IN-SITU EXPRESSION AND SERUM LEVELS OF TUMOR-NECROSIS-FACTOR-ALPHA RECEPTORS IN PATIENTS WITH EARLY STAGES OF SYSTEMIC-SCLEROSIS

Tumor necrosis factor-alpha (TNF-alpha) is an important cytokine in th e early stage of systemic sclerosis (SSc), which is characterized by m ononuclear cell infiltration and microvascular alterations. Most effec ts of TNF-alpha are mediated by its interaction with 2 types of TNF re ceptors and depend on their surface expression on individual cell subs ets. Our purpose was to correlate the serum levels of soluble TNF rece ptors - TNF-RI(p55) and RII(p75) - with (1) their in situ expression a nd distribution in lesional skin and on peripheral blood mononuclear c ells (PBMC), and (2) the clinical disease progression and inflammatory serum variables in patients with SSc. Methods. Serum samples of 32 pa tients with SSc and 36 healthy probands were examined by ELISA. We per formed immunohistological stainings and in situ hybridization on cryos tat sections of skin lesions, cytometric analysis on PBMC, and reverse transcriptase polymerase chain reactions using RNA from cultured skin fibroblasts in 17 of these 36 patients. Results. In contrast to healt hy skin and chronic fibrotic SSc, TNF-RI is expressed on about 30% of mononuclear infiltrating cells in early skin lesions. Neither TNF-RI n or RII was detectable on fibroblasts by immunohistochemistry, but spec ific mRNA could be found on the transcriptional level. TNF-RII is foun d on most lymphocytes and on 30-50% of endothelial cells, especially i n early SSc. Expression of both receptor types on PBMC in patients and controls was not significantly different. Serum levels of soluble TNF -RI and RII correlated well with their in situ expression and with cli nical and laboratory signs of inflammation and disease progression in patients with SSc. Conclusion. Our data provide evidence for a central role of the TNF-alpha/TNF-R system in the early pathological events o f scleroderma with prominent inflammation and endothelial cell damage. Determination of TNF-R serum levels provides a useful diagnostic tool for characterization of the disease stage and progression, and to gui de experimental therapy in patients with SSc.