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B Cell-Activating Factor Neutralization Aggravates Atherosclerosis.

ABSTRACT: BACKGROUND:Atherosclerotic cardiovascular disease (heart attacks and strokes) is the major cause of death globally and is caused by the buildup of a plaque in the arterial wall. Genomic data showed that the B cell-activating factor (BAFF) receptor pathway, which is specifically essential for the survival of conventional B lymphocytes (B-2 cells), is a key driver of coronary heart disease. Deletion or antibody-mediated blockade of BAFF receptor ablates B-2 cells and decreases experimental atherosclerosis. Anti-BAFF immunotherapy is approved for treatment of autoimmune systemic lupus erythematosus, and can therefore be expected to limit their associated cardiovascular risk. However, direct effects of anti-BAFF immunotherapy on atherosclerosis remain unknown. METHODS:To investigate the effect of BAFF neutralization in atherosclerosis, the authors treated Apoe-/- and Ldlr-/- mice with a well-characterized blocking anti-BAFF antibody. Moreover, to investigate the mechanism by which BAFF impacts atherosclerosis, the authors studied atherosclerosis-prone mice that lack the alternative receptor for BAFF: transmembrane activator and calcium modulator and cyclophilin ligand interactor. RESULTS:The authors demonstrate here that anti-BAFF antibody treatment increased atherosclerosis in mice, despite efficient depletion of mature B-2 cells, suggesting a unique mechanism of action. Indeed, myeloid cell-specific deletion of transmembrane activator and calcium modulator and cyclophilin ligand interactor also results in increased atherosclerosis, while B cell-specific transmembrane activator and calcium modulator and cyclophilin ligand interactor deletion had no effect. Mechanistically, BAFF-transmembrane activator and calcium modulator and cyclophilin ligand interactor signaling represses macrophage IRF7-dependent (but not NF-?B-dependent) Toll-like receptor 9 responses including proatherogenic CXCL10 production. CONCLUSIONS:These data identify a novel B cell-independent anti-inflammatory role for BAFF in atherosclerosis and may have important clinical implications.

SUBMITTER: Tsiantoulas D

PROVIDER: S-EPMC6181204 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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B Cell-Activating Factor Neutralization Aggravates Atherosclerosis.

Tsiantoulas Dimitrios D Sage Andrew P AP Göderle Laura L Ozsvar-Kozma Maria M Murphy Deirdre D Porsch Florentina F Pasterkamp Gerard G Menche Jörg J Schneider Pascal P Mallat Ziad Z Binder Christoph J CJ

Circulation 20181101 20

<h4>Background</h4>Atherosclerotic cardiovascular disease (heart attacks and strokes) is the major cause of death globally and is caused by the buildup of a plaque in the arterial wall. Genomic data showed that the B cell-activating factor (BAFF) receptor pathway, which is specifically essential for the survival of conventional B lymphocytes (B-2 cells), is a key driver of coronary heart disease. Deletion or antibody-mediated blockade of BAFF receptor ablates B-2 cells and decreases experimental ...[more]

PMID: 29858401

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Project description:BackgroundImmunotherapy has revolutionized cancer treatment. However, immune checkpoint inhibitors (ICIs) that target PD-1 (programmed cell death protein-1) and/or CTLA-4 (cytotoxic T lymphocyte-associated antigen-4) are commonly associated with acute immune-related adverse events. Accumulating evidence also suggests that ICIs aggravate existing inflammatory diseases.ObjectivesAs inflammation drives atherosclerotic cardiovascular disease, we studied the propensity of short-term ICI therapy to aggravate atherosclerosis.MethodsWe used 18F-FDG (2-deoxy-2-[fluorine-18]fluoro-D-glucose) positron emission tomography-computed tomography to detect macrophage-driven vascular and systemic inflammation in pembrolizumab and nivolumab/ipilimumab-treated melanoma patients. In parallel, atherosclerotic Ldlr -/- mice were treated with CTLA-4 and PD-1 inhibition to study the proinflammatory consequences of immune checkpoint inhibition.ResultsICI treatment did not affect 18F-FDG uptake in the large arteries, spleen, and bone marrow of melanoma patients, nor myeloid cell activation in blood and lymphoid organs in hyperlipidemic mice. In contrast, we found marked changes in the adaptive immune response (i.e., increased CD4+ effector T cell and CD8+ cytotoxic T cell numbers in lymphoid organs and the arterial wall of our hyperlipidemic mice). Although plaque size was unaffected, plaques had progressed toward a lymphoid-based inflammatory phenotype, characterized by a 2.7-fold increase of CD8+ T cells and a 3.9-fold increase in necrotic core size. Increased endothelial activation was observed with a 2.2-fold and 1.6-fold increase in vascular cell adhesion molecule-1 and intercellular adhesion molecule-1, respectively.ConclusionsThis study demonstrates that combination therapy with anti-CTLA-4 and anti-PD-1 antibodies does not affect myeloid-driven vascular and systemic inflammation in melanoma patients and hyperlipidemic mice. However, short-term ICI therapy in mice induces T cell-mediated plaque inflammation and drives plaque progression.

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B Cell-Activating Factor Neutralization Aggravates Atherosclerosis.

Publications

B Cell-Activating Factor Neutralization Aggravates Atherosclerosis.

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