Abstract 21236: Novel Immune Regulatory Defects Contribute to Abdominal Aortic Aneurysm Formation

Abstract

Abdominal aortic aneurysm (AAA) is a significant and serious health problem with an incidence as high as 9% and is associated with 15,000 deaths each year in the U.S. Recently AAA has increasingly been considered to be an autoimmune disease, where a pro-inflammatory cascade with cytotoxic and proteolytic features results aortic wall degradation and aneurysm formation, but the underlying causes of this imbalance remain unknown. Regulatory T cells prevent both the activation and effector function of reactive T cells sensitized to auto-antigens. Critical in this process are Type 1 regulatory T-cells (Tr1) which are antigen-specific and identified by expression of CD49b and lymphocyte activation gene 3 (LAG-3). Tr1 cells exhibit strong immunosuppressive activity and are able to restore tolerance in several immune-mediated diseases, through the secretion of high amounts of IL-10. Most importantly IL-10 is essential in the induction as well as immune suppressor activity of Tr1 cells. We found that AAA patients have a decreased number of Tr1 cells compared to risk-factor matched controls, and that those cells are functionally defective, producing reduced levels of IL-10 and having impaired immune suppression abilities. Moreover, naive CD4+ T cells from AAA patients were resistant to Tr1 induction in vitro , and AAA plasma likewise impaired the induction of Tr1 cells from healthy CD4+ T cells. Plasma miRNA analysis revealed a profile of expression changes in AAA patients that inhibit IL-10 expression. Together, these results suggest a critical defect of Tr1 cells in AAA, driven by impaired IL-10 expression, which could contribute to AAA disease pathology.