TY - JOUR
T1 - Autoantibodies to fibroblasts induce a proadhesive and proinflammatory fibroblast phenotype in patients with systemic sclerosis
AU - Chizzolini, Carlo
AU - Raschi, Elena
AU - Rezzonico, Roger
AU - Testoni, Cinzia
AU - Mallone, Roberto
AU - Gabrielli, Armando
AU - Facchini, Andrea
AU - Del Papa, Nicoletta
AU - Borghi, Maria Orietta
AU - Dayer, Jean Michel
AU - Meroni, Pier Luigi
PY - 2002
Y1 - 2002
N2 - Objective. Fibroblasts play a major role in the development of systemic sclerosis (SSc), and the occurrence of serum autoantibodies reacting with fibroblast plasma membrane antigens in SSc has been reported. This study was undertaken to investigate whether IgG from SSc sera that react with human fibroblasts modulates the fibroblasts' function. Methods. Sera from 69 patients with SSc (28 with limited cutaneous SSc [cSSc] and 41 with diffuse cutaneous SSc [dcSSc]), 30 patients with sarcoidosis, and 50 matched healthy controls were examined. We evaluated antibody binding to human skin and lung fibroblasts by cell-based enzyme-linked immunosorbent assay (ELISA), indirect immunofluorescence, and flow cytometry. We further investigated the ability of purifled IgG to modulate 1) intercellular adhesion molecule 1 (ICAM-1) expression, 2) U937 cell adhesion to fibroblasts, and 3) fibroblast steady-state messenger RNA (mRNA) levels of interleukin-1α (IL-1α), IL-β, and IL-6, and IL-6 protein production. Results. Of 69 SSc sera tested by cell-based ELISA, 58% bound to normal skin and lung fibroblasts. The prevalence of binding was significantly higher in dcSSc than in cSSc (P <0.05). Only IgG from SSc sera that were positive for antifibroblast antibody (AFA) induced a dose-dependent up-regulation of ICAM-1 expression and IL-6 production, enhancement of U937 cell adhesion, and increased levels of IL-1α, IL-β, and IL-6 mRNA in fibroblasts. Up-regulation of ICAM-1 mediated by AFA IgG was inhibited by the addition of IL-1 receptor antagonist, indicating an autocrine activation loop. Conclusion. Our findings confirm the presence of AFAs in SSc sera and demonstrate, for the first time, that autoantibodies reacting with fibroblast surface molecules act as an extrinsic stimulus inducing fibroblast activation in vitro.
AB - Objective. Fibroblasts play a major role in the development of systemic sclerosis (SSc), and the occurrence of serum autoantibodies reacting with fibroblast plasma membrane antigens in SSc has been reported. This study was undertaken to investigate whether IgG from SSc sera that react with human fibroblasts modulates the fibroblasts' function. Methods. Sera from 69 patients with SSc (28 with limited cutaneous SSc [cSSc] and 41 with diffuse cutaneous SSc [dcSSc]), 30 patients with sarcoidosis, and 50 matched healthy controls were examined. We evaluated antibody binding to human skin and lung fibroblasts by cell-based enzyme-linked immunosorbent assay (ELISA), indirect immunofluorescence, and flow cytometry. We further investigated the ability of purifled IgG to modulate 1) intercellular adhesion molecule 1 (ICAM-1) expression, 2) U937 cell adhesion to fibroblasts, and 3) fibroblast steady-state messenger RNA (mRNA) levels of interleukin-1α (IL-1α), IL-β, and IL-6, and IL-6 protein production. Results. Of 69 SSc sera tested by cell-based ELISA, 58% bound to normal skin and lung fibroblasts. The prevalence of binding was significantly higher in dcSSc than in cSSc (P <0.05). Only IgG from SSc sera that were positive for antifibroblast antibody (AFA) induced a dose-dependent up-regulation of ICAM-1 expression and IL-6 production, enhancement of U937 cell adhesion, and increased levels of IL-1α, IL-β, and IL-6 mRNA in fibroblasts. Up-regulation of ICAM-1 mediated by AFA IgG was inhibited by the addition of IL-1 receptor antagonist, indicating an autocrine activation loop. Conclusion. Our findings confirm the presence of AFAs in SSc sera and demonstrate, for the first time, that autoantibodies reacting with fibroblast surface molecules act as an extrinsic stimulus inducing fibroblast activation in vitro.
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U2 - 10.1002/art.10361
DO - 10.1002/art.10361
M3 - Article
C2 - 12115192
AN - SCOPUS:0036269002
VL - 46
SP - 1602
EP - 1613
JO - Arthritis care and research : the official journal of the Arthritis Health Professions Association
JF - Arthritis care and research : the official journal of the Arthritis Health Professions Association
SN - 0893-7524
IS - 6
ER -