The complement system in the pathogenesis of cutaneous sclerosis: comparison between Sclerodermatous GVHD and Systemic Sclerosis

Systemic Sclerosis (SSc) and sclerodermatous GVHD (ScGVHD) are similar diseases, poorly understood and still lacking an effective therapy. On one hand, they share clinical features and immunological mechanisms . On the other hand they differ in the microvascular damage, that is higher in SSc than in ScGVHD. Since there are some evidences that complement system could be involved in both diseases, we evaluated complement activation (by C5b-9 expression) and the expression of a regulatory protein, Membrane Cofactor Protein (MCP or CD46), in both conditions. We also investigated some genetic polymorphisms (SNPs) in complement regulation gene cluster. Seventy one patients with diagnosis of SSc, 6 with ScGVHD and 27 healthy volunteers were enrolled in the University Hospital of Verona, Italy. Serum and DNA of all patients and volunteers were collected. Elisa was performed on 47 SSc, 5 ScGVHD patients and 18 healthy volunteers. Skin biopsies, obtained from 8 SSc and 3 ScGVHD patients, underwent immunohistochemistry analysis and immunofluorescence stainings for detecting the expression of complement Membrane Attack Complex (C5b-9) and MCP on endothelial cells. Archival skin biopsies of control diseases and normal individuals were also analyzed. Statistical analysis was performed using STATA 10.1 software. Circulating levels of C5b-9 and MCP did not differ between healthy subjects, SSc and ScGVHD patients. Immunofluoresce stainings of skin biopsies showed a pronounced complement activation in ScGVHD and a little less remarkable activation in SSc vessels, if compared with healthy volunteers. MCP was lower in SSc than in ScGVHD, both in immunohistochemistry analysis and in immunofluorescence stainings and in both diseases it was lower than in healthy controls. Finally, the minor variants of two SNPs in MCP promoter region were over-expressed in SSc patients. The same uncommon alleles were not found in ScGVHD. In conclusion we confirm that complement system is involved in the pathogenesis of both diseases. Particularly in SSc its role seems to be partially related to an impaired function of regulatory protein MCP. Further researches about these topics would be useful, since some complement inhibitor drugs are on clinical trials for different diseases and others will be probably developed in future.