title: B-1b Cells Secrete Atheroprotective IgM and Attenuate Atherosclerosis.
abstract: BACKGROUND
  B cells contribute to atherosclerosis through subset-specific mechanisms. Whereas some controversy exists about the role of B-2 cells, B-1a cells are atheroprotective because of secretion of atheroprotective IgM antibodies independent of antigen. B-1b cells, a unique subset of B-1 cells that respond specifically to T-cell-independent antigens, have not been studied within the context of atherosclerosis.
  
  
  OBJECTIVE
  To determine whether B-1b cells produce atheroprotective IgM antibodies and function to protect against diet-induced atherosclerosis.
  
  
  RESULTS
  We demonstrate that B-1b cells are sufficient to produce IgM antibodies against oxidation-specific epitopes on low-density lipoprotein both in vitro and in vivo. In addition, we demonstrate that B-1b cells provide atheroprotection after adoptive transfer into B- and T-cell deficient (Rag1(-/-)Apoe(-/-)) hosts. We implicate inhibitor of differentiation 3 (Id3) in the regulation of B-1b cells as B-cell-specific Id3 knockout mice (Id3(BKO)Apoe(-/-)) have increased numbers of B-1b cells systemically, increased titers of oxidation-specific epitope-reactive IgM antibodies, and significantly reduced diet-induced atherosclerosis when compared with Id3(WT)Apoe(-/-) controls. Finally, we report that the presence of a homozygous single nucleotide polymorphism in ID3 in humans that attenuates Id3 function is associated with an increased percentage of circulating B-1 cells and anti-malondialdehyde-low-density lipoprotein IgM suggesting clinical relevance.
  
  
  CONCLUSIONS
  These results provide novel evidence that B-1b cells produce atheroprotective oxidation-specific epitope-reactive IgM antibodies and protect against atherosclerosis in mice and suggest that similar mechanisms may occur in humans.
authors.affiliation: From the Cardiovascular Research Center (S.M.R., H.M.P., P.S., S.G., D.D., C.M., C.A.M.), Department of Pathology (S.M.R., H.M.P.), Department of Medicine, Division of Cardiovascular Medicine (A.M.T., C.A.M.), and Beirne B. Carter Center for Immunology Research (T.P.B., C.A.M.), University of Virginia, Charlottesville; and Department of Medicine, Division of Endocrinology and Metabolism (A.G., T.A.P., J.L.W.) and Department of Medicine, Division of Cardiology (S.T.), University of California San Diego, La Jolla.
authors.forename: Sam M
authors.initials: SM
authors.lastname: Rosenfeld
authors.affiliation: From the Cardiovascular Research Center (S.M.R., H.M.P., P.S., S.G., D.D., C.M., C.A.M.), Department of Pathology (S.M.R., H.M.P.), Department of Medicine, Division of Cardiovascular Medicine (A.M.T., C.A.M.), and Beirne B. Carter Center for Immunology Research (T.P.B., C.A.M.), University of Virginia, Charlottesville; and Department of Medicine, Division of Endocrinology and Metabolism (A.G., T.A.P., J.L.W.) and Department of Medicine, Division of Cardiology (S.T.), University of California San Diego, La Jolla.
authors.forename: Heather M
authors.initials: HM
authors.lastname: Perry
authors.affiliation: From the Cardiovascular Research Center (S.M.R., H.M.P., P.S., S.G., D.D., C.M., C.A.M.), Department of Pathology (S.M.R., H.M.P.), Department of Medicine, Division of Cardiovascular Medicine (A.M.T., C.A.M.), and Beirne B. Carter Center for Immunology Research (T.P.B., C.A.M.), University of Virginia, Charlottesville; and Department of Medicine, Division of Endocrinology and Metabolism (A.G., T.A.P., J.L.W.) and Department of Medicine, Division of Cardiology (S.T.), University of California San Diego, La Jolla.
