The Journal of Experimental Medicine
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Published 16 December 2002. doi:10.1084/jem.20020515
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© Rockefeller University Press, 0022-1007/2002/12/1593/ $5.00
The Journal of Experimental Medicine, Volume 196, Number 12, December 16, 2002 1593-1604
Sustained Activation of Lyn Tyrosine Kinase In Vivo Leads to Autoimmunity

Margaret L. Hibbs1, Kenneth W. Harder1, Jane Armes3, Nicole Kountouri1, Cathy Quilici1, Franca Casagranda1, Ashley R. Dunn1 and David M. Tarlinton2

1 Ludwig Institute for Cancer Research, Melbourne Tumour Biology Branch
2 Walter and Eliza Hall Institute of Medical Research, Royal Melbourne Hospital, Victoria 3050, Australia
3 Melbourne Pathology, Royal Women's Hospital, Victoria 3053, Australia and Victorian Breast Cancer Research Consortium, Department of Pathology, University of Melbourne, Victoria 3052, Australia

Address correspondence to Margaret L. Hibbs, Ludwig Institute for Cancer Research, Melbourne Tumour Biology Branch, P.O. Box 2008, Royal Melbourne Hospital, Victoria 3050, Australia. Phone: 61-3-9341-3155; Fax: 61-3-9341-319; E-mail: Margaret.Hibbs{at}ludwig.edu.au

Genetic ablation of the Lyn tyrosine kinase has revealed unique inhibitory roles in B lymphocyte signaling. We now report the consequences of sustained activation of Lyn in vivo using a targeted gain-of-function mutation (Lynup/up mice). Lynup/up mice have reduced numbers of conventional B lymphocytes, down-regulated surface immunoglobulin M and costimulatory molecules, and elevated numbers of B1a B cells. Lynup/up B cells are characterized by the constitutive phosphorylation of negative regulators of B cell antigen receptor (BCR) signaling including CD22, SHP-1, and SHIP-1, and display attributes of lymphocytes rendered tolerant by constitutive engagement of the antigen receptor. However, exaggerated positive signaling is also apparent as evidenced by the constitutive phosphorylation of Syk and phospholipase C{gamma}2 in resting Lynup/up B cells. Similarly, Lynup/up B cells show a heightened calcium flux in response to BCR stimulation. Surprisingly, Lynup/up mice develop circulating autoreactive antibodies and lethal autoimmune glomerulonephritis, suggesting that enhanced positive signaling eventually overrides constitutive negative signaling. These studies highlight the difficulty in maintaining tolerance in the face of chronic stimulation and emphasize the pivotal role of Lyn in B cell signaling.

Key Words: B cell signal transduction • Src family kinase • Lyn gain-of-function mutant mice • autoimmune disease • B cell tolerance


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