B cells and immunoglobulins promotes aortic dissection in mice

Abstract

Abstract Background Aortic dissection (AD) is a devastating aortic disease with high mortality, for which molecular pathogenesis is largely unknown. Recent studies have highlighted the importance of inflammatory response in AD. We have reported that B cells and immunoglobulins promote inflammatory response in the aorta and are involved in the pathogenesis of abdominal aortic aneurysm, another form of aortic disease. However, it is not known whether and how B cells participate in AD development or progression. 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 genetically deficient for B cells and immunoglobulins, BAPN+AngII induced significantly less severe AD compared to that in wild type. 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. Transcriptome analysis revealed that IgG administration enhanced the expression of inflammation-related genes in muMT mice before BAPN+AngII infusion, indicating that IgG increased susceptibility to AD. Immunohistochemistry of aorta confirmed exogenous IgG deposition, colocalized with C3, which is known to contribute to innate immunity. Conclusion These findings demonstrated B cells and IgG are critically involved in the destructive inflammation of AD pathogenesis. Further, the aortic deposition of IgG and C3, a part of the components of innate immunity, precedes the development of AD. These findings may provide the therapeutic opportunities to AD.