B cell depletion reduces the development of atherosclerosis in mice.
B cell depletion significantly reduces the burden of several immune-mediated diseases. However, B cell activation has been until now associated with a protection against atherosclerosis, suggesting that B cell-depleting therapies would enhance cardiovascular risk. We unexpectedly show that mature B cell depletion using a CD20-specific monoclonal antibody induces a significant reduction of atherosclerosis in various mouse models of the disease. This treatment preserves the production of natural and potentially protective anti-oxidized low-density lipoprotein (oxLDL) IgM autoantibodies over IgG type anti-oxLDL antibodies, and markedly reduces pathogenic T cell activation. B cell depletion diminished T cell-derived IFN-gamma secretion and enhanced production of IL-17; neutralization of the latter abrogated CD20 antibody-mediated atheroprotection. These results challenge the current paradigm that B cell activation plays an overall protective role in atherogenesis and identify new antiatherogenic strategies based on B cell modulation.
Ait-Oufella
Hafid
H
Institut National de la Santé et de la Recherche Médicale (INSERM), Unit 970, Paris Cardiovascular Research Center, 75015 Paris, France.
Herbin
Olivier
O
Bouaziz
Jean-David
JD
Binder
Christoph J
CJ
Uyttenhove
Catherine
C
Laurans
Ludivine
L
Taleb
Soraya
S
Van Vré
Emily
E
Esposito
Bruno
B
Vilar
José
J
Sirvent
Jérôme
J
Van Snick
Jacques
J
Tedgui
Alain
A
Tedder
Thomas F
TF
Mallat
Ziad
Z
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D018951:Antigens, CD20 / Q000276:immunology; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D049109:Cell Proliferation; D002784:Cholesterol / Q000097:blood; D003713:Dendritic Cells / Q000276:immunology; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D007075:Immunoglobulin M / Q000097:blood / Q000276:immunology; D007371:Interferon-gamma / Q000378:metabolism; D020381:Interleukin-17 / Q000276:immunology / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D008212:Lymphocyte Depletion; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011973:Receptors, LDL / Q000235:genetics; D012850:Sinus of Valsalva / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology
D000911:Antibodies, Monoclonal; D018951:Antigens, CD20; D001057:Apolipoproteins E; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D020381:Interleukin-17; D008077:Lipoproteins, LDL; D011973:Receptors, LDL; C099252:oxidized low density lipoprotein; D007371:Interferon-gamma; D002784:Cholesterol