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Abstract
BackgroundCardiovascular disease is a leading cause of death in ANCA-associated vasculitis (AAV). An expansion of CD4+CD28null T cells is seen mainly in cytomegalovirus (CMV)-seropositive individuals and has been linked to increased cardiovascular disease risk in other conditions. The aims of this study were to phenotype CD4+CD28null T cells in AAV with respect to their pro-inflammatory capacity and ability to target and damage the endothelium and to investigate their relationship to arterial stiffness, a marker of cardiovascular mortality.MethodsCD4+CD28null T cells were phenotyped in 53 CMV-seropositive AAV patients in stable remission and 30 age-matched CMV-seropositive healthy volunteers by flow cytometry following stimulation with CMV lysate. The expression of endothelial homing markers and cytotoxic molecules was evaluated in unstimulated CD4+CD28null T cells. Arterial stiffness was measured by carotid-to-femoral pulse wave velocity (PWV) in patients with AAV.ResultsCD4+CD28null T cells were CMV-specific and expressed a T helper 1 (Th1) phenotype with high levels of interferon-gamma (IFN-γ) and tumour necrosis factor-alpha (TNF-α) secretion. They also co-expressed the endothelial homing markers CX3CR1, CD49d and CD11b and cytotoxic molecules perforin and granzyme B. CD4+CD28null T cells were phenotypically similar in patients with AAV and healthy volunteers but their proportion was almost twice as high in patients with AAV (11.3% [3.7–19.7] versus 6.7 [2.4–8.8]; P = 0.022). The size of the CD4+CD28null T-cell subset was independently linked to increased PWV in AAV (0.66 m/s increase per 10% increase in CD4+CD28null cells, 95% confidence interval 0.13–1.19; P = 0.016).ConclusionThe host cellular immune response to CMV leads to the expansion of cytotoxic CD4+CD28null T cells that express endothelial homing markers and are independently linked to increased arterial stiffness, a marker of cardiovascular mortality. Suppression of CMV in AAV may be of therapeutic value in reducing the risk of cardiovascular disease.
Highlights
Cardiovascular disease is a leading cause of death in Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV)
The aims of this study were to characterise the phenotype of CD4+CD28null T cells in AAV, with respect to their pro-inflammatory capacity and ability to target and damage the endothelium, and to determine whether expansion of this cell subset is associated with arterial stiffness, a marker of cardiovascular mortality
The percentage of CD4+CD28null T cells was strongly correlated with the total CMV-specific CD4+ response, indicating that the size of the CD4+CD28null T-cell accumulation is a good measure of the impact of CMV infection on the CD4 compartment in this population
Summary
Cardiovascular disease is a leading cause of death in ANCA-associated vasculitis (AAV). The relationship between inflammation and cardiovascular disease (CVD) is evident in patients with rheumatic disorders such as rheumatoid arthritis, systemic lupus erythematosus and ANCA-associated vasculitis (AAV), in which CVD is a leading cause of death [3,4,5]. Traditional risk factors do not fully explain the increased incidence of CVD seen in these conditions [6], and it is thought that inflammation and immunopathology may accelerate atherosclerosis [7]. Several studies in patients with inflammatory disorders such as rheumatoid arthritis have demonstrated that expansion of CD4+CD28null T cells is independently associated with increased incidence of CVD and cardiovascular mortality [15,16,17,18,19]
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