In situ expression and serum levels of tumor necrosis factor-alpha receptors in patients with early stages of systemic sclerosis.

Objective. Tumor necrosis factor-α (TNF-α) is an important cytokine in the early stage of systemic sclerosis (SSc). which is characterized by mononuclear cell infiltration and microvascular alterations. Most effects of TNF-α are mediated by its interaction with 2 types of TNF receptors and depend on their surface expression on individual cell subsets. Out purpose was to correlate the serum levels of soluble TNF receptors - TNF-Rl(p55) and RI1(p75) - with (1) their in situ expression and distribution in lesional skin and on peripheral hlood mononuclear cells (PBMC), and (2) the clinical disease progression and inflammatory serum variables in patients with SSc. Methods. Serum samples of 32 patients with SSc and 36 healthy probands were examined by ELISA. We performed immunohistological stainings and in situ hybridization on cryostat 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 healthy skin and chronic fibrotic SSc, TNF-R1 is expressed on about 30%. of mononuclear infiltrating cells in early skin lesions. Neither TNF-RI nor R11 was detectable on fibroblasts by immunohistochemistry, but specific mRNA could be found on the transcriptional level. TNF-Rll is found on most lymphocytes and on 30-50% of endothelial cells, especially in 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 clinical and laboratory signs of inflammation and disease progression in patients with SSc. Conclusion. Out data provide evidence for a central role of the TNF-α/TNF-R system in the early pathological events of 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 guide experimental therapy in patients with SSc.