This Article Full Text Full Text (PDF) All Versions of this Article: 109/22/2744    most recent 01.CIR.0000131450.66017.B3v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Gerli, R. Articles by Mannarino, E. Search for Related Content PubMed PubMed Citation Articles by Gerli, R. Articles by Mannarino, E. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Joint Disorders Rheumatoid Arthritis Related Collections Pathophysiology Risk Factors Cell biology/structural biology Chronic ischemic heart disease Endothelium/vascular type/nitric oxide Mechanism of atherosclerosis/growth factors

(Circulation. 2004;109:2744-2748.)
© 2004 American Heart Association, Inc.

Clinical Investigation and Reports

CD4+CD28– T Lymphocytes Contribute to Early Atherosclerotic Damage in Rheumatoid Arthritis Patients

Roberto Gerli, MD; Giuseppe Schillaci, MD; Andrea Giordano, MD; Elena Bartoloni Bocci, MD; Onelia Bistoni, BiolSc; Gaetano Vaudo, MD; Simona Marchesi, MD; Matteo Pirro, MD; Federica Ragni, MD; Yehuda Shoenfeld, MD, FRCP; Elmo Mannarino, MD

From the Section of Internal Medicine and Oncological Sciences, Center for the Study of Rheumatic Diseases (R.G., A.G., E.B.B., O.B., F.R.), Section of Internal Medicine, Angiology, and Atherosclerosis Diseases (G.S., G.V., S.M., M.P., E.M.), Department of Clinical and Experimental Medicine, University of Perugia, Perugia, Italy, and Department of Medicine B and Center for Autoimmune Diseases, Chaim Sheba Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel-Hashomer, Israel (Y.S.).

Correspondence to R. Gerli, MD, Center for the Study of Rheumatic Diseases, Section of Internal Medicine and Oncological Sciences, Department of Clinical and Experimental Medicine, University of Perugia, Policlinico di Monteluce, I-06122 Perugia, Italy. E-mail gerlir{at}unipg.it

Received September 9, 2003; de novo received December 1, 2003; revision received March 4, 2004; accepted March 9, 2004.

Background— Peripheral blood expansion of an unusual CD4+ T-cell subset lacking surface CD28 has been suggested to predispose rheumatoid arthritis (RA) patients to develop more aggressive disease. However, the potential association between CD4+CD28^null T cells and early atherosclerotic changes in RA has never been investigated.

Methods and Results— The number of circulating CD4+CD28^null cells was evaluated in 87 RA and 33 control subjects who also underwent evaluation of carotid artery intima-media thickness (IMT) and endothelial function via flow-mediated vasodilation (FMV). Patients had higher IMT and lower FMV compared with control subjects. The frequency of CD4+CD28^null cells was significantly higher in patients than in control subjects. Twenty patients with persistent expansion of circulating CD4+CD28^null cells had more marked increase of carotid artery IMT and stronger decrease of brachial artery FMV. Blockade of tumor necrosis factor- led to a partial reappearance of the CD28 molecule on the CD4+ cell surface.

Conclusions— Circulating CD4+CD28^null lymphocytes are increased in RA. Patients with persistent CD4+CD28^null cell expansion show preclinical atherosclerotic changes, including arterial endothelial dysfunction and carotid artery wall thickening, more significantly than patients without expansion. These findings suggest a contribution of this cell subset in atheroma development in RA. Moreover, the demonstration that tumor necrosis factor- blockade is able to reverse, at least in part, the CD28 deficiency on the CD4+ cell surface may be of interest for possible innovative therapeutic strategies in cardiovascular diseases.

Key Words: arthritis, rheumatoid • cells • endothelium • vasodilation

This article has been cited by other articles:

				M. Turiel, F. Atzeni, L. Tomasoni, S. de Portu, L. Delfino, B. D. Bodini, M. Longhi, S. Sitia, M. Bianchi, P. Ferrario, et al. Non-invasive assessment of coronary flow reserve and ADMA levels: a case-control study of early rheumatoid arthritis patients Rheumatology, July 1, 2009; 48(7): 834 - 839. [Abstract] [Full Text] [PDF]

				A. Recio-Mayoral, J. C. Mason, J. C. Kaski, M. B. Rubens, O. A. Harari, and P. G. Camici Chronic inflammation and coronary microvascular dysfunction in patients without risk factors for coronary artery disease Eur. Heart J., June 5, 2009; (2009) ehp205v1. [Abstract] [Full Text] [PDF]

				M. Pirro, G. Schillaci, P. F. Romagno, M. R. Mannarino, F. Bagaglia, R. Razzi, L. Pasqualini, G. Vaudo, and E. Mannarino Influence of Short-term Rosuvastatin Therapy on Endothelial Progenitor Cells and Endothelial Function Journal of Cardiovascular Pharmacology and Therapeutics, March 1, 2009; 14(1): 14 - 21. [Abstract] [PDF]

				I. E. Dumitriu, E. T. Araguas, C. Baboonian, and J. C. Kaski CD4+CD28null T cells in coronary artery disease: when helpers become killers Cardiovasc Res, January 1, 2009; 81(1): 11 - 19. [Abstract] [Full Text] [PDF]

