Increased CD40 expression in skin fibroblasts from patients with systemic sclerosis (SSc): role of CD40-CD154 in the phenotype of SSc fibroblasts

Systemic sclerosis (SSc) is a connective tissue disease of unknown etiology that is characterized by tissue fibrosis, which may result from the activation of lesional fibroblasts exhibiting excessive production of extracellular matrix components. However, it has yet to be determined how SSc fibroblasts are activated. CD40 is a cell surface molecule expressed on various cells that is important for the response to activated T cells through CD154. CD40 mRNA was found to be constitutively expressed in both SSc and normal fibroblasts by reverse transcription PCR. Expression of CD40 protein was increased on SSc fibroblasts compared to normal fibroblasts as measured by flow cytometry. Ligation of CD40 by recombinant human CD154 (0.5-2 mug/ml) resulted in increased production of IL-6, IL-8, and monocyte chemoattractant protein-1 in SSc fibroblasts in a dose-dependent manner, whereas these phenomena were not shown in normal fibroblasts even with the addition of CD154. CD80, a costimulatory molecule, was also induced on SSc fibroblasts by CD40 ligation. In the present study, our findings suggest the possibility of a cell-mediated response between fibroblasts and T cells in the lesional skin of SSc patients. Since it is suggested that the CD40-CD154 system may play a crucial role in the aberrant production of immune mediators by SSc fibroblasts, blockage of CD40-CD154 may be a novel therapeutic strategy for SSc.