Refining the role of B cells in atherosclerosis.

L ymphocytes and plasma cells have long been detected in the plaque and adventitia of atherosclerotic human arteries, 1 yet their role in regulating atherosclerosis has only recently begun to emerge. 2–6 Two important studies published in 2002 provide evidence for an atheroprotective role for B cells. 3,4 More recently, 2 groups broadened our understanding of B cells and atherosclerosis by providing evidence that B cells can also promote atherosclerosis. Treating atheroscle-rosis-prone mice with an anti-CD20 monoclonal antibody that depleted mature B2, but not B1a cells, attenuated ath-erosclerosis. 5,6 This B2 cell depletion was associated with decreased activated splenic CD4 + T cells, T-cell proliferation, and lesional T cells, suggesting that B2 cells aggravate ath-erosclerosis through a T-cell–dependent mechanism. Further evidence for an atherogenic role for B2 cells was provided by studies by Kyaw et al 6 who found aggravated atherosclerosis in lymphocyte-deficient apolipoprotein E −/− recombination activating gene 2 −/− common cytokine receptor γ chain-deficient or to B-cell–deficient atherogenic mice after adoptive transfer of 5×10 6 B2, but not B1, B cells. Sage et al 7 present another important study on the impact of loss of B2 cells on atherosclerosis by using a genetic strategy of B cell-activating factor receptor (BAFFR) deficiency to deplete B2 cells. BAFFR is a tumor necrosis factor receptor family member that is critical for maintaining mature B2 B cells. 8 The authors reconstituted lethally irradiated low-density lipoprotein receptor −/− mice with bone marrow from BAFFR-deficient mice leading to a markedly diminished ability to replenish B2 cells in peripheral lymphoid tissue or blood. This was associated with reduced atherosclerosis, measured by Oil Red O + staining of the aortic root, after 6 and 8 weeks of high-fat diet. Low-density lipoprotein receptor −/− mice reconstituted with 80% µMT/20% Baffr −/− also had reduced atherosclerosis compared with those reconstituted with control 80% µMT/20% C57BL/6 marrow, providing evidence that it is the loss of BAFFR on B cells mediating this effect. In agreement with their previous findings using anti-CD20 monoclonal antibody depletion of B2 cells, 5 they also found that B2 B cell depletion due to BAFFR deficiency reduces the proportion of spleen-derived activated CD4 + T cells and CD4 + T-cell proliferation. Additionally, they found reduced numbers of T cells in aortic roots from Baffr −/− reconstituted mice at 6 (but not 8) weeks of high-fat diet, and at 8 weeks of diet in lesions from µMT/Baffr …