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(American Journal of Pathology. 2004;165:1583-1591.)
© 2004 American Society for Investigative Pathology

Rheumatic Heart Disease

Proinflammatory Cytokines Play a Role in the Progression and Maintenance of Valvular Lesions

Luiza Guilherme^*, Patricia Cury^*, Lea M.F. Demarchi^*, Verônica Coelho^*, Lúcia Abel^*, Ana P. Lopez^*, Sandra Emiko Oshiro^*, Selma Aliotti^*, Edécio Cunha-Neto^*, Pablo M.A. Pomerantzeff^*, Ana C. Tanaka^* and Jorge Kalil^*

From the Heart Institute,^* School of Medicine, and the Department of Clinical Medicine, Clinical Immunology, and Allergy, University of São Paulo, São Paulo, Brazil

Heart lesions of rheumatic heart disease (RHD) patients contain T-cell clones that recognize heart proteins and streptococcal M peptides. To functionally characterize heart-infiltrating T lymphocytes, we evaluated their cytokine profile, both directly in situ and in T-cell lines derived from the heart (HIL). Interferon (IFN)-, tumor necrosis factor (TNF)-, interleukin (IL)-4, and IL-10 expressions were characterized in 20 heart tissue infiltrates from 14 RHD patients by immunohistochemistry. IFN--, TNF--, and IL-10-positive cells were consistently predominant, whereas IL-4 was scarce in the valves. In agreement with these data, the in vitro experiments, in which 13 HILs derived from heart samples of eight patients were stimulated with M5 protein and the immunodominant M5 (81-96) peptide, IL-4 was detected in HIL derived from the atrium (three of six) but not from the valve (zero of seven). IFN- and IL-10 production were detected in culture supernatants in 11 of 13 and 6 of 12 HILs, respectively. The predominant IFN- and TNF- expression in the heart suggests that Th1-type cytokines could mediate RHD. Unlike in reversible myocardium inflammation, the significantly lower IL-4 expression in the valvular tissue (P = 0.02) may contribute to the progression of the RHD leading to permanent valvular damage (relative risk, 4.3; odds ratio, 15.8). The lack of IL-4 in vitro production by valve-derived HIL also emphasizes the more severe tissue destruction in valves observed in RHD.

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