authors.forename: Ayelet
authors.initials: A
authors.lastname: Gonen
authors.affiliation: From the Cardiovascular Research Center (S.M.R., H.M.P., P.S., S.G., D.D., C.M., C.A.M.), Department of Pathology (S.M.R., H.M.P.), Department of Medicine, Division of Cardiovascular Medicine (A.M.T., C.A.M.), and Beirne B. Carter Center for Immunology Research (T.P.B., C.A.M.), University of Virginia, Charlottesville; and Department of Medicine, Division of Endocrinology and Metabolism (A.G., T.A.P., J.L.W.) and Department of Medicine, Division of Cardiology (S.T.), University of California San Diego, La Jolla.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Prohaska
authors.affiliation: From the Cardiovascular Research Center (S.M.R., H.M.P., P.S., S.G., D.D., C.M., C.A.M.), Department of Pathology (S.M.R., H.M.P.), Department of Medicine, Division of Cardiovascular Medicine (A.M.T., C.A.M.), and Beirne B. Carter Center for Immunology Research (T.P.B., C.A.M.), University of Virginia, Charlottesville; and Department of Medicine, Division of Endocrinology and Metabolism (A.G., T.A.P., J.L.W.) and Department of Medicine, Division of Cardiology (S.T.), University of California San Diego, La Jolla.
authors.forename: Prasad
authors.initials: P
authors.lastname: Srikakulapu
authors.affiliation: From the Cardiovascular Research Center (S.M.R., H.M.P., P.S., S.G., D.D., C.M., C.A.M.), Department of Pathology (S.M.R., H.M.P.), Department of Medicine, Division of Cardiovascular Medicine (A.M.T., C.A.M.), and Beirne B. Carter Center for Immunology Research (T.P.B., C.A.M.), University of Virginia, Charlottesville; and Department of Medicine, Division of Endocrinology and Metabolism (A.G., T.A.P., J.L.W.) and Department of Medicine, Division of Cardiology (S.T.), University of California San Diego, La Jolla.
authors.forename: Sukhdeep
authors.initials: S
authors.lastname: Grewal
authors.affiliation: From the Cardiovascular Research Center (S.M.R., H.M.P., P.S., S.G., D.D., C.M., C.A.M.), Department of Pathology (S.M.R., H.M.P.), Department of Medicine, Division of Cardiovascular Medicine (A.M.T., C.A.M.), and Beirne B. Carter Center for Immunology Research (T.P.B., C.A.M.), University of Virginia, Charlottesville; and Department of Medicine, Division of Endocrinology and Metabolism (A.G., T.A.P., J.L.W.) and Department of Medicine, Division of Cardiology (S.T.), University of California San Diego, La Jolla.
authors.forename: Deepanjana
authors.initials: D
authors.lastname: Das
authors.affiliation: From the Cardiovascular Research Center (S.M.R., H.M.P., P.S., S.G., D.D., C.M., C.A.M.), Department of Pathology (S.M.R., H.M.P.), Department of Medicine, Division of Cardiovascular Medicine (A.M.T., C.A.M.), and Beirne B. Carter Center for Immunology Research (T.P.B., C.A.M.), University of Virginia, Charlottesville; and Department of Medicine, Division of Endocrinology and Metabolism (A.G., T.A.P., J.L.W.) and Department of Medicine, Division of Cardiology (S.T.), University of California San Diego, La Jolla.
authors.forename: Chantel
authors.initials: C
authors.lastname: McSkimming
authors.affiliation: From the Cardiovascular Research Center (S.M.R., H.M.P., P.S., S.G., D.D., C.M., C.A.M.), Department of Pathology (S.M.R., H.M.P.), Department of Medicine, Division of Cardiovascular Medicine (A.M.T., C.A.M.), and Beirne B. Carter Center for Immunology Research (T.P.B., C.A.M.), University of Virginia, Charlottesville; and Department of Medicine, Division of Endocrinology and Metabolism (A.G., T.A.P., J.L.W.) and Department of Medicine, Division of Cardiology (S.T.), University of California San Diego, La Jolla.
