proteins; D018834:Chaperonin 60; D000949:Histocompatibility Antigens Class II; D007132:Immunoglobulin Isotypes; D008077:Lipoproteins, LDL; D011973:Receptors, LDL; C074119:heat-shock protein 65, Mycobacterium; C045084:invariant chain; C502964:malondialdehyde-low density lipoprotein, mouse; C099252:oxidized low density lipoprotein; D008315:Malondialdehyde