Vascular Biology and Atherosclerosis, Baker Heart and Diabetes Institute, 75 Commercial Road, Melbourne, VIC 3004, Australia.
Centre for Inflammatory Diseases, Department of Medicine, Medical Centre, 246 Clayton Road, Clayton, VIC 3168, Australia.
Eur Heart J. 2021 Mar 1;42(9):938-947. doi: 10.1093/eurheartj/ehaa995.
Myocardial infarction (MI) accelerates atherosclerosis and greatly increases the risk of recurrent cardiovascular events for many years, in particular, strokes and MIs. Because B cell-derived autoantibodies produced in response to MI also persist for years, we investigated the role of B cells in adaptive immune responses to MI.
We used an apolipoprotein-E-deficient (ApoE-/-) mouse model of MI-accelerated atherosclerosis to assess the importance of B cells. One week after inducing MI in atherosclerotic mice, we depleted B cells using an anti-CD20 antibody. This treatment prevented subsequent immunoglobulin G accumulation in plaques and MI-induced accelerated atherosclerosis. In gain of function experiments, we purified spleen B cells from mice 1 week after inducing MI and transferred these cells into atherosclerotic ApoE-/- mice, which greatly increased immunoglobulin G (IgG) accumulation in plaque and accelerated atherosclerosis. These B cells expressed many cytokines that promote humoural immunity and in addition, they formed germinal centres within the spleen where they differentiated into antibody-producing plasma cells. Specifically deleting Blimp-1 in B cells, the transcriptional regulator that drives their terminal differentiation into antibody-producing plasma cells prevented MI-accelerated atherosclerosis. Alarmins released from infarcted hearts were responsible for activating B cells via toll-like receptors and deleting MyD88, the canonical adaptor protein for inflammatory signalling downstream of toll-like receptors, prevented B-cell activation and MI-accelerated atherosclerosis.
Our data implicate early B-cell activation and autoantibodies as a central cause for accelerated atherosclerosis post-MI and identifies novel therapeutic strategies towards preventing recurrent cardiovascular events such as MI and stroke.
心肌梗死（MI）会加速动脉粥样硬化，并在多年内大大增加再次发生心血管事件的风险，特别是中风和 MI。由于 MI 引发的 B 细胞源性自身抗体也会持续多年，我们研究了 B 细胞在 MI 适应性免疫反应中的作用。
我们使用载脂蛋白 E 缺陷（ApoE-/-）小鼠的 MI 加速动脉粥样硬化模型来评估 B 细胞的重要性。在动脉粥样硬化小鼠发生 MI 1 周后，我们使用抗 CD20 抗体耗竭 B 细胞。这种治疗方法可防止随后在斑块中积累免疫球蛋白 G 并阻止 MI 诱导的加速动脉粥样硬化。在功能获得实验中，我们从 MI 诱导后 1 周的小鼠中纯化脾 B 细胞，并将这些细胞转移到动脉粥样硬化的 ApoE-/-小鼠中，这大大增加了斑块中的免疫球蛋白 G（IgG）积累并加速了动脉粥样硬化。这些 B 细胞表达了许多促进体液免疫的细胞因子，此外，它们在脾内形成生发中心，在那里分化为产生抗体的浆细胞。具体来说，在 B 细胞中特异性删除 Blimp-1，这是驱动其终末分化为产生抗体的浆细胞的转录调节剂，可防止 MI 加速的动脉粥样硬化。从梗死心脏释放的警报素通过 Toll 样受体激活 B 细胞，删除 Toll 样受体下游炎症信号的经典衔接蛋白 MyD88，可防止 B 细胞激活和 MI 加速的动脉粥样硬化。
我们的数据表明，MI 后早期 B 细胞激活和自身抗体是加速动脉粥样硬化的核心原因，并确定了预防 MI 和中风等复发性心血管事件的新治疗策略。
