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(American Journal of Pathology. 2006;169:954-966.)
© 2006 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2006.060205

B-Lymphocyte Depletion Reduces Skin Fibrosis and Autoimmunity in the Tight-Skin Mouse Model for Systemic Sclerosis

Minoru Hasegawa*, Yasuhito Hamaguchi{dagger}, Koichi Yanaba{dagger}, Jean-David Bouaziz{dagger}, Junji Uchida{dagger}, Manabu Fujimoto*, Takashi Matsushita*, Yukiyo Matsushita*, Mayuka Horikawa*, Kazuhiro Komura*, Kazuhiko Takehara*, Shinichi Sato{ddagger} and Thomas F. Tedder{dagger}

From the Department of Dermatology,* Kanazawa University Graduate School of Medical Science, Kanazawa, Japan; the Department of Dermatology,{ddagger} Nagasaki University Graduate School of Biomedical Science, Nagasaki, Japan; and the Department of Immunology,{dagger} Duke University Medical Center, Durham, North Carolina

Systemic sclerosis (scleroderma) is an autoimmune disease characterized by excessive extracellular matrix deposition in the skin. A direct role for B lymphocytes in disease development or progression has remained controversial, although autoantibody production is a feature of this disease. To address this issue, skin sclerosis and autoimmunity were assessed in tight-skin mice, a genetic model of human systemic sclerosis, after circulating and tissue B-cell depletion using an anti-mouse CD20 monoclonal antibody before (day 3 after birth) and after disease development (day 56). CD20 monoclonal antibody treatment (10 to 20 µg) depleted the majority (85 to 99%) of circulating and tissue B cells in newborn and adult tight-skin mice by days 56 and 112, respectively. B-cell depletion in newborn tight-skin mice significantly suppressed (~43%) the development of skin fibrosis, autoantibody production, and hypergammaglobulinemia. B-cell depletion also restored a more normal balance between Th1 and Th2 cytokine mRNA expression in the skin. By contrast, B-cell depletion did not affect skin fibrosis, hypergammaglobulinemia, and autoantibody levels in adult mice with established disease. Thereby, B-cell depletion during disease onset suppressed skin fibrosis, indicating that B cells contribute to the initiation of systemic sclerosis pathogenesis in tight-skin mice but are not required for disease maintenance.




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