title: Helix-loop-helix factor inhibitor of differentiation 3 regulates interleukin-5 expression and B-1a B cell proliferation.
abstract: OBJECTIVE
  Natural immunity is emerging as an important mediator of protection from atherogenesis. Natural IgM antibodies that recognize oxidation-specific epitopes on low-density lipoprotein or phospholipids and the B-1a B cells that produce them attenuate atherosclerosis. We previously demonstrated that Apoe(-/-) mice globally deficient in the helix-loop-helix protein inhibitor of differentiation 3 (Id3) develop early diet-induced atherosclerosis. Furthermore, B cell-mediated attenuation of atherosclerosis in B cell-deficient mice was dependent on Id3. Here, we sought to determine whether Id3 regulates B-1a B cells and the natural antibodies that they produce and identify mechanisms mediating these effects.
  
  
  RESULTS
  Mice lacking Id3 had significantly fewer B-1a B cells in the spleen and peritoneal cavity and reduced serum levels of the natural antibody E06. B cell-specific deletion of Id3 revealed that this effect was not because of the loss of Id3 in B cells. Interleukin (IL)-33 induced abundant, Id3-dependent IL-5 production in the recently identified innate lymphoid cell, the natural helper (NH) cell, but not Th2 or mast cells. In addition, delivery of IL-5 to Id3-deficient mice restored B-1a B cell proliferation. B-1a B cells were present in aortic samples also containing NH cells. Aortic NH cells produced IL-5, a B-1a B cell mitogen in response to IL-33 stimulation.
  
  
  CONCLUSIONS
  These studies are the first to identify NH and B-1a B cells in the aorta and provide evidence that Id3 is a key regulator of NH cell IL-5 production and B-1a B cell homeostasis.
authors.affiliation: From the Cardiovascular Research Center (H.M.P., S.N.O., D.B.H., C.A.M.), Department of Pathology (H.M.P.), Department of Medicine (S.N.O.), Beirne B. Carter Center for Immunology Research (S.P.F., C.A.M.), Department of Microbiology, Immunology and Cancer Biology (S.P.F., T.P.B.), Department of Biochemistry, Molecular Biology and Genetics (D.B.H., T.P.B.), Department of Medicine, Cardiovascular Division (C.A.M.), Department of Molecular Physiology and Biological Physics (C.A.M.), University of Virginia, Charlottesville; and the Department of Medicine, University of California, San Diego (X.Q., A.G., S.T., J.L.W.).
authors.forename: Heather M
authors.initials: HM
authors.lastname: Perry
authors.forename: Stephanie N
authors.initials: SN
authors.lastname: Oldham
authors.forename: Shawn P
authors.initials: SP
authors.lastname: Fahl
authors.forename: Xuchu
authors.initials: X
authors.lastname: Que
authors.forename: Ayelet
authors.initials: A
authors.lastname: Gonen
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Harmon
authors.forename: Sotirios
authors.initials: S
authors.lastname: Tsimikas
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Witztum
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Bender
authors.forename: Coleen A
authors.initials: CA
authors.lastname: McNamara
mesh_terms: D000818:Animals; D018941:Antigens, CD19 / Q000235:genetics / Q000378:metabolism; D001011:Aorta / Q000276:immunology*; D001018:Aortic Diseases / Q000235:genetics / Q000276:immunology*; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000235:genetics / Q000276:immunology*; D016175:B-Lymphocyte Subsets / Q000276:immunology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D007113:Immunity, Innate; D051796:Inhibitor of Differentiation Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000067596:Interleukin-33; D015848:Interleukin-5 / Q000235:genetics / Q000378:metabolism*; D007378:Interleukins / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000378:metabolism; D014162:Transfection
chemical_list: D018941:Antigens, CD19; D001057:Apolipoproteins E; C508599:IL5 protein, human; C506535:Il33 protein, mouse; D051796:Inhibitor of Differentiation Proteins; D000067596:Interleukin-33; D015848:Interleukin-5; D007378:Interleukins; D009363:Neoplasm Proteins; C067679:Idb3 protein, mouse; C075640:ID3 protein, human
keywords: arteriosclerosis; basic helix-loop-helix transcription factors; mmune system