title: Sterile inflammation in the spleen during atherosclerosis provides oxidation-specific epitopes that induce a protective B-cell response.
abstract: The B-cell response in atherosclerosis is directed toward oxidation-specific epitopes such as phosphorylcholine (PC) that arise during disease-driven oxidation of self-antigens. PC-bearing antigens have been used to induce atheroprotective antibodies against modified low-density lipoproteins (oxLDL), leading to plaque reduction. Previous studies have found that B-cell transfer from aged atherosclerotic mice confers protection to young mice, but the mechanism is unknown. Here, we dissected the atheroprotective response in the spleen and found an ongoing germinal center reaction, accumulation of antibody-forming cells, and inflammasome activation in apolipoprotein E-deficient mice (Apoe(-/-)). Specific B-cell clone expansion involved the heavy chain variable region (Vh) 5 and Vh7 B-cell receptor families that harbor anti-PC reactivity. oxLDL also accumulated in the spleen. To investigate whether protection could be induced by self-antigens alone, we injected apoptotic cells that carry the same oxidation-specific epitopes as oxLDL. This treatment reduced serum cholesterol and inhibited the development of atherosclerosis in a B-cell-dependent manner. Thus, we conclude that the spleen harbors a protective B-cell response that is initiated in atherosclerosis through sterile inflammation. These data highlight the importance of the spleen in atherosclerosis-associated immunity.
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet Solna Campus, Karolinska Institutet, SE-171 77 Stockholm, Sweden; and.
authors.forename: Emilie K
authors.initials: EK
authors.lastname: Grasset
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet Solna Campus, Karolinska Institutet, SE-171 77 Stockholm, Sweden; and.
authors.forename: Amanda
authors.initials: A
authors.lastname: Duhlin
authors.affiliation: Centre for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital L8:01, SE-171 76 Stockholm, Sweden.
authors.forename: Hanna E
authors.initials: HE
authors.lastname: Agardh
authors.affiliation: Centre for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital L8:01, SE-171 76 Stockholm, Sweden.
authors.forename: Olga
authors.initials: O
authors.lastname: Ovchinnikova
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet Solna Campus, Karolinska Institutet, SE-171 77 Stockholm, Sweden; and.
authors.forename: Thomas
authors.initials: T
authors.lastname: Hägglöf
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet Solna Campus, Karolinska Institutet, SE-171 77 Stockholm, Sweden; and.
authors.forename: Mattias N
authors.initials: MN
authors.lastname: Forsell
authors.affiliation: Centre for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital L8:01, SE-171 76 Stockholm, Sweden.
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Paulsson-Berne
authors.affiliation: Centre for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital L8:01, SE-171 76 Stockholm, Sweden.
authors.forename: Göran K
authors.initials: GK
authors.lastname: Hansson
authors.affiliation: Centre for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital L8:01, SE-171 76 Stockholm, Sweden.
authors.forename: Daniel F J
authors.initials: DF
authors.lastname: Ketelhuth
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet Solna Campus, Karolinska Institutet, SE-171 77 Stockholm, Sweden; and mikael.karlsson@ki.se.
authors.forename: Mikael C I
authors.initials: MC
authors.lastname: Karlsson
mesh_terms: D000375:Aging / Q000473:pathology; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000378:metabolism; D017209:Apoptosis; D050197:Atherosclerosis / Q000276:immunology* / Q000473:pathology; D001402:B-Lymphocytes / Q000276:immunology*; D002784:Cholesterol / Q000378:metabolism; D002999:Clone Cells; D000939:Epitopes / Q000276:immunology*; D018858:Germinal Center / Q000276:immunology; D058847:Inflammasomes / Q000378:metabolism; D007249:Inflammation / Q000276:immunology*; D008077:Lipoproteins, LDL / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D008810:Mice, Inbred C57BL; D010084:Oxidation-Reduction; D010713:Phosphatidylcholines / Q000378:metabolism; D013154:Spleen / Q000276:immunology* / Q000473:pathology*
chemical_list: D001057:Apolipoproteins E; D000939:Epitopes; D058847:Inflammasomes; D008077:Lipoproteins, LDL; D010713:Phosphatidylcholines; C099252:oxidized low density lipoprotein; D002784:Cholesterol
keywords: B cells; atherosclerosis; inflammasome
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