Myocardial-associated B lymphocytes and inflammatory injury

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Project Summary/Abstract: Heart failure is a debilitating disease. A growing body of evidence indicates that inflammation plays an important role in the development and progression of this disease. However, the development of immunomodulatory based treatments for heart failure has, so far, been mostly unsuccessful. The PI recently described a population of circulating B cells that adheres to the myocardial endothelium and found that B cell deficient animals have alterations in cardiac structure and function. Moreover, he found that, in rodents, small molecule-mediated modulation of myocardial B cells improves cardiac function after heart attacks. These findings, together with emerging evidence from other research groups, suggest that B cells might be a powerful target for the development of immunomodulatory therapies to prevent and treat cardiac dysfunction. However, our current understanding of myocardial B cell biology is critically lacking. Heart damage triggers a local and systemic inflammatory response characterized by recruitment of inflammatory cells to the injured heart and rapid changes in the spleen. Currently, it is unclear if and how B cells are recruited into the injured myocardium. Moreover, even though B cells account for about half of all the cells in the spleen, and splenic inflammatory changes induced by heart damage have been shown to play a critical role in the progression of heart failure, it is unclear if B cells play a role in the splenic immune response triggered by heart damage. In addition, it remains unknown whether B cell mediated antigen presentation (that together with antibody production and cytokine secretion is one of the 3 prototypical functions of B cells) plays any role within the inflammatory response triggered by cardiac injury. Finally, at an even more basic level, it is unknown how B cells adhere to the endothelium of the uninjured heart. Here, the PI proposes to fill these gaps in knowledge by testing the hypothesis that circulating B cells bind to the myocardial endothelium through specific adhesion molecules and, in response to myocardial injury, enter the myocardium through a CXCL13-CCR5 dependent process, are activated and proliferate in an antigen independent manner, and recirculate between the heart and the spleen to amplify the inflammatory reaction elicited by cardiac damage via MHC-II mediated antigen presentation. The long-term goal of the PI is to use the knowledge gained to facilitate the development of B cell-targeted therapies for heart failure. The PI has been a pioneer in the study of the interaction between B cells and the heart. He is a junior investigator, but he has mastered all the techniques needed to test this hypothesis, he is supported by several seasoned scientists that are co-investigators or collaborators in this proposal, and works within a highly collaborative research environment focused on excellence and innovation. He, therefore, is aptly qualified to effectively test this innovative hypothesis and address, within the timeline of this proposal, the critical knowledge gaps described.