Atherosclerosis is a chronic inflammatory arterial disease characterized by focal accumulation of lipid and inflammatory cells. It is the number one cause of deaths in the Western world because of its complications of heart attacks and strokes. Statins are effective in only approximately one third of patients, underscoring the urgent need for additional therapies. B cells that accumulate in atherosclerotic lesions and the aortic adventitia of humans and mice are considered to protect against atherosclerosis development. Unexpectedly, we found that selective B cell depletion in apolipoprotein E-deficient (ApoE−/−) mice using a well-characterized mAb to mouse CD20 reduced atherosclerosis development and progression without affecting the hyperlipidemia imposed by a high-fat diet. Adoptive transfer of 5 × 106 or 5 × 107 conventional B2 B cells but not 5 × 106 B1 B cells to a lymphocyte-deficient ApoE−/− Rag-2−/− common cytokine receptor γ-chain–deficient mouse that was fed a high-fat diet augmented atherosclerosis by 72%. Transfer of 5 × 106 B2 B cells to an ApoE−/− mouse deficient only in B cells aggravated atherosclerosis by >300%. Our findings provide compelling evidence for the hitherto unrecognized proatherogenic role of conventional B2 cells. The data indicate that B2 cells can potently promote atherosclerosis development entirely on their own in the total absence of all other lymphocyte populations. Additionally, these B2 cells can also significantly augment atherosclerosis development in the presence of T cells and all other lymphocyte populations. Our findings raise the prospect of B cell depletion as a therapeutic approach to inhibit atherosclerosis development and progression in humans.

Background-Some animal studies suggest that transforming growth factor-␤ (TGF-␤) protects vessels from atherosclerosis by preventing intima formation, but others indicate a role in vessel proteoglycan accumulation and lipoprotein retention. To distinguish between these possibilities in humans, immunohistochemical studies were performed examining the coexpression of TGF-␤ isoforms and the TGF-␤ receptors ALK-5 and T␤R-II in aorta during the various stages of atherosclerotic lesion development. Methods and Results-The spatial relationships between TGF-␤ 1 , TGF-␤ 3 , ALK-5, and T␤R-II expression were compared in aortic segments from 21 subjects. Nonatherosclerotic intima contained predominantly TGF-␤ 1 , low concentrations of T␤R-II, and barely detectable amounts of ALK-5. In contrast, fatty streaks/fibrofatty lesions contained high concentrations of both TGF-␤ isoforms. Smooth muscle cells (SMCs), macrophages, and foam cells of macrophage and SMC origin contributed to these high levels. These lesions also contained high, colocalized concentrations of ALK-5 and T␤R-II. Despite fibrous plaques containing TGF-␤ 1 , its receptors were at detection limits. We found no evidence for truncated T␤R-II expression in either normal intima or the various atherosclerotic lesions. Conclusions-TGF-␤ appears to be most active in lipid-rich aortic intimal lesions. The findings support the hypothesis that TGF-␤ contributes primarily to the pathogenesis of lipid-rich atherosclerotic lesions by stimulating the production of lipoprotein-trapping proteoglycans, inhibiting smooth muscle proliferation, and activating proteolytic mechanisms in macrophages. (Circulation. 1999;99:2883-2891.)

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Objective-High-mobility group box protein 1 (HMGB1) is a DNA-binding protein and cytokine highly expressed in atherosclerotic lesions, but its pathophysiological role in atherosclerosis is unknown. We investigated its role in the development of atherosclerosis in ApoEϪ/Ϫ mice. Methods and Results-Apolipoprotein E-deficient (ApoEϪ/Ϫ) mice fed a high-fat diet were administered a monoclonal anti-HMGB1 neutralizing antibody, and the effects on lesion size, immune cell accumulation, and proinflammatory mediators were assessed using Oil Red O, immunohistochemistry, and real-time polymerase chain reaction. As with human atherosclerotic lesions, lesions in ApoEϪ/Ϫ mice expressed HMGB1. Treatment with the neutralizing antibody attenuated atherosclerosis by 55%. Macrophage accumulation was reduced by 43%, and vascular cell adhesion molecule-1 and monocyte chemoattractant protein-1 expression was attenuated by 48% and 72%, respectively. CD11cϩ dendritic cells were reduced by 65%, and the mature (CD83ϩ) population was reduced by 60%. Treatment also reduced CD4ϩ cells by nearly 50%. mRNAs in lesions encoding tumor necrosis factor-␣ and interleukin-1␤ tended to be reduced. Mechanistically, HMGB1 stimulated macrophage migration in vitro and in vivo; in vivo, it markedly augmented the accumulation of F4/80ϩGr-1(Ly-6C)ϩ macrophages and also increased F4/80ϩCD11bϩ macrophage numbers. Conclusion-HMGB1