Center for Systems Biology, Massachusetts General Hospital, Boston (I.H., I.T., L.M.S.G., C.S.R., G.F.W., Y.I., C.W., H.Y.L., M.N., R.W., F.K.S.); Department of Internal Medicine VI, Infectious Diseases, Immunology Rheumatology, Pneumology, University Hospital of Innsbruck, Innsbruck, Austria (I.T.); Toronto General Research Institute, University Health Network, Toronto, ON, Canada (C.S.R., N.D.); Department of Medicine, University of California, San Diego, La Jolla (A.G., J.L.W.); Department of Gastroenterology, Hepatology and Infectious Diseases, University of Duesseldorf, Duesseldorf, Germany (T.A.W.H.); Department of Cardiology and Angiology I, University Heart Center Freiburg, Freiburg, Germany (C.W., A.Z.); Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA (G.K.S., P.L.); Department of Pathology (J.B.) and Division of Vascular Surgery (B.B.R.), Peter Munk Cardiac Centre, Toronto General Hospital, Toronto, ON, Canada; and Department of Systems Biology, Harvard Medical School, Boston, MA (R.W.).
Circulation. 2014 Apr 22;129(16):1677-87. doi: 10.1161/CIRCULATIONAHA.113.006381. Epub 2014 Jan 31.
Atherosclerotic lesions grow via the accumulation of leukocytes and oxidized lipoproteins in the vessel wall. Leukocytes can attenuate or augment atherosclerosis through the release of cytokines, chemokines, and other mediators. Deciphering how leukocytes develop, oppose, and complement each other's function and shape the course of disease can illuminate our understanding of atherosclerosis. Innate response activator (IRA) B cells are a recently described population of granulocyte macrophage colony-stimulating factor-secreting cells of hitherto unknown function in atherosclerosis.
Here, we show that IRA B cells arise during atherosclerosis in mice and humans. In response to a high-cholesterol diet, IRA B cell numbers increase preferentially in secondary lymphoid organs via Myd88-dependent signaling. Mixed chimeric mice lacking B cell-derived granulocyte macrophage colony-stimulating factor develop smaller lesions with fewer macrophages and effector T cells. Mechanistically, IRA B cells promote the expansion of classic dendritic cells, which then generate interferon γ-producing T helper-1 cells. This IRA B cell-dependent T helper-1 skewing manifests in an IgG1-to-IgG2c isotype switch in the immunoglobulin response against oxidized lipoproteins.
Granulocyte macrophage colony-stimulating factor-producing IRA B cells alter adaptive immune processes and shift the leukocyte response toward a T helper-1-associated milieu that aggravates atherosclerosis.
动脉粥样硬化病变通过血管壁中白细胞和氧化脂蛋白的积累而发展。白细胞可以通过释放细胞因子、趋化因子和其他介质来减轻或加剧动脉粥样硬化。了解白细胞如何发展、对抗和补充彼此的功能并塑造疾病进程，可以加深我们对动脉粥样硬化的理解。先天反应激活（IRA）B 细胞是最近描述的一种粒细胞巨噬细胞集落刺激因子分泌细胞群体，其在动脉粥样硬化中的功能尚不清楚。
在这里，我们表明 IRA B 细胞在小鼠和人类的动脉粥样硬化中产生。在高胆固醇饮食的刺激下，IRA B 细胞数量通过 Myd88 依赖性信号在次级淋巴器官中优先增加。缺乏 B 细胞衍生的粒细胞巨噬细胞集落刺激因子的混合嵌合小鼠，其病变较小，巨噬细胞和效应 T 细胞较少。从机制上讲，IRA B 细胞促进经典树突状细胞的扩增，然后生成产生干扰素 γ 的 T 辅助 1 细胞。这种 IRA B 细胞依赖性 T 辅助 1 偏倚表现在针对氧化脂蛋白的免疫球蛋白反应中 IgG1 向 IgG2c 的同种型转换。
产生粒细胞巨噬细胞集落刺激因子的 IRA B 细胞改变了适应性免疫过程，并将白细胞反应转向与 T 辅助 1 相关的环境，从而加重了动脉粥样硬化。
