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The host cellular immune response to cytomegalovirus targets the endothelium and is associated with increased arterial stiffness in ANCA-associated vasculitis.
Arthritis Research & Therapy 2018 August 30
BACKGROUND: Cardiovascular 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.
METHODS: CD4+ 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.
RESULTS: CD4+ 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).
CONCLUSION: The 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.
METHODS: CD4+ 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.
RESULTS: CD4+ 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).
CONCLUSION: The 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.
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