Class IB-phosphatidylinositol 3-kinase (PI3K) deficiency ameliorates IA-PI3K-induced systemic lupus but not T cell invasion
Class IB-phosphatidylinositol 3-kinase (PI3K) deficiency ameliorates IA-PI3K-induced systemic lupus but not T cell invasion
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DOI：
10.4049/jimmunol.176.1.589
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发表时间：
2006-01-01
影响因子：
4.4
通讯作者：
Carrera, AC
中科院分区：
文献类型：
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作者：
Barber, DF;Bartolomé, A;Carrera, AC
I类PI 3 K催化3-聚磷酸肌醇的形成。该家族分为由Tyr激酶激活的I-A亚型和由G蛋白偶联受体激活的I-B亚型（PI 3 K γ）。影响PI 3 K的突变与慢性炎症有关，尽管尚未阐明每种亚型对病理学的不同贡献。T细胞中I-A-PI 3 K类的增强激活延长了CD 4（+）记忆细胞的存活，引发了侵袭性淋巴组织增生性疾病和系统性狼疮。由于I-A-和1（B）-PI 3 K同种型都调节T细胞活化，并且活化的致病性CD 4（+）记忆细胞参与触发系统性狼疮，我们检测了I-B的缺失是否可以减轻I-A-PI 3 K活性增加的病理后果。I-B-PI 3 K γ缺乏不能消除侵袭或淋巴细胞增殖，但减少了CD 4（+）记忆细胞存活、自身抗体产生、肾小球肾炎和系统性狼疮。因此，I-B-PI 3 K γ亚型的缺失降低了致病性CD 4（+）记忆细胞的存活率，选择性地抑制了系统性狼疮的发展。这些结果验证了PI 3 K γ同种型作为系统性红斑狼疮治疗的靶标。
Class I PI3K catalyzes formation of 3-poly-phosphoinositides. The family is divided into I-A isoforms, activated by Tyr kinases and I-A the I-B isoform (PI3K gamma), activated by G protein-coupled receptors. Mutations that affect PI3K are implicated in chronic inflammation, although the differential contribution of each isoform to pathology has not been elucidated. Enhanced activation of class I-A-PI3K in T cells extends CD4(+) memory cell survival, triggering an invasive lymphoproliferative disorder and systemic lupus. As both I-A- and 1(B)-PI3K isoforms regulate T cell activation, and activated pathogenic CD4(+) memory cells are involved in triggering systemic lupus, we examined whether deletion of I-B could reduce the pathological consequences of increased I-A-PI3K activity. I-B-PI3K gamma deficiency did not abolish invasion or lymphoproliferation, but reduced CD4(+) memory cell survival, autoantibody production, glomerulonephritis, and systemic lupus. Deletion of the I-B-PI3K gamma isoform thus decreased survival of pathogenic CD4(+) memory cells, selectively inhibiting systemic lupus development. These results validate the PI3K gamma isoform as a target for systemic lupus erythernatosus treatment.