Function blocking autoantibodies against matrix metalloproteinase-1 in patients with systemic sclerosis.
Systemic sclerosis is characterized by fibrosis and systemic autoimmunity; however, roles of autoantibodies in the development of fibrosis remain unknown in systemic sclerosis. The net accumulation of extracellular matrix is dependent on the balance between the synthesis and degradation of extracellular matrix components, the latter process regulated by matrix metalloproteinases. Matrix metalloproteinase-1 (interstitial collagenase-1) can initiate degradation of collagen types I-III that are major extracellular matrix constituents in affected skin of systemic sclerosis. In this study, we tested the hypothesis that systemic autoimmunity in systemic sclerosis induced anti-matrix metalloproteinase-1 autoantibodies that inhibited matrix metallo-proteinase-1 activity, resulting in collagen accumulation. Enzyme-linked immunosorbent assay using human recombinant matrix metalloproteinase-1 revealed that IgG anti-matrix metalloproteinase-1 autoantibody levels were significantly elevated in sera from patients with systemic sclerosis, but not patients with active systemic lupus erythematosus or dermatomyositis, relative to normal controls. IgG anti-matrix metalloproteinase-1 autoantibody levels were significantly higher in patients with diffuse cutaneous systemic sclerosis than those found in patients with limited cutaneous systemic sclerosis. Furthermore, IgG anti-matrix metalloproteinase-1 antibody levels significantly correlated with the extent of fibrosis in the skin, lung, and renal blood vessels. The presence of IgG anti-matrix metalloproteinase-1 autoantibody in sera from systemic sclerosis patients was confirmed by immunoblotting analysis. Remarkably, IgG anti-matrix metalloproteinase-1 autoantibody in sera from systemic sclerosis patients inhibited matrix metalloproteinase-1 collagenase activity. Collectively, the results of this study suggest that anti-matrix metalloproteinase-1 autoantibody contributes to the development of fibrosis by inhibiting matrix metalloproteinase-1 collagenase activity and reducing the extracellular matrix turnover and suggest that the presence of anti-matrix metalloproteinase-1 autoantibody in systemic sclerosis is the link between systemic autoimmunity and fibrosis.
Sato
Shinichi
S
Department of Dermatology, Kanazawa University Graduate School of Medical Science, Japan. s-sato@med.kanazawa-u.ac.jp
Hayakawa
Ikuko
I
Hasegawa
Minoru
M
Fujimoto
Manabu
M
Takehara
Kazuhiko
K
D000328:Adult; D001323:Autoantibodies / Q000097:blood*; D004797:Enzyme-Linked Immunosorbent Assay; D005109:Extracellular Matrix / Q000276:immunology; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D007075:Immunoglobulin M / Q000097:blood; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000276:immunology* / Q000378:metabolism; D008875:Middle Aged; D012595:Scleroderma, Systemic / Q000201:enzymology* / Q000276:immunology*
D001323:Autoantibodies; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D020781:Matrix Metalloproteinase 1