Pathogenic Mechanisms in Rheumatic Carditis: Focus on Valvular Endothelium
Suzanne Roberts,1,a,b Stanley Kosanke,2,a S. Terrence Dunn,2 David Jankelow,3 Carlos M. G. Duran,4 and Madeleine W. Cunningham1
Departments of 1Microbiology and Immunology and 2Pathology, University of Oklahoma Health Sciences Center, Oklahoma City; 3 Department of Medicine, Division ofCardiology, University of Witwatersrand, Johannesburg, South Africa; 4Cardiovascular Sciences Division, University of Montana and International Heart Institute, Missoula
To clarify immune-mediated mechanisms in rheumatic heart disease caused by group A streptococcal infection, valve tissues from rheumatic patients with valvular heart disease who required valve replacement were studied forreactivity with monoclonal anti-CD4 or antiCD8 monoclonal antibodies or anti–vascular cell adhesion molecule–1 (VCAM-1). At the valve surface, CD4+ and CD8+ T lymphocytes were adherent to valve endothelium and penetrated through the subendothelial layer. T cell extravasation into the valve through the surface valvular endothelium appeared to be an important event in the development of rheumatic heartdisease. VCAM-1 was expressed on the valvular endothelium in rheumatic valves. Evidence suggested that the pathogenesis of rheumatic heart disease involved the activation of surface valvular endothelium with the expression of VCAM-1 and the extravasation of CD4+ and CD8+ lymphocytes through the activated endothelium into the valve. Lymphocytic inﬁltration through the valve surface endothelium hasnot been appreciated as a potential initiating step in disease pathogenesis.
Group A streptococci are important human pathogens that cause a number of suppurative infections in humans, including pharyngitis, which can lead to acute rheumatic fever (ARF) in a susceptible host . ARF is a leading cause of heart disease in children worldwide , and since 1985 there has been a resurgence ofARF in the United States . The pathogenesis of ARF is complex and may depend on a number of streptococcal and host factors, particularly autoimmune responses against host tissues. Both hereditary and environmental factors inﬂuence susceptibility to ARF . Major clinical manifestations of ARF include carditis/valvulitis, chorea, polyarthritis, erythema marginatum, and sub-
Received 17 July2000; revised 9 October 2000; electronically published 20 December 2000. Presented in part: American Association of Immunologists meeting, New Orleans, 1996 (abstract LB-119; addendum: FASEB J 1996; 10:36). Human experimentation guidelines of the US Department of Health and Human Services and those of the authors’ institutions were followed in the conduct of the clinical research. Financialsupport: National Institutes of Health (HL-35280). a S.R. and S.K. contributed equally to this work. b Present afﬁliation: Emergency Department, Northshore University Hospital, Manhasset, New York. Reprints or correspondence: Dr. Madeleine W. Cunningham, Dept. of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Biomedical Research Center, 975 N.E. 10th St., Oklahoma City, OK73104 (email@example.com).
The Journal of Infectious Diseases 2001; 183:507–11 2001 by the Infectious Diseases Society of America. All rights reserved. 0022-1899/2001/18303-0020$02.00
cutaneous nodules . Carditis is the most serious . Pathologic signs of rheumatic carditis, which include Anitshkow myocytes  and Aschoff’s nodules, may develop in heart tissues of ARFpatients . In valvular injury, verrucae or nodules form on the mitral valve with edema and cellular inﬁltration of the leaﬂets. Valves are damaged, resulting in valvular stenosis or regurgitation. Previous studies showed the presence of both CD4 and CD8 T cell subsets within ARF valves [6–8] and major histocompatibility complex (MHC) class II antigen expression on vessel endothelium and valvular...
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