Schaheen Basil, Downs Emily A, Serbulea Vlad, Almenara Camila C P, Spinosa Michael, Su Gang, Zhao Yunge, Srikakulapu Prasad, Butts Cherié, McNamara Coleen A, Leitinger Norbert, Upchurch Gilbert R, Meher Akshaya K, Ailawadi Gorav
From the Departments of Surgery (B.S., E.A.D., M.S., G.S., Y.Z., G.R.U., A.K.M., G.A.), Pharmacology (V.S., C.C.P.A., N.L., A.K.M.), and Robert M. Berne Cardiovascular Research Center (P.S., C.A.M.N.), University of Virginia, Charlottesville; Biogen Idec, Cambridge, MA (C.B.); Department of Molecular Physiology and Biological Physics (G.R.U.) and Biomedical Engineering (G.A.), University of Virginia, Charlottesville.
Arterioscler Thromb Vasc Biol. 2016 Nov;36(11):2191-2202. doi: 10.1161/ATVBAHA.116.307559. Epub 2016 Sep 15.
B-cell depletion therapy is widely used for treatment of cancers and autoimmune diseases. B cells are abundant in abdominal aortic aneurysms (AAA); however, it is unknown whether B-cell depletion therapy affects AAA growth. Using experimental models of murine AAA, we aim to examine the effect of B-cell depletion on AAA formation.
Wild-type or apolipoprotein E-knockout mice were treated with mouse monoclonal anti-CD20 or control antibodies and subjected to an elastase perfusion or angiotensin II infusion model to induce AAA, respectively. Anti-CD20 antibody treatment significantly depleted B1 and B2 cells, and strikingly suppressed AAA growth in both models. B-cell depletion resulted in lower circulating IgM levels, but did not affect the levels of IgG or cytokine/chemokine levels. Although the total number of leukocyte remained unchanged in elastase-perfused aortas after anti-CD20 antibody treatment, the number of B-cell subtypes was significantly lower. Interestingly, plasmacytoid dendritic cells expressing the immunomodulatory enzyme indole 2,3-dioxygenase were detected in the aortas of B-cell-depleted mice. In accordance with an increase in indole 2,3-dioxygenase+ plasmacytoid dendritic cells, the number of regulatory T cells was higher, whereas the expression of proinflammatory genes was lower in aortas of B-cell-depleted mice. In a coculture model, the presence of B cells significantly lowered the number of indole 2,3-dioxygenase+ plasmacytoid dendritic cells without affecting total plasmacytoid dendritic cell number.
The present results demonstrate that B-cell depletion protects mice from experimental AAA formation and promotes emergence of an immunosuppressive environment in aorta.
B细胞耗竭疗法广泛用于癌症和自身免疫性疾病的治疗。B细胞在腹主动脉瘤（AAA）中大量存在；然而，B细胞耗竭疗法是否影响AAA生长尚不清楚。我们利用小鼠AAA实验模型，旨在研究B细胞耗竭对AAA形成的影响。
野生型或载脂蛋白E基因敲除小鼠分别用小鼠单克隆抗CD20抗体或对照抗体处理，然后分别采用弹性蛋白酶灌注或血管紧张素II输注模型诱导AAA。抗CD20抗体治疗显著减少了B1和B2细胞，并在两种模型中均显著抑制了AAA生长。B细胞耗竭导致循环IgM水平降低，但不影响IgG水平或细胞因子/趋化因子水平。虽然抗CD20抗体治疗后弹性蛋白酶灌注主动脉中的白细胞总数保持不变，但B细胞亚群的数量显著降低。有趣的是，在B细胞耗竭小鼠的主动脉中检测到表达免疫调节酶吲哚2,3-双加氧酶的浆细胞样树突状细胞。随着吲哚2,3-双加氧酶阳性浆细胞样树突状细胞数量的增加，B细胞耗竭小鼠主动脉中调节性T细胞数量增多，而促炎基因的表达降低。在共培养模型中，B细胞的存在显著降低了吲哚2,3-双加氧酶阳性浆细胞样树突状细胞的数量，但不影响浆细胞样树突状细胞总数。
目前的结果表明，B细胞耗竭可保护小鼠免受实验性AAA形成，并促进主动脉中免疫抑制环境的出现。
