title: Expansions of Cytotoxic CD4+CD28-T Cells Drive Excess Cardiovascular Mortality in Rheumatoid Arthritis and Other Chronic Inflammatory Conditions and Are Triggered by CMV Infection.
abstract: A large proportion of cardiovascular (CV) pathology results from immune-mediated damage, including systemic inflammation and cellular proliferation, which cause a narrowing of the blood vessels. Expansions of cytotoxic CD4+T cells characterized by loss of CD28 ("CD4+CD28-T cells" or "CD4+CD28nullcells") are closely associated with cardiovascular disease (CVD), in particular coronary artery damage. Direct involvement of these cells in damaging the vasculature has been demonstrated repeatedly. Moreover, CD4+CD28-T cells are significantly increased in rheumatoid arthritis (RA) and other autoimmune conditions. It is striking that expansions of this subset beyond 1-2% occur exclusively in CMV-infected people. CMV infection itself is known to increase the severity of autoimmune diseases, in particular RA and has also been linked to increased vascular pathology. A review of the recent literature on immunological changes in CVD, RA, and CMV infection provides strong evidence that expansions of cytotoxic CD4+CD28-T cells in RA and other chronic inflammatory conditions are limited to CMV-infected patients and driven by CMV infection. They are likely to be responsible for the excess CV mortality observed in these situations. The CD4+CD28-phenotype convincingly links CMV infection to CV mortality based on a direct cellular-pathological mechanism rather than epidemiological association.
authors.affiliation: Division of Medicine, Brighton and Sussex Medical School , Brighton , UK.
authors.forename: Iain
authors.initials: I
authors.lastname: Broadley
authors.affiliation: Division of Medicine, Brighton and Sussex Medical School, Brighton, UK; Department of Immunology, Maimonides Institute for Biomedical Research (IMIBIC), Reina Sofía University Hospital, University of Cordoba, Cordoba, Spain.
authors.forename: Alejandra
authors.initials: A
authors.lastname: Pera
authors.affiliation: Division of Medicine, Brighton and Sussex Medical School , Brighton , UK.
authors.forename: George
authors.initials: G
authors.lastname: Morrow
authors.affiliation: Division of Medicine, Brighton and Sussex Medical School , Brighton , UK.
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Davies
authors.affiliation: Division of Medicine, Brighton and Sussex Medical School , Brighton , UK.
authors.forename: Florian
authors.initials: F
authors.lastname: Kern
keywords: CD4 T cells; autoimmune diseases; cardiovascular diseases; chronic inflammatory disease; cytotoxic T cells