Innate response activator B cells aggravate atherosclerosis by stimulating T helper-1 adaptive immunity.
BACKGROUND
Atherosclerotic lesions grow via the accumulation of leukocytes and oxidized lipoproteins in the vessel wall. Leukocytes can attenuate or augment atherosclerosis through the release of cytokines, chemokines, and other mediators. Deciphering how leukocytes develop, oppose, and complement each other's function and shape the course of disease can illuminate our understanding of atherosclerosis. Innate response activator (IRA) B cells are a recently described population of granulocyte macrophage colony-stimulating factor-secreting cells of hitherto unknown function in atherosclerosis.


RESULTS
Here, we show that IRA B cells arise during atherosclerosis in mice and humans. In response to a high-cholesterol diet, IRA B cell numbers increase preferentially in secondary lymphoid organs via Myd88-dependent signaling. Mixed chimeric mice lacking B cell-derived granulocyte macrophage colony-stimulating factor develop smaller lesions with fewer macrophages and effector T cells. Mechanistically, IRA B cells promote the expansion of classic dendritic cells, which then generate interferon γ-producing T helper-1 cells. This IRA B cell-dependent T helper-1 skewing manifests in an IgG1-to-IgG2c isotype switch in the immunoglobulin response against oxidized lipoproteins.


CONCLUSIONS
Granulocyte macrophage colony-stimulating factor-producing IRA B cells alter adaptive immune processes and shift the leukocyte response toward a T helper-1-associated milieu that aggravates atherosclerosis.
Center for Systems Biology, Massachusetts General Hospital, Boston (I.H., I.T., L.M.S.G., C.S.R., G.F.W., Y.I., C.W., H.Y.L., M.N., R.W., F.K.S.); Department of Internal Medicine VI, Infectious Diseases, Immunology Rheumatology, Pneumology, University Hospital of Innsbruck, Innsbruck, Austria (I.T.); Toronto General Research Institute, University Health Network, Toronto, ON, Canada (C.S.R., N.D.); Department of Medicine, University of California, San Diego, La Jolla (A.G., J.L.W.); Department of Gastroenterology, Hepatology and Infectious Diseases, University of Duesseldorf, Duesseldorf, Germany (T.A.W.H.); Department of Cardiology and Angiology I, University Heart Center Freiburg, Freiburg, Germany (C.W., A.Z.); Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA (G.K.S., P.L.); Department of Pathology (J.B.) and Division of Vascular Surgery (B.B.R.), Peter Munk Cardiac Centre, Toronto General Hospital, Toronto, ON, Canada; and Department of Systems Biology, Harvard Medical School, Boston, MA (R.W.).
Ingo
I
Hilgendorf
Igor
I
Theurl
Louisa M S
LM
Gerhardt
Clinton S
CS
Robbins
Georg F
GF
Weber
Ayelet
A
Gonen
Yoshiko
Y
Iwamoto
Norbert
N
Degousee
Tobias A W
TA
Holderried
Carla
C
Winter
Andreas
A
Zirlik
Herbert Y
HY
Lin
Galina K
GK
Sukhova
Jagdish
J
Butany
Barry B
BB
Rubin
Joseph L
JL
Witztum
Peter
P
Libby
Matthias
M
Nahrendorf
Ralph
R
Weissleder
Filip K
FK
Swirski
D056704:Adaptive Immunity / Q000235:genetics; D000818:Animals; D050197:Atherosclerosis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology; D001854:Bone Marrow Cells / Q000276:immunology / Q000473:pathology; D002791:Cholesterol, Dietary / Q000008:administration & dosage / Q000009:adverse effects; D018920:Coculture Techniques; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011828:Radiation Chimera; D018417:Th1 Cells / Q000276:immunology* / Q000473:pathology
D002791:Cholesterol, Dietary
B-lymphocytes; T-lymphocytes; atherosclerosis; dendritic cells; granulocyte-macrophage colony-stimulating factor; immunology