The host cellular immune response to cytomegalovirus targets the endothelium and is associated with increased arterial stiffness in ANCA-associated vasculitis

Research output: Contribution to journalArticle

Authors

  • Lovesh Dyall
  • Phoebe Sharp
  • Lucy Powley
  • Serena Johal
  • Jessica Bowen
  • Peter Nightingale
  • Charles Ferro

External organisations

  • University Hospitals Birmingham NHS Foundation Trust
  • Institute of Translational Medicine Birmingham (ITM)

Abstract

Background: Cardiovascular disease is a leading cause of death in ANCA-associated vasculitis (AAV). An expansion of CD4+CD28null T-cells is mainly seen 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 in respect of their proinflammatory capacity and ability to target and damage the endothelium, and 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 AAV patients.


Results: CD4+CD28null T-cells were CMV-specific and expressed a Th1 phenotype with high levels of IFN- and TNF- 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 within AAV and healthy volunteers but their proportion was almost twice as high in AAV patients (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 (0.66m/s increase per 10% increase in CD4+CD28null cells [95%CI0.13–1.19]; 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.

Details

Original languageEnglish
Article number194
Pages (from-to)194
JournalArthritis Research & Therapy
Volume20
Issue number1
Publication statusPublished - 29 Aug 2018

Keywords

  • ANCA, vasculitis, cytomegalovirus, inflammation, t-cells, arterial stiffness, cardiovascular disease