Lesion development and response to immunization reveal a complex role for CD4 in atherosclerosis.
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.
Zhou
Xinghua
X
Department of Medicine and Centre for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden. Xinghua.Zhou@cmm.ki.se
Robertson
Anna-Karin L
AK
Rudling
Mats
M
Parini
Paolo
P
Hansson
Göran K
GK
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics; D015214:Antigens, Differentiation, Myelomonocytic / Q000096:biosynthesis / Q000235:genetics; D001018:Aortic Diseases / Q000097:blood / Q000209:etiology / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D001161:Arteriosclerosis / Q000097:blood / Q000209:etiology / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D001323:Autoantibodies / Q000096:biosynthesis / Q000097:blood / Q000276:immunology; D001324:Autoantigens / Q000276:immunology*; D015704:CD4 Antigens / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002784:Cholesterol / Q000097:blood; D018450:Disease Progression; D005260:Female; D005620:Freund's Adjuvant / Q000494:pharmacology / Q000627:therapeutic use; D005802:Genes, MHC Class II; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis; D007114:Immunization; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000097:blood / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis / Q000235:genetics; D008077:Lipoproteins, LDL / Q000276:immunology* / Q000627:therapeutic use; D008315:Malondialdehyde / Q000031:analogs & derivatives* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011897:Random Allocation; D011971:Receptors, Immunologic / Q000378:metabolism; D051116:Receptors, Scavenger; D037182:T-Cell Antigen Receptor Specificity; D014280:Triglycerides / Q000097:blood; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics; D014657:Vasculitis / Q000097:blood / Q000150:complications / Q000276:immunology / Q000517:prevention & control; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D001057:Apolipoproteins E; D001323:Autoantibodies; D001324:Autoantigens; D015704:CD4 Antigens; D002784:Cholesterol; D005620:Freund's Adjuvant; D000949:Histocompatibility Antigens Class II; D007074:Immunoglobulin G; D007371:Interferon-gamma; D015847:Interleukin-4; D008077:Lipoproteins, LDL; D008315:Malondialdehyde; D012333:RNA, Messenger; D011971:Receptors, Immunologic; D051116:Receptors, Scavenger; D014280:Triglycerides; D019010:Vascular Cell Adhesion Molecule-1; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C474482:I-A(b) antigen, mouse; C502964:malondialdehyde-low density lipoprotein, mouse; C099252:oxidized low density lipoprotein