Sustained activation of Lyn tyrosine kinase in vivo leads to autoimmunity

Hibbs, ML; Harder, KW; Armes, J; Kountouri, N; Quilici, C; Casagranda, F; Dunn, AR; Tarlinton, DM

Author(s): Hibbs, ML; Harder, KW; Armes, J; Kountouri, N; Quilici, C; Casagranda, F; Dunn, AR; Tarlinton, DM;
Details: Publication Year 2002-12-16,Volume 196,Issue #12,Page 1593-1604
Journal Title: JOURNAL OF EXPERIMENTAL MEDICINE
Publication Type: Journal Article
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 (Lyn(up/up) mice). Lyn(up/up) mice have reduced numbers of conventional B lymphocytes, down-regulated surface immunoglobulin M and costimulatory molecules, and elevated numbers of B1a B cells. Lyn(up/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 Cy2 in resting Lyn(up/up) B cells. Similarly, Lyn(up/up) B cells show a heightened calcium flux in response to BCR stimulation. Surprisingly, Lyn(up/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.
Publisher: ROCKEFELLER UNIV PRESS
Keywords: REACTIVE B-CELLS; FC-GAMMA-RIIB; ANTIGEN-RECEPTOR; NEGATIVE REGULATOR; DEFICIENT MICE; LYMPHOCYTES-B; SIGNAL-TRANSDUCTION; TRANSGENIC MICE; CD22-DEFICIENT MICE; IMMUNE-SYSTEM
Publisher's Version: https://doi.org/10.1084/jem.20020515
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2002-12-16 12:00:00