Oxidation-specific epitopes are dominant targets of innate natural antibodies in mice and humans.
Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of oxidized lipoproteins and apoptotic cells. Adaptive immune responses to various oxidation-specific epitopes play an important role in atherogenesis. However, accumulating evidence suggests that these epitopes are also recognized by innate receptors, such as scavenger receptors on macrophages, and plasma proteins, such as C-reactive protein (CRP). Here, we provide multiple lines of evidence that oxidation-specific epitopes constitute a dominant, previously unrecognized target of natural Abs (NAbs) in both mice and humans. Using reconstituted mice expressing solely IgM NAbs, we have shown that approximately 30% of all NAbs bound to model oxidation-specific epitopes, as well as to atherosclerotic lesions and apoptotic cells. Because oxidative processes are ubiquitous, we hypothesized that these epitopes exert selective pressure to expand NAbs, which in turn play an important role in mediating homeostatic functions consequent to inflammation and cell death, as demonstrated by their ability to facilitate apoptotic cell clearance. These findings provide novel insights into the functions of NAbs in mediating host homeostasis and into their roles in health and diseases, such as chronic inflammatory diseases and atherosclerosis.
Department of Medicine, UCSD, La Jolla, California 92093, USA.
Meng-Yun
MY
Chou
Linda
L
Fogelstrand
Karsten
K
Hartvigsen
Lotte F
LF
Hansen
Douglas
D
Woelkers
Peter X
PX
Shaw
Jeomil
J
Choi
Thomas
T
Perkmann
Fredrik
F
Bäckhed
Yury I
YI
Miller
Sohvi
S
Hörkkö
Maripat
M
Corr
Joseph L
JL
Witztum
Christoph J
CJ
Binder
D019264:Adoptive Transfer; D000818:Animals; D000915:Antibody Affinity / Q000276:immunology; D000917:Antibody Formation / Q000276:immunology; D000918:Antibody Specificity / Q000276:immunology; D017209:Apoptosis / Q000276:immunology; D050197:Atherosclerosis / Q000276:immunology / Q000473:pathology; D016175:B-Lymphocyte Subsets / Q000276:immunology / Q000637:transplantation; D000939:Epitopes / Q000276:immunology*; D005260:Female; D005312:Fetal Blood / Q000276:immunology; D005856:Germ-Free Life / Q000276:immunology; D018398:Homeodomain Proteins / Q000235:genetics; D007113:Immunity, Innate / Q000276:immunology*; D007075:Immunoglobulin M / Q000097:blood / Q000276:immunology*; D008077:Lipoproteins, LDL / Q000276:immunology; D017737:Macrophages, Peritoneal / Q000276:immunology; D008297:Male; D008315:Malondialdehyde / Q000031:analogs & derivatives / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010084:Oxidation-Reduction; D010587:Phagocytosis / Q000276:immunology; D010767:Phosphorylcholine / Q000031:analogs & derivatives / Q000276:immunology; D011973:Receptors, LDL / Q000235:genetics; D012710:Serum Albumin, Bovine / Q000276:immunology
D000939:Epitopes; D018398:Homeodomain Proteins; D007075:Immunoglobulin M; D008077:Lipoproteins, LDL; D011973:Receptors, LDL; C502964:malondialdehyde-low density lipoprotein, mouse; C099252:oxidized low density lipoprotein; C076110:phosphorylcholine-bovine serum albumin; D010767:Phosphorylcholine; C064658:RAG-1 protein; D012710:Serum Albumin, Bovine; D008315:Malondialdehyde