High Prevalence of Circulating CD4⁺CD28⁻T-Cells in Patients With Small Abdominal Aortic Aneurysms

Abstract

Objective-To assess the possible role of proinflammatory CD28Ϫ T cells in abdominal aortic aneurysms (AAAs). Animal studies and human tissue studies suggest a role for interferon (IFN)-␥-producing T cells in the development and progression of AAAs. Methods and Results-Fluorescence-activated cells sorter analysis of peripheral blood samples and measurement of AAA size using sonography were performed in 101 AAA patients and 38 healthy controls. Key Words: aortic disease Ⅲ aneurysms Ⅲ leukocytes Ⅲ immune system Ⅲ human A bdominal aortic aneurysm (AAA) is a common disease with a prevalence of 3% of individuals aged 60 years and older and is a potentially lethal disorder causing Ϸ15 000 deaths annually in the United States. 1 Recent human tissue studies and animal models have led now to a paradigm shift in the pathogenetic concept of AAAs. Rather than a simple degenerative process, the majority of AAAs has proven to be a complex and dynamic remodeling process. In brief, studies of human AAA tissues have identified extensive inflammatory infiltrates in both the media and the adventitia, 2 leading to an increased expression of proinflammatory cytokines and C-reactive protein (CRP) in aneurysmal tissue. [3][4][5] The presence of vascular-associated lymphoid tissue (VALT) with lymphoid follicles and lymph node-like structures in the adventitia of AAAs suggests a role for immunocompetent and antigen presenting cells not only in atherosclerosis 6 but also in AAA disease. 2 The role for T cells has been further supported by immunogenetic findings with associations between AAA and human leukocyte antigen class II molecules. 7 Infiltration of the adventitia usually occurs together with medial thinning. This inflammatory process triggers the production of metalloproteinases and apoptosis of medial smooth muscle cells thus explaining the disruption of the orderly lamellar structure in aortic aneurysms.Recently, a subgroup of proinflammatory T cells has been identified in patients with immune-mediated disorders including rheumatoid arthritis, 8 -9 ankylosing spondylitis, 10 multiple sclerosis, 11 Wegener granulomatosis, 12 and unstable angina, 13 which lack the costimulatory molecule CD28 on their surface and are considered as markers for chronic inflammation and early aging. 14 Under these circumstances the CD28 Ϫ T cells are part of the CD4 ϩ as well as the CD8 ϩ T cell compartment, persist over years, and include most of the oligoclonally expanded T cells. Phenotypically, CD4 ϩ CD28 Ϫ T cells from rheumatoid arthritis and ankylosing spondylitis patients and CD8 ϩ CD28 Ϫ T cells from aged persons, rheumatoid arthritis, and melanoma patients share the expression of various natural killer (NK) cell receptors and lack the expression of the lymphocyte marker CD7. 9,15-16 Functionally these T cells are capable to release large amounts of interferon (IFN)-␥, perforin, and granzyme B, providing them with the possibility to lyse target cells. 17 In the pathogenesis of coronary arteriosclerosis, the critical role of IFN-␥ was alread...

Deficient CD4 + CD25 + T Regulatory Cell Function in Patients With Abdominal Aortic Aneurysms

“…7 The process of apoptosis is important both for the elimination of autoreactive lymphocytes and the downregulation of appropriately generated immune responses. Thus these data suggest a deficiency of the immune response-silencing system where potentially pathogenic, autoreactive T cells have the capacity to survive and proliferate in AAA patients and induce a process of autoimmune injury related to the dilation of the abdominal aorta.…”

Aortic Aneurysms

“…78 In human AAA, high levels of IFN-␥ transcripts, but not of interleukin-4, have been reported. 51,76,77 Increased proportions of IFN-␥-producing CD4 ϩ CD28 Ϫ T cells (lacking the costimulatory molecule CD28) have been reported both in AAA tissue and in peripheral blood of patients with AAA. 76 These studies demonstrate the critical role of T cells and IFN-␥ in the pathogenesis of AAA.…”

“…51,76,77 Increased proportions of IFN-␥-producing CD4 ϩ CD28 Ϫ T cells (lacking the costimulatory molecule CD28) have been reported both in AAA tissue and in peripheral blood of patients with AAA. 76 These studies demonstrate the critical role of T cells and IFN-␥ in the pathogenesis of AAA. The overexpression of the transcription factor T-bet taken in connection with the absence of significant expression of the GATA-3 factor suggests that a Th1-type response predominates in AAAs.…”

CD16+Monocyte Subsets Are Increased in Large Abdominal Aortic Aneurysms and Are Differentially Related with Circulating and Cell-Associated Biochemical and Inflammatory Biomarkers

“…In addition to neutrophils [7] and lymphocytes [8], monocytes may play a role for the progression of damage in AAA by migrating through the endothelium and differentiating into tissue macrophages.…”