Abstract
Atherosclerosis is a complex disease, bearing many of the characteristics of a chronic inflammatory process. Both cellular and humoral immune responses may be involved in the disease development. Oxidized low-density lipoprotein (oxLDL) is suggested to be an autoantigen in atherosclerosis. A protective effect against atherosclerosis has been demonstrated in animals immunized with oxLDL. Such a protection is associated with elevation of T cell-dependent IgG antibodies against oxLDL. In addition, it has been shown that immunization with Freund adjuvant alone also confers protection against development of atherosclerosis. We therefore hypothesized that CD4+ T cells are critical in the development of atherosclerosis and that they are involved in protective immune reactions after immunization. The development of atherosclerosis was studied in apolipoprotein E knockout (apoE KO) mice and CD4/apoE double knockout (dKO) mice that were immunized with either oxLDL in Freund adjuvant or adjuvant alone, or left untreated. Our results show that (1) the absence of CD4+ cells in apoE KO mice leads to reduced atherosclerosis, indicating that CD4+ cells constitute a major proatherogenic cell population, and (2) the atheroprotective effect of LDL immunization does not depend on CD4+ cells, whereas (3) the atheroprotective effect of adjuvant injection is CD4-dependent. These findings demonstrate complex roles of immune cell-cell interactions in the regulation of the atherosclerotic process and point to several possible targets in the treatment and prevention of atherosclerosis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigen-Presenting Cells / immunology
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Antigen-Presenting Cells / metabolism
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Antigens, CD / biosynthesis
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Antigens, CD / genetics
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Antigens, Differentiation, Myelomonocytic / biosynthesis
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Antigens, Differentiation, Myelomonocytic / genetics
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Aortic Diseases / blood
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Aortic Diseases / etiology
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Aortic Diseases / immunology*
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Aortic Diseases / pathology
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Aortic Diseases / prevention & control
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Apolipoproteins E / deficiency
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Apolipoproteins E / genetics
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Arteriosclerosis / blood
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Arteriosclerosis / etiology
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Arteriosclerosis / immunology*
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Arteriosclerosis / pathology
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Arteriosclerosis / prevention & control
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Autoantibodies / biosynthesis
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Autoantibodies / blood
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Autoantibodies / immunology
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Autoantigens / immunology*
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CD4 Antigens / genetics
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CD4 Antigens / immunology
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CD4 Antigens / physiology*
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CD4-Positive T-Lymphocytes / immunology*
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Cholesterol / blood
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Disease Progression
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Female
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Freund's Adjuvant / pharmacology
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Freund's Adjuvant / therapeutic use
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Genes, MHC Class II
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Histocompatibility Antigens Class II / biosynthesis
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Immunization*
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Immunoglobulin G / biosynthesis
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Immunoglobulin G / blood
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Immunoglobulin G / immunology
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Interferon-gamma / biosynthesis
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Interleukin-4 / biosynthesis
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Interleukin-4 / genetics
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Lipoproteins, LDL / immunology*
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Lipoproteins, LDL / therapeutic use
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Malondialdehyde / analogs & derivatives*
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Malondialdehyde / immunology
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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RNA, Messenger / biosynthesis
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RNA, Messenger / genetics
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Random Allocation
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Receptors, Immunologic / metabolism
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Receptors, Scavenger
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T-Cell Antigen Receptor Specificity
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Triglycerides / blood
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Vascular Cell Adhesion Molecule-1 / biosynthesis
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Vascular Cell Adhesion Molecule-1 / genetics
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Vasculitis / blood
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Vasculitis / complications
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Vasculitis / immunology
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Vasculitis / prevention & control
Substances
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Antigens, CD
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Antigens, Differentiation, Myelomonocytic
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Apolipoproteins E
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Autoantibodies
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Autoantigens
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CD4 Antigens
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CD68 antigen, human
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Histocompatibility Antigens Class II
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I-A(b) antigen, mouse
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Immunoglobulin G
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Lipoproteins, LDL
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RNA, Messenger
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Receptors, Immunologic
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Receptors, Scavenger
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Triglycerides
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Vascular Cell Adhesion Molecule-1
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malondialdehyde-low density lipoprotein, mouse
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oxidized low density lipoprotein
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Interleukin-4
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Malondialdehyde
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Interferon-gamma
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Freund's Adjuvant
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Cholesterol