				R Gerli, E B. Bocci, Y Sherer, G Vaudo, S Moscatelli, and Y Shoenfeld Association of anti-cyclic citrullinated peptide antibodies with subclinical atherosclerosis in patients with rheumatoid arthritis Ann Rheum Dis, May 1, 2008; 67(5): 724 - 725. [Full Text] [PDF]

				S. I. van Leuven, R. Franssen, J. J. Kastelein, M. Levi, E. S. G. Stroes, and P. P. Tak Systemic inflammation as a risk factor for atherothrombosis Rheumatology, January 1, 2008; 47(1): 3 - 7. [Abstract] [Full Text] [PDF]

				M. Thewissen, V. Somers, N. Hellings, J. Fraussen, J. Damoiseaux, and P. Stinissen CD4+CD28null T Cells in Autoimmune Disease: Pathogenic Features and Decreased Susceptibility to Immunoregulation J. Immunol., November 15, 2007; 179(10): 6514 - 6523. [Abstract] [Full Text] [PDF]

				G. Liuzzo, L. M. Biasucci, G. Trotta, S. Brugaletta, M. Pinnelli, G. Digianuario, V. Rizzello, A. G. Rebuzzi, C. Rumi, A. Maseri, et al. Unusual CD4+CD28null T Lymphocytes and Recurrence of Acute Coronary Events J. Am. Coll. Cardiol., October 9, 2007; 50(15): 1450 - 1458. [Abstract] [Full Text] [PDF]

				F. Del Porto, B. Lagana, S. Lai, I. Nofroni, F. Tinti, M. Vitale, E. Podesta, A. P. Mitterhofer, and R. D'Amelio Response to anti-tumour necrosis factor alpha blockade is associated with reduction of carotid intima-media thickness in patients with active rheumatoid arthritis Rheumatology, July 1, 2007; 46(7): 1111 - 1115. [Abstract] [Full Text] [PDF]

				Y. Sherer, R. Gerli, B. Gilburd, E. Bartoloni Bocci, G. Vaudo, E. Mannarino, and Y. Shoenfeld Thickened carotid artery intima-media in rheumatoid arthritis is associated with elevated anticardiolipin antibodies Lupus, April 1, 2007; 16(4): 259 - 264. [Abstract] [PDF]

				K. M. Maki-Petaja, F. C. Hall, A. D. Booth, S. M.L. Wallace, Yasmin, P. W.P. Bearcroft, S. Harish, A. Furlong, C. M. McEniery, J. Brown, et al. Rheumatoid Arthritis Is Associated With Increased Aortic Pulse-Wave Velocity, Which Is Reduced by Anti-Tumor Necrosis Factor-{alpha} Therapy Circulation, September 12, 2006; 114(11): 1185 - 1192. [Abstract] [Full Text] [PDF]

				V. Rizzello, G. Liuzzo, S. Brugaletta, A. Rebuzzi, L. M. Biasucci, and F. Crea Modulation of CD4+CD28null T Lymphocytes by Tumor Necrosis Factor-{alpha} Blockade in Patients With Unstable Angina Circulation, May 16, 2006; 113(19): 2272 - 2277. [Abstract] [Full Text] [PDF]

				S I van Leuven, J J. Kastelein, D P D'Cruz, G R Hughes, and E S Stroes Atherogenesis in rheumatology Lupus, March 1, 2006; 15(3): 117 - 121. [Abstract] [PDF]

				K M J Douglas, A V Pace, G J Treharne, A Saratzis, P Nightingale, N Erb, M J Banks, and G D Kitas Excess recurrent cardiac events in rheumatoid arthritis patients with acute coronary syndrome Ann Rheum Dis, March 1, 2006; 65(3): 348 - 353. [Abstract] [Full Text] [PDF]

				M. J. Roman, E. Moeller, A. Davis, S. A. Paget, M. K. Crow, M. D. Lockshin, L. Sammaritano, R. B. Devereux, J. E. Schwartz, D. M. Levine, et al. Preclinical carotid atherosclerosis in patients with rheumatoid arthritis. Ann Intern Med, February 21, 2006; 144(4): 249 - 256. [Abstract] [Full Text] [PDF]

				F. C. Hall and N. Dalbeth Disease modification and cardiovascular risk reduction: two sides of the same coin? Rheumatology, December 1, 2005; 44(12): 1473 - 1482. [Abstract] [Full Text] [PDF]

				Y. Shoenfeld, R. Gerli, A. Doria, E. Matsuura, M. M. Cerinic, N. Ronda, L. J. Jara, M. Abu-Shakra, P. L. Meroni, and Y. Sherer Accelerated Atherosclerosis in Autoimmune Rheumatic Diseases Circulation, November 22, 2005; 112(21): 3337 - 3347. [Full Text] [PDF]

				R Gerli and N J Goodson Cardiovascular involvement in rheumatoid arthritis Lupus, September 1, 2005; 14(9): 679 - 682. [Abstract] [PDF]

				G Liuzzo, G Giubilato, and M Pinnelli T cells and cytokines in atherogenesis Lupus, September 1, 2005; 14(9): 732 - 735. [Abstract] [PDF]