Impaired Fas-induced apoptosis of T lymphocytes in patients with abdominal aortic aneurysms

ObjectiveHomeostasis of the immune system is maintained by apoptotic elimination of potentially pathogenic autoreactive lymphocytes. Emerging evidence shows that Fas-mediated apoptosis is impaired in activated lymphocytes from patients with autoimmune disease. The aim of this work was to assess apoptosis mediated by the cell death receptor Fas in peripheral T lymphocytes from patients with abdominal aortic aneurysms (AAA).MethodsThe apoptotic pathway was triggered by anti-Fas monoclonal antibodies in cultured and activated peripheral T-cell lines from 20 AAA patients with control groups of 15 patients with aortic atherosclerotic occlusive disease (AOD) and 25 healthy individuals. Cell survival and death (apoptosis) rate were assessed.ResultsCross-linkage of Fas receptor exerted a strong apoptotic response on T cells from AOD patients and healthy controls, but a much less pronounced effect on T cells from AAA patients. The evaluation of cell survival rate showed a significantly higher percentage in AAA group (98.9% ± 10.3%) than in the AOD subjects (58.9% ± 15.2%) or the healthy group (59.4% ± 12.9%; P < .001). Apoptosis assessment by annexin V and propidium iodide staining and flow cytometry showed similar results. The defect in AAA group was not due to decreased Fas expression, since Fas was expressed at normal levels. Moreover, it specifically involved the Fas system because cell death was induced in the normal way by methylprednisolone. Complementary DNA sequencing identified no causal Fas gene mutation, but two silent single nucleotide polymorphisms with higher frequency were found in the AAA group.ConclusionsFas-induced apoptosis in activated T cells from AAA patients is impaired. This may disturb the normal down-regulation of the immune response and thus provide a new insight into possible mechanisms and routes in the pathogenesis of AAA.

Clinical RelevanceAbdominal aortic aneurysm (AAA) represents a common degenerative vascular condition associated with progressive aortic dilation and life-threatening implications. Despite surgical advances, the recent interest in developing new therapies for treating small, asymptomatic, non-operation-indicated AAA has led to greater efforts to investigate and define the cellular and molecular nature of aneurysm degeneration. So far, the clinical aspects of the immune response in AAA remain limited. This study demonstrated an impaired Fas-induced apoptosis of T lymphocytes in AAA patients, suggesting a deficiency of the immune response–silencing system. This deficiency may be a novel factor involved in the development of aortic aneurysm-specific autoimmunity. Thus, our results are important to establish a role for autoimmunity in the etiology of AAA and are important for the further strategy to develop new therapies for AAA.