Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies, Monoclonal / immunology
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Antibodies, Monoclonal / pharmacology
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Antigens, CD20 / immunology
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Apolipoproteins E / genetics
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Atherosclerosis / immunology*
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Atherosclerosis / pathology
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Atherosclerosis / prevention & control*
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B-Lymphocytes / cytology
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B-Lymphocytes / drug effects
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B-Lymphocytes / immunology*
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Cell Proliferation
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Cholesterol / blood
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Dendritic Cells / immunology
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Immunoglobulin G / blood
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Immunoglobulin G / immunology
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Immunoglobulin M / blood
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Immunoglobulin M / immunology
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Interferon-gamma / metabolism
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Interleukin-17 / immunology
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Interleukin-17 / metabolism
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Lipoproteins, LDL / immunology
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Lymphocyte Activation / immunology
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Lymphocyte Depletion*
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Receptors, LDL / genetics
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Sinus of Valsalva / pathology
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T-Lymphocytes / immunology
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T-Lymphocytes / metabolism
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T-Lymphocytes / pathology
Substances
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Antibodies, Monoclonal
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Antigens, CD20
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Apolipoproteins E
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Immunoglobulin G
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Immunoglobulin M
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Interleukin-17
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Lipoproteins, LDL
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Receptors, LDL
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oxidized low density lipoprotein
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Interferon-gamma
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Cholesterol