Involvement of B cells, immunoglobulins, and Syk in the pathogenesis of abdominal aortic aneurysm II

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 Mmp9. Administration of exogenous immunoglobulins restored the blunted Syk activation and AAA development in muMT mice. Additionally, exogenous immunoglobulins induced IL-6 and MMP9 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. We used wild type (WT) or B cell-deficient (uMT) mice to obtain this data set of mouse aortic transcriptome. Mice were without (pre) or with periaortic application of 0.5 M CaCl2 (Ca) to induce abdominal aortic aneurysm. Aortic samples were obtained 7 days (day7) or 42 days (day42) after the CaCl2 challenge. Sham operation was performed with periaortic application of physiological saline instead of CaCl2. Aortic tissues were homogenized in TRIzol (Invitrogen) and total RNA was isolated with RNeasy (Qiagen). Transcriptome analyses were performed using the SurePrint G3 Mouse Gene Expression 8x60K Microarray Kit (Agilent).