Abstract-Abdominal aortic aneurysm (AAA) is histologically characterized by medial degeneration and various degrees of chronic adventitial inflammation, although the mechanisms for progression of aneurysm are poorly understood. In the present study, we carried out histological study of AAA tissues of patients, and interventional animal and cell culture experiments to investigate a role of mast cells in the pathogenesis of AAA. The number of mast cells was found to increase in the outer media or adventitia of human AAA, showing a positive correlation between the cell number and the AAA diameter. Aneurysmal dilatation of the aorta was seen in the control (ϩ/ϩ) rats following periaortic application of calcium chloride (CaCl 2 ) treatment but not in the mast cell-deficient mutant Ws/Ws rats. The AAA formation was accompanied by accumulation of mast cells, T lymphocytes and by activated matrix metalloproteinase 9, reduced elastin levels and augmented angiogenesis in the aortic tissue, but these changes were much less in the Ws/Ws rats than in the controls. Similarly, mast cells were accumulated and activated at the adventitia of aneurysmal aorta in the apolipoprotein E-deficient mice. The pharmacological intervention with the tranilast, an inhibitor of mast cell degranulation, attenuated AAA development in these rodent models. In the cell culture experiment, a mast cell directly augmented matrix metalloproteinase 9 activity produced by the monocyte/macrophage. Collectively, these data suggest that adventitial mast cells play a critical role in the progression of AAA. Key Words: adventitia Ⅲ inflammation Ⅲ mast cell Ⅲ matrix metalloproteinase Ⅲ aneurysm A bdominal aortic aneurysm (AAA), a relatively common disorder among elderly people, is pathologically characterized by atherosclerosis of the intima and disruption or attenuation of the elastic media with various degrees of adventitial inflammatory infiltration. 1,2 Because approximately 4% of adults older than 65 years harbor AAA, it is among the leading 15 causes of death in elderly persons in the United States. 3 Although substantial efforts have been made to clarify the mechanism of development of AAA, there is currently no effective method to inhibit enlargement of AAA. Repair surgery is necessary to prevent rupture in patients with progressively enlarging AAA, whereas the operative risk is often relatively high because of the other complications resulting from aging.Recent reports suggest that chronic inflammation of the aortic wall and progressive degradation of extracellular matrix proteins are involved in the development, progression, or rupture of AAA. 2,4 -8 As a component of the immune system, mast cells play a critical role in defending hosts against pathogens by releasing a number of immunoregulatory mediators. 9 These cells have also been shown to initiate the inflammatory response by releasing proinflammatory cytokines, growth factors, angiogenic mediators, and proteases, 10 as well as by recruiting other inflammatory cells, such as neutrophils, macrop...
Intestinal intraepithelial lymphocytes (IEL) bearing TCRγδ represent a major T cell population in the murine intestine. However, the role of γδ IEL in inflammatory bowel diseases (IBD) remains controversial. In this study, we show that γδ IEL is an important protective T cell population against IBD. γδ T cell-deficient (Cδ−/−) mice developed spontaneous colitis with age and showed high susceptibility to Th1-type 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis at a young age. Transfer of γδ IEL to Cδ−/− mice ameliorated TNBS-induced colitis, which correlated with decrease of IFN-γ and TNF-α production and an increase of TGF-β production by IEL. Furthermore, a high level of IL-15, which inhibits activation-induced cell death to terminate inflammation, was expressed more in intestinal epithelial cells (EC) from TNBS-treated Cδ−/− mice than in those from wild-type mice. EC from wild-type mice significantly suppressed the IFN-γ production of IEL from TNBS-treated Cδ−/− mice, whereas EC from TNBS-treated Cδ−/− mice did not. These data indicate that γδ IEL play important roles in controlling IBD by regulating mucosal T cell activation cooperated with EC function. Our study suggests that enhancement of regulatory γδ T cell activity is a possible new cell therapy for colitis.
Multiple SARS-CoV-2 variants have mutations in the spike receptor binding domain (RBD) with potential to evade neutralizing antibody. In particular, the Beta and Omicron variants escape from antibody neutralizing activity in those who received two doses of BNT162b2 mRNA vaccine. Nonetheless, boosting with a third vaccine dose or by breakthrough infection improves the overall breadth of the neutralizing antibodies, but the mechanism remains unclear. Here, we longitudinally profiled the cellular composition of RBD-binding memory B cell subsets and their antibody binding and neutralizing activity against SARS-CoV-2 variants after the second dose of mRNA vaccine. Two doses of the mRNA vaccine elicited plasma neutralizing antibodies with a limited activity against Beta and Omicron but induced an expanded antibody breadth overtime, up to 4.9 months after vaccination. In contrast, more than one-third of RBD-binding IgG + memory B cells with a resting phenotype initially bound the Beta and Omicron variants and steadily increased the B cell receptor breadth overtime. As a result, a fraction of the resting memory B cell subset secreted Beta and Omicron-neutralizing antibody when stimulated in vitro. The neutralizing breadth of the resting memory B cell subset helps us understand the prominent recall of Omicron-neutralizing antibodies after an additional booster or breakthrough infection in fully vaccinated individuals.
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