authors.forename: Angela M
authors.initials: AM
authors.lastname: Taylor
authors.affiliation: From the Cardiovascular Research Center (S.M.R., H.M.P., P.S., S.G., D.D., C.M., C.A.M.), Department of Pathology (S.M.R., H.M.P.), Department of Medicine, Division of Cardiovascular Medicine (A.M.T., C.A.M.), and Beirne B. Carter Center for Immunology Research (T.P.B., C.A.M.), University of Virginia, Charlottesville; and Department of Medicine, Division of Endocrinology and Metabolism (A.G., T.A.P., J.L.W.) and Department of Medicine, Division of Cardiology (S.T.), University of California San Diego, La Jolla.
authors.forename: Sotirios
authors.initials: S
authors.lastname: Tsimikas
authors.affiliation: From the Cardiovascular Research Center (S.M.R., H.M.P., P.S., S.G., D.D., C.M., C.A.M.), Department of Pathology (S.M.R., H.M.P.), Department of Medicine, Division of Cardiovascular Medicine (A.M.T., C.A.M.), and Beirne B. Carter Center for Immunology Research (T.P.B., C.A.M.), University of Virginia, Charlottesville; and Department of Medicine, Division of Endocrinology and Metabolism (A.G., T.A.P., J.L.W.) and Department of Medicine, Division of Cardiology (S.T.), University of California San Diego, La Jolla.
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Bender
authors.affiliation: From the Cardiovascular Research Center (S.M.R., H.M.P., P.S., S.G., D.D., C.M., C.A.M.), Department of Pathology (S.M.R., H.M.P.), Department of Medicine, Division of Cardiovascular Medicine (A.M.T., C.A.M.), and Beirne B. Carter Center for Immunology Research (T.P.B., C.A.M.), University of Virginia, Charlottesville; and Department of Medicine, Division of Endocrinology and Metabolism (A.G., T.A.P., J.L.W.) and Department of Medicine, Division of Cardiology (S.T.), University of California San Diego, La Jolla.
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Witztum
authors.affiliation: From the Cardiovascular Research Center (S.M.R., H.M.P., P.S., S.G., D.D., C.M., C.A.M.), Department of Pathology (S.M.R., H.M.P.), Department of Medicine, Division of Cardiovascular Medicine (A.M.T., C.A.M.), and Beirne B. Carter Center for Immunology Research (T.P.B., C.A.M.), University of Virginia, Charlottesville; and Department of Medicine, Division of Endocrinology and Metabolism (A.G., T.A.P., J.L.W.) and Department of Medicine, Division of Cardiology (S.T.), University of California San Diego, La Jolla. cam8c@virginia.edu.
authors.forename: Coleen A
authors.initials: CA
authors.lastname: McNamara
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000918:Antibody Specificity; D001011:Aorta / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency; D050197:Atherosclerosis / Q000097:blood / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D016175:B-Lymphocyte Subsets / Q000276:immunology* / Q000637:transplantation; D002478:Cells, Cultured; D002784:Cholesterol / Q000097:blood; D003300:Copper / Q000276:immunology; D066273:Diet, Western / Q000009:adverse effects; D000939:Epitopes / Q000276:immunology; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007075:Immunoglobulin M / Q000276:immunology*; D051796:Inhibitor of Differentiation Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D008077:Lipoproteins, LDL / Q000737:chemistry / Q000276:immunology*; D018655:Lymphocyte Count; D008297:Male; D008315:Malondialdehyde / Q000031:analogs & derivatives* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology; D010084:Oxidation-Reduction; D058226:Plaque, Atherosclerotic / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D051197:Toll-Like Receptor 4 / Q000276:immunology
chemical_list: D001057:Apolipoproteins E; D000939:Epitopes; D018398:Homeodomain Proteins; D007075:Immunoglobulin M; D051796:Inhibitor of Differentiation Proteins; D008077:Lipoproteins, LDL; D009363:Neoplasm Proteins; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C502964:malondialdehyde-low density lipoprotein, mouse; C064658:RAG-1 protein; C067679:Idb3 protein, mouse; C075640:ID3 protein, human; D008315:Malondialdehyde; D003300:Copper; D002784:Cholesterol
keywords: antibodies; atherosclerosis; immunoglobulin M; lymphocyte; malondialdehyde