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Sustained Activation of Lyn Tyrosine Kinase In Vivo Leads to Autoimmunity

Authors :
Cathy Quilici
Franca Casagranda
Kenneth W. Harder
Jane E. Armes
Margaret L. Hibbs
Nicole Kountouri
David M. Tarlinton
Ashley R. Dunn
Source :
The Journal of Experimental Medicine
Publication Year :
2002
Publisher :
Rockefeller University Press, 2002.

Abstract

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 Cγ2 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.

Details

ISSN :
15409538 and 00221007
Volume :
196
Database :
OpenAIRE
Journal :
Journal of Experimental Medicine
Accession number :
edsair.doi.dedup.....214ef7b35433405666be4dd0995642f1
Full Text :
https://doi.org/10.1084/jem.20020515