Sustained activation of Lyn tyrosine kinase in vivo leads to autoimmunity.
Sustained activation of Lyn tyrosine kinase in vivo leads to autoimmunity.
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DOI：
10.1084/jem.20020515
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发表时间：
2002-12-16
期刊：
影响因子：
--
通讯作者：
Tarlinton DM
中科院分区：
文献类型：
--
作者：
Hibbs ML;Harder KW;Armes J;Kountouri N;Quilici C;Casagranda F;Dunn AR;Tarlinton DM
林恩酪氨酸激酶的基因消除揭示了在B淋巴细胞信号传导中的独特抑制作用。我们现在报告的后果持续激活林恩在体内使用靶向功能获得性突变（Lynup/up小鼠）。Lynup/up小鼠的常规B淋巴细胞数量减少，表面免疫球蛋白M和共刺激分子下调，B1 a B细胞数量增加。Lynup/up B细胞的特征在于B细胞抗原受体（BCR）信号传导的负调节物（包括CD 22、SHP-1和SHIP-1）的组成性磷酸化，并显示出通过抗原受体的组成性接合而变得耐受的淋巴细胞的属性。然而，过度的正信号传导也是明显的，如由静息Lynup/up B细胞中Syk和磷脂酶Cγ2的组成性磷酸化所证明的。类似地，Lynup/up B细胞响应于BCR刺激显示出升高的钙通量。令人惊讶的是，Lynup/up小鼠产生循环自身反应性抗体和致命的自身免疫性肾小球肾炎，这表明增强的阳性信号最终覆盖了组成性阴性信号。这些研究强调了在面对慢性刺激时维持耐受性的困难，并强调了林恩在B细胞信号传导中的关键作用。
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.
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DOI：
10.1084/jem.179.2.425
发表时间：
1994-02-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Cooke MP;Heath AW;Shokat KM;Zeng Y;Finkelman FD;Linsley PS;Howard M;Goodnow CC
通讯作者：
Goodnow CC
DOI：
10.1084/jem.186.11.1923
发表时间：
1997-12-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Inaoki M;Sato S;Weintraub BC;Goodnow CC;Tedder TF
通讯作者：
Tedder TF
影响因子：
64.8
作者：
GOODNOW, CC;CROSBIE, J;BASTEN, A
通讯作者：
BASTEN, A
影响因子：
32.4
作者：
Healy, JI;Dolmetsch, RE;Goodnow, CC
通讯作者：
Goodnow, CC
影响因子：
64.5
作者：
HIBBS, ML;TARLINTON, DM;DUNN, ARR
通讯作者：
DUNN, ARR