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体内Lyn酪氨酸激酶的持续激活会导致自身免疫。

Sustained activation of Lyn tyrosine kinase in vivo leads to autoimmunity.

作者信息

Hibbs Margaret L, Harder Kenneth W, Armes Jane, Kountouri Nicole, Quilici Cathy, Casagranda Franca, Dunn Ashley R, Tarlinton David M

机构信息

Ludwig Institute for Cancer Research, Melbourne Tumour Biology Branch. Walter and Eliza Hall Institute of Medical Research, Royal Melbourne Hospital, Victoria 3050, Australia.

出版信息

J Exp Med. 2002 Dec 16;196(12):1593-604. doi: 10.1084/jem.20020515.

DOI:10.1084/jem.20020515
PMID:12486102
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2196073/
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 Cgamma2 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.

摘要

Lyn酪氨酸激酶的基因敲除揭示了其在B淋巴细胞信号传导中的独特抑制作用。我们现在报告使用靶向功能获得性突变（Lyn(up/up)小鼠）在体内持续激活Lyn的后果。Lyn(up/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，B1a B细胞数量增加。Lyn(up/up) B细胞的特征是B细胞抗原受体（BCR）信号传导的负调节因子包括CD22、SHP-1和SHIP-1的组成型磷酸化，并表现出因抗原受体的组成型结合而产生耐受的淋巴细胞的特征。然而，过度的正向信号传导也很明显，静息的Lyn(up/up) B细胞中Syk和磷脂酶Cγ2的组成型磷酸化证明了这一点。同样，Lyn(up/up) B细胞在BCR刺激下显示出增强的钙通量。令人惊讶的是，Lyn(up/up)小鼠产生循环自身反应性抗体并发展为致命的自身免疫性肾小球肾炎，这表明增强的正向信号最终会超过组成型负向信号。这些研究突出了面对慢性刺激时维持耐受性的困难，并强调了Lyn在B细胞信号传导中的关键作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0730/2196073/2c28e21efd06/20020515f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0730/2196073/d4ca11601fb3/20020515f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0730/2196073/c751eb525f70/20020515f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0730/2196073/28844dd82667/20020515f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0730/2196073/ca8485183279/20020515f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0730/2196073/785af49a2fdb/20020515f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0730/2196073/e114b79647e9/20020515f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0730/2196073/2c28e21efd06/20020515f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0730/2196073/d4ca11601fb3/20020515f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0730/2196073/c751eb525f70/20020515f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0730/2196073/28844dd82667/20020515f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0730/2196073/ca8485183279/20020515f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0730/2196073/785af49a2fdb/20020515f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0730/2196073/e114b79647e9/20020515f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0730/2196073/2c28e21efd06/20020515f7.jpg

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2
Gain- and loss-of-function Lyn mutant mice define a critical inhibitory role for Lyn in the myeloid lineage.功能获得和功能缺失的Lyn突变小鼠确定了Lyn在髓系谱系中的关键抑制作用。
Immunity. 2001 Oct;15(4):603-15. doi: 10.1016/s1074-7613(01)00208-4.
3
Proximal protein tyrosine kinases in immunoreceptor signaling.
Lyn 酪氨酸激酶在免疫细胞信号转导中的双重作用：对系统性红斑狼疮的影响。
Front Immunol. 2024 Jun 28;15:1395427. doi: 10.3389/fimmu.2024.1395427. eCollection 2024.
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Distinct transcriptomes and autocrine cytokines underpin maturation and survival of antibody-secreting cells in systemic lupus erythematosus.系统性红斑狼疮中分泌抗体细胞的成熟和存活依赖于独特的转录组和自分泌细胞因子。
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