Heinrichs Margarete, Ashour DiyaaElDin, Siegel Johanna, Büchner Lotte, Wedekind Georg, Heinze Katrin G, Arampatzi Panagiota, Saliba Antoine-Emmanuel, Cochain Clement, Hofmann Ulrich, Frantz Stefan, Campos Ramos Gustavo
Department of Internal Medicine I, University Hospital Würzburg, Am Schwarzenberg 15, 97078 Würzburg, Germany.
Comprehensive Heart Failure Centre, University Hospital Würzburg, Am Schwarzenberg 15, 97078, Würzburg, Germany.
Cardiovasc Res. 2021 Nov 22;117(13):2664-2676. doi: 10.1093/cvr/cvab181.
Recent studies have revealed that B cells and antibodies can influence inflammation and remodelling following a myocardial infarction (MI) and culminating in heart failure-but the mechanisms underlying these observations remain elusive. We therefore conducted in mice a deep phenotyping of the post-MI B-cell responses in infarcted hearts and mediastinal lymph nodes, which drain the myocardium. Thereby, we sought to dissect the mechanisms controlling B-cell mobilization and activity in situ.
Histological, flow cytometry, and single-cell RNA-sequencing (scRNA-seq) analyses revealed a rapid accumulation of diverse B-cell subsets in infarcted murine hearts, paralleled by mild clonal expansion of germinal centre B cells in the mediastinal lymph nodes. The repertoire of cardiac B cells was largely polyclonal and showed no sign of antigen-driven clonal expansion. Instead, it included a distinct subset exclusively found in the heart, herein termed 'heart-associated B cells' (hB) that expressed high levels of Cd69 as an activation marker, C-C-chemokine receptor type 7 (Ccr7), CXC-chemokine receptor type 5 (Cxcr5), and transforming growth factor beta 1 (Tgfb1). This distinct signature was not shared with any other cell population in the healing myocardium. Moreover, we detected a myocardial gradient of CXC-motif chemokine ligand 13 (CXCL13, the ligand of CXCR5) on Days 1 and 5 post-MI. When compared with wild-type controls, mice treated with a neutralizing CXCL13-specific antibody as well as CXCR5-deficient mice showed reduced post-MI infiltration of B cells and reduced local Tgfb1 expression but no differences in contractile function nor myocardial morphology were observed between groups.
Our study reveals that polyclonal B cells showing no sign of antigen-specificity readily infiltrate the heart after MI via the CXCL13-CXCR5 axis and contribute to local TGF-ß1 production. The local B-cell responses are paralleled by mild antigen-driven germinal centre reactions in the mediastinal lymph nodes that might ultimately lead to the production of specific antibodies.
最近的研究表明，B细胞和抗体可影响心肌梗死（MI）后的炎症和重塑，并最终导致心力衰竭，但这些观察结果背后的机制仍不清楚。因此，我们在小鼠中对梗死心脏和引流心肌的纵隔淋巴结中MI后的B细胞反应进行了深入的表型分析。借此，我们试图剖析原位控制B细胞动员和活性的机制。
组织学、流式细胞术和单细胞RNA测序（scRNA-seq）分析显示，梗死小鼠心脏中多种B细胞亚群迅速积累，同时纵隔淋巴结中生发中心B细胞出现轻度克隆扩增。心脏B细胞库在很大程度上是多克隆的，没有抗原驱动的克隆扩增迹象。相反，它包括一个仅在心脏中发现的独特亚群，在此称为“心脏相关B细胞”（hB），其表达高水平的Cd69作为激活标记、C-C趋化因子受体7型（Ccr7）、CXC趋化因子受体5型（Cxcr5）和转化生长因子β1（Tgfb1）。这种独特的特征在愈合心肌中的任何其他细胞群体中都不存在。此外，我们在MI后第1天和第5天检测到心肌中CXC基序趋化因子配体13（CXCL13，CXCR5的配体）的梯度。与野生型对照相比，用中和性CXCL13特异性抗体处理的小鼠以及CXCR5缺陷小鼠在MI后B细胞浸润减少，局部Tgfb1表达降低，但各实验组之间的收缩功能和心肌形态没有差异。
我们的研究表明，无抗原特异性迹象的多克隆B细胞在MI后通过CXCL13-CXCRs轴容易浸润心脏，并促进局部TGF-β1的产生。局部B细胞反应与纵隔淋巴结中轻度抗原驱动的生发中心反应同时发生，这最终可能导致特异性抗体的产生。
