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Involvement of B Cells, Immunoglobulins, and Syk in the Pathogenesis of Abdominal Aortic Aneurysm.

ABSTRACT: BACKGROUND:Abdominal aortic aneurysm (AAA) is a potentially life-threatening disease that is common in older individuals. Currently, therapeutic options are limited to surgical interventions. Although it has long been known that AAA tissue is enriched in B cells and immunoglobulins, their involvement in AAA pathogenesis remains controversial. METHODS AND RESULTS:We investigated the role of B cells and immunoglobulins in a murine model of AAA, induced with a periaortic application of CaCl2, and in human AAA. Both human and mouse AAA tissue showed B-cell infiltration. Mouse AAA tissue showed deposition of IgG and activation of Syk, a key molecule in B-cell activation and immunoglobulin function, which were localized to infiltrating cells including B cells and macrophages. B-cell-deficient muMT mice showed suppression of AAA development that was associated with reduced activation of Syk and less expression of matrix metalloproteinase-9. Administration of exogenous immunoglobulins restored the blunted Syk activation and AAA development in muMT mice. Additionally, exogenous immunoglobulins induced interleukin-6 and metalloproteinase-9 secretions in human AAA tissue cultures. Furthermore, administration of R788, a specific Syk inhibitor, suppressed AAA expansion, reduced inflammatory response, and reduced immunoglobulin deposition in AAA tissue. CONCLUSIONS:From these results, we concluded that B cells and immunoglobulins participated in AAA pathogenesis by promoting inflammatory and tissue-destructive activities. Finally, we identified Syk as a potential therapeutic target.

SUBMITTER: Furusho A

PROVIDER: S-EPMC5907549 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Involvement of B Cells, Immunoglobulins, and Syk in the Pathogenesis of Abdominal Aortic Aneurysm.

Furusho Aya A Aoki Hiroki H Ohno-Urabe Satoko S Nishihara Michihide M Hirakata Saki S Nishida Norifumi N Ito Sohei S Hayashi Makiko M Imaizumi Tsutomu T Hiromatsu Shinichi S Akashi Hidetoshi H Tanaka Hiroyuki H Fukumoto Yoshihiro Y

Journal of the American Heart Association 20180315 6

<h4>Background</h4>Abdominal aortic aneurysm (AAA) is a potentially life-threatening disease that is common in older individuals. Currently, therapeutic options are limited to surgical interventions. Although it has long been known that AAA tissue is enriched in B cells and immunoglobulins, their involvement in AAA pathogenesis remains controversial.<h4>Methods and results</h4>We investigated the role of B cells and immunoglobulins in a murine model of AAA, induced with a periaortic application ...[more]

PMID: 29545260

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Project description:BackgroundAbdominal aortic aneurysms (AAAs) represent a complex multifactorial hemodynamic, thrombotic, and inflammatory process that can ultimately result in aortic rupture and death. Despite improved screening and surgical management of AAAs, the mortality rates have remained high after rupture, and little progress has occurred in the development of nonoperative treatments. Intraluminal thrombus (ILT) is present in most AAAs and might be involved in AAA pathogenesis. The present review examined the latest clinical and experimental evidence for possible involvement of the ILT in AAA growth and rupture.MethodsA literature review was performed after a search of the PubMed database from 2012 to June 2020 using the terms "abdominal aortic aneurysm" and "intraluminal thrombus."ResultsThe structure, composition, and hemodynamics of ILT formation and propagation were reviewed in relation to the hemostatic and proteolytic factors favoring ILT deposition. The potential effects of the ILT on AAA wall degeneration and rupture, including a review of the current controversies regarding the position, thickness, and composition of ILT, are presented. Although initially potentially protective against increased wall stress, increasing evidence has shown that an increased volume and greater age of the ILT have direct detrimental effects on aortic wall integrity, which might predispose to an increased rupture risk.ConclusionsILT does not appear to be an innocent bystander in AAA pathophysiology. However, its exact role remains elusive and controversial. Despite computational evidence of a possible protective role of the ILT in reducing wall stress, increasing evidence has shown that the ILT promotes AAA wall degeneration in humans and in animal models. Further research, with large animal models and with more chronic ILT is crucial for a better understanding of the role of the ILT in AAAs and for the potential development of targeted therapies to slow or halt AAA progression.

Dataset Information

Involvement of B Cells, Immunoglobulins, and Syk in the Pathogenesis of Abdominal Aortic Aneurysm.

Publications

Involvement of B Cells, Immunoglobulins, and Syk in the Pathogenesis of Abdominal Aortic Aneurysm.

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