Myocardial B cells are a subset of circulating lymphocytes with delayed transit through the heart

Abstract

+ cells, suggesting that the latter population is not derived from BM progenitors, thus disproving our initial hypothesis. To confirm these results and to eliminate potential confounding effects associated with radiation-induced damage to the heart, we repeated the experiment by performing limited BM ablation through focused irradiation of the femurs. This altered irradiation strategy did not qualitatively alter the results and confirmed that most myocardial B cells are BM derived (Supplemental Figure 1, A-C; supplemental material available online with this article; https://doi.org/10.1172/jci.insight.134700DS1).Myocardial B cells recirculate between the heart, blood, and spleen. The investigation of the origin of myocardial B cells described above did not explain the existence of a large pool of myocardial B cells. Therefore, we formulated a different hypothesis. Since several populations of resident lymphocytes have been described (14), and the heart harbors resident leukocyte populations (15), we hypothesized that myocardial B cells might represent a population of tissue-resident B lymphocytes. To test this hypothesis, we conjoined CD45.1 and CD45.2 mice via parabiosis and analyzed myocardial B cell chimerism 3 weeks after surgery. The results indicated that both CD19 + CD11b + and CD19 + CD11bcells displayed approximately 50% chimerism after 3 weeks of parabiosis ( Figure 1C), suggesting that the vast majority of myocardial B cells have immediate access to the circulation and freely recirculate between conjoined animals. To confirm this result and investigate the trafficking dynamics of myocardial B cells, we performed heterotopic heart transplant. We transplanted the heart of a CD45.2 mouse into the abdomen of a CD45.1 mouse so that both hearts were connected to the vasculature and perfused at the same time. Untransplanted hearts from CD45.1 and CD45.2 mice displayed clear populations of CD45.1 + B cells and CD45.2 + B cells, respectively ( Figure 1D). The transplant recipient mice were sacrificed 4 days after surgery, and the recipient and transplanted hearts were harvested and analyzed. Virtually all donor-derived B cells in the transplanted heart were replaced by recipient-derived B cells ( Figure 1D). Only a very small population of donor-derived cells remained in the transplanted heart ( Figure 1D). A small population of donor-derived cells was detected in the endogenous heart of the recipient mouse ( Figure 1D), whereas the vast majority of cells transplanted with the donor heart were not observed in the myocardial tissue of the recipient mouse. This result confirmed that the vast majority of myocardial B cells are not tissue-resident cells and also suggested that myocardial B cells can migrate from the heart to other organs.To identify where myocardial B cells traffic after leaving the heart, we analyzed the spleen and blood of mice that received the heart transplant. The results showed that, similarly to the myocardium, the spleen and blood of recipient mice also contained a small but clearly detecte...

The role of B cells in heart failure and implications for future immunomodulatory treatment strategies

“…[40][41][42] There, B cells are involved in modulating the myocardial immune cell traffic as well as left ventricular structure and function. 42 Similarly, in patients with failing heart tissue, B cells are present in the intravasculature and in close contact with the endothelium. 42 Following cardiac damage, damage-associated molecular patterns (DAMPs) are released from damaged cardiac cells, interacting with antigen-presenting cells such as B cells.…”

“…42 Similarly, in patients with failing heart tissue, B cells are present in the intravasculature and in close contact with the endothelium. 42 Following cardiac damage, damage-associated molecular patterns (DAMPs) are released from damaged cardiac cells, interacting with antigen-presenting cells such as B cells. 2,43 Therefore, B cells have an important role in cardiac tissue and can undergo DAMP-mediated activation, which in turn activates T cells, overall contributing to the pro-inflammatory milieu.…”

“…40 In this mouse model of HF, it was previously demonstrated that the splenic plasma cells (CD19 +-CD138 + ) and activated B cells (CD19 + CD86 + ) are increased, 67 which could migrate to the heart. 42 Activated B cell secretes cytokines and chemokines that may be directly involved in pathways that lead to adverse cardiac remodelling such as increased recruitment of monocytes, higher differentiation of pro-fibrotic macrophages, and increased expression of TGFβ, collagen-I, and IL-1β by fibroblast and macrophages. 65,67 Activated B cells recruited inflammatory monocytes (Ly6C + ) to the myocardium in a CCL7-dependent fashion contributing to adverse ventricular remodelling 65 that is impaired by B cell-activating factor (BAFF) neutralization, which promotes B-cell depletion.…”

What Is the Role of the Inflammation in the Pathogenesis of Heart Failure?

“…The risk of chronic inflammation to become systemic is also closely related to the induction of an autoimmune scenario, where the initial damage of the tissue is associated with the presentation of an antigen or a similar self-antigen, thereby initiating the damage modulated by CD4 cells and promoted by CD8 cytotoxic cells by its perforin, granzyme, and FASmediated apoptosis induction mechanism. Alongside the effects of T cells, B cells have an active and critical role in the development of HF remodeling and dysfunction [7,[17][18][19], either by modulating inflammatory cell recruitment [16,18] or by increasing the inflammatory response through the production of autoantibodies [7] and fibrosis [19]. Moreover, interfering T cell co-stimulation by antigen presenting cell (dendritic cell, macrophages, and B cells) attenuates heart dysfunction mediated by IL-10-producing B cells [69].…”

“…Thus, the fact that these mechanisms promote inflammation and that inflammation leads to HF indicates that the immune system plays a central role in HF progression. Moreover, recent studies indicate that cells of the immune system not only contribute to the pathology, but are also key regulators of heart function [15,16], highlighting the role of immune system cells in heart homeostasis and the ability to respond and become activated.…”