B Cell-Activating Factor Neutralization Aggravates Atherosclerosis

Area of Science:

• Immunology
• Cardiovascular Science
• Genomics

Background:

• Atherosclerotic cardiovascular disease is a leading global cause of death, driven by arterial plaque buildup.
• Genomic studies implicate the B cell-activating factor (BAFF) pathway in coronary heart disease.
• Existing anti-BAFF therapies for autoimmune diseases suggest potential cardiovascular benefits, but direct effects on atherosclerosis are unknown.

Purpose of the Study:

• To investigate the impact of BAFF neutralization on atherosclerosis.
• To elucidate the mechanisms by which BAFF influences atherosclerosis progression.

Main Methods:

• Treatment of Apoe-/- and Ldlr-/- mice with an anti-BAFF antibody.
• Analysis of atherosclerosis-prone mice lacking the BAFF receptor, transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI).
• Investigation of myeloid cell-specific and B cell-specific TACI deletions.

Main Results:

• Anti-BAFF antibody treatment paradoxically increased atherosclerosis in mice, despite B cell depletion.
• Myeloid cell-specific TACI deletion, but not B cell-specific deletion, also increased atherosclerosis.
• BAFF-TACI signaling was found to suppress macrophage IRF7-dependent Toll-like receptor 9 responses and proatherogenic CXCL10 production.

Conclusions:

• BAFF plays a novel, B cell-independent anti-inflammatory role in atherosclerosis.
• These findings may have significant clinical implications for managing cardiovascular risk.