The role of B cells and IgG in aortic dissection

Abstract

Abstract Background Aortic dissection (AD) is one of the destructive and fatal aortic diseases, for which molecular pathogenesis is largely unknown. Recent studies have highlighted the importance of inflammatory response in AD. We and others reported that B cells and immunoglobulins participate in pathogenesis of abdominal aortic aneurysm, another form of aortic destructive disease, by promoting inflammatory response. It is not known whether and how B cells participate in AD pathogenesis. Methods and results Immunohistochemical staining of human AD tissue revealed that B cells were clustered together with T cells, macrophages and neutrophils at the entry site of AD with medial disruption. B cell cluster was also observed at the site of medial disruption in mouse model of AD that was induced by continuous infusion of beta-aminopropionitrile and angiotensin II (BAPN+AngII). In muMT mouse, which is deficient for B cells and immunoglobulins due to genetic deletion of immunoglobulin heavy chain, BAPN+AngII induced significantly less severe AD compared to that in wild type. Depositions of IgG and fibrinogen, one of the endogenous antigen for natural IgG, were observed after BAPN+AngII infusion before and after AD development in wild type mice. Deposition of fibrinogen was also observed in mMT mice after BAPN+AngII infusion. The rate of aortic rupture and sudden death was approximately 42% in wild type mice, while that in muMT mouse was 12% (P<0.05). Administration of mouse normal polyclonal IgG to muMT mice resulted in dramatic increase in aortic rupture and sudden death, starting at day 7 of BAPN+AngII infusion, and reaching 69% of rupture rate, indicating the critical role of IgG in AD. Conclusion These findings demonstrated B cells and IgG are critically involved in the destructive inflammation of AD pathogenesis. Further, the deposition of fibrinogen, one of the targets of natural IgG, precedes the development of AD. Our findings may provide the conceptual foundation of the diagnostic strategy for on-going tissue destruction and for the therapeutic opportunities to intervene the progressive tissue destruction in AD. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): The Japan Society for the Promotion of Science