This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Asano, N. Articles by Sato, S. Search for Related Content PubMed PubMed Citation Articles by Asano, N. Articles by Sato, S.

(American Journal of Pathology. 2004;165:641-650.)
© 2004 American Society for Investigative Pathology

B Lymphocyte Signaling Established by the CD19/CD22 Loop Regulates Autoimmunity in the Tight-Skin Mouse

Noriko Asano^*, Manabu Fujimoto^*, Norihito Yazawa^*, Senji Shirasawa, Minoru Hasegawa, Hitoshi Okochi^*, Kunihiko Tamaki, Thomas F. Tedder^¶ and Shinichi Sato

From the Departments of Regenerative Medicine^* and Pathology, Research Institute, International Medical Center of Japan, Tokyo, Japan; the Department of Dermatology, Faculty of Medicine, University of Tokyo, Tokyo, Japan; the Department of Dermatology, Kanazawa University Graduate School of Medical Science, Ishikawa, Japan; and the Department of Immunology,^¶ Duke University Medical Center, Durham, North Carolina

Systemic sclerosis (SSc) is characterized by fibrosis and autoimmmunity. Peripheral blood B cells from SSc patients specifically overexpress CD19, a critical cell-surface signal transduction molecule in B cells. CD19 deficiency in B cells also attenuates skin fibrosis in the tight-skin (TSK/+) mouse, a genetic model for SSc. Herein we analyzed two transgenic mouse lines that overexpress CD19. Remarkably, 20% increase of CD19 expression in mice spontaneously induced SSc-specific anti-DNA topoisomerase I (topo I) antibody (Ab) production, which was further augmented by 200% overexpression. In TSK/+ mice overexpressing CD19, skin thickness did not increase, although anti-topo I Ab levels were significantly augmented, indicating that abnormal CD19 signaling influences autoimmunity in TSK/+ mice and also that anti-topo I Ab does not have a pathogenic role. The molecular mechanisms for abnormal CD19 signaling were further assessed. B-cell antigen receptor crosslinking induced exaggerated calcium responses and augmented activation of extracellular signal-regulated kinase in TSK/+ B cells. CD22 function was specifically impaired in TSK/+ B cells. Consistently, CD19, a major target of CD22-negative regulation, was hyperphosphorylated in TSK/+ B cells. These findings indicate that reduced inhibitory signal provided by CD22 results in abnormal activation of signaling pathways including CD19 in TSK/+ mice and also suggest that this disrupted B cell signaling contribute to specific autoantibody production.

This article has been cited by other articles:

				K Komura, M Fujimoto, K Yanaba, T Matsushita, Y Matsushita, M Horikawa, F Ogawa, K Shimizu, M Hasegawa, K Takehara, et al. Blockade of CD40/CD40 ligand interactions attenuates skin fibrosis and autoimmunity in the tight-skin mouse Ann Rheum Dis, June 1, 2008; 67(6): 867 - 872. [Abstract] [Full Text] [PDF]

				M. Hasegawa, Y. Hamaguchi, K. Yanaba, J.-D. Bouaziz, J. Uchida, M. Fujimoto, T. Matsushita, Y. Matsushita, M. Horikawa, K. Komura, et al. B-Lymphocyte Depletion Reduces Skin Fibrosis and Autoimmunity in the Tight-Skin Mouse Model for Systemic Sclerosis Am. J. Pathol., September 1, 2006; 169(3): 954 - 966. [Abstract] [Full Text] [PDF]

				T. Matsushita, M. Fujimoto, M. Hasegawa, K. Komura, K. Takehara, T. F. Tedder, and S. Sato Inhibitory Role of CD19 in the Progression of Experimental Autoimmune Encephalomyelitis by Regulating Cytokine Response Am. J. Pathol., March 1, 2006; 168(3): 812 - 821. [Abstract] [Full Text] [PDF]