Role of PI3-kinase in the development of mast cells and anti-helminth immunity

我们使用p85α缺陷小鼠研究了IA类PI 3 K在肥大细胞分化中的作用，发现p85 α缺陷小鼠选择性缺乏胃肠道和腹膜肥大细胞，而肥大细胞在正常生理条件下容易在其他组织如皮肤中发现。在p85α缺陷小鼠中始终观察到强烈的被动全身过敏反应，表明这些小鼠中的肥大细胞具有功能活性。c-Kit-PI 3 K信号通路的缺乏似乎是p85α缺陷小鼠中肥大细胞独特发育障碍的机制，因为在p85 α缺陷肥大细胞中，响应SCF的增殖和JNK活化严重受损。由于SCF诱导的肥大细胞增殖需要通过Rac 1激活JNK活性，因此JNK激活的损伤可能会导致p85α缺陷肥大细胞响应SCF的促有丝分裂能力缺陷。IA类PI 3 K对肥大细胞的分化也是至关重要的。 关于我们 病原免疫期。p85α缺陷小鼠在委内瑞拉圆线虫感染期间表现出肥大细胞增多症的严重缺陷。p85α缺陷小鼠肠系膜淋巴细胞产生IL-3的能力受损可能是蠕虫感染期间导致肥大细胞增多症受损的主要缺陷。此外，在p85α缺陷小鼠中，肠系膜淋巴细胞响应寄生虫抗原的Th 2细胞因子的产生显著受损。除了IL-3产生受损外，其他Th 2细胞因子的产生缺陷可能影响肥大细胞增多症，导致p85α缺陷小鼠中肠线虫的清除延迟。事实上，过继转移用Th 2细胞因子预处理的骨髓来源的肥大细胞，而不是未经处理的肥大细胞，能够恢复驱逐S.委内瑞拉野生型水平。进一步证明，在p85α缺陷小鼠中，树突状细胞响应微生物刺激而过度产生IL-12导致Th 1应答增强。我们的数据表明，IA类PI 3 K在调节Th 1和Th 2反应之间的平衡中起着重要作用，特别是在诱导或抑制Th 2或Th 1反应中。在p85α缺陷小鼠中，肥大细胞自主（受损的c-Kit介导的信号）和环境（Th 1与Th 2的异常偏斜）缺陷可能导致缺陷性肥大细胞增多症和随后的肠道线虫感染免疫应答受损。少

We examined the role of class IA PI3K in mast cell differentiation using p85α-deficient mice and found that p85α-deficient mice selectively lack gastrointestinal and peritoneal mast cells whereas mast cells are readily found in other tissues such as skin under normal physiological conditions. Strong passive systemic anaphylaxis was consistently observed in p85α-deficient mice, suggesting that mast cells in these mice are functionally competent. The lack of the c-Kit-PI3K signaling pathway seems the mechanism accounting for the unique developmental impairment of mast cells in p85α-deficient mice as proliferation and JNK activation in response to SCF was severely impaired in p85α-deficient mast cells. Since SCF-induced proliferation of mast cells requires JNK activity through Rac1 activation, impairment in JNK activation may cause the defective mitogenic capacity of p85α-deficient mast cells in response to SCF. The class IA PI3K is also critical for the differentiation of mast cells in t … More he pathogenic immune phase. The p85α-deficient mice demonstrated severe defects in mastocytosis during infection by Strongyloides venezuelensis. Impaired IL-3 production by mesenteric lymphocytes in p85α-deficient mice is likely the main defect leading to impaired mastocytosis during helminth infection. Furthermore, production of Th2 cytokines by mesenteric lymphocytes in response to the parasites' antigens was dramatically impaired in p85α-deficient mice. In addition to the impaired IL-3 production, defective production of other Th2 cytokines may influence mastocytosis, resulting in the delayed clearance of intestinal nematodes in p85α-deficient mice. Indeed, adoptive transfer of bone marrow-derived mast cells pretreated with Th2 cytokines but not untreated mast cells was able to restore the ability to expel S. venezuelensis to wild type levels. It was further demonstrated that hyperproduction of IL-12 by dendritic cells in response to microbial stimuli in p85α-deficient mice causes an enhanced Th1 response. Our data show that class IA PI3K plays an important role in the regulation of the balance between Th1 and Th2 responses, especially in the induction or suppression of Th2 or Th1 responses, respectively. In p85α-deficient mice, both mast cell autonomous (impaired c-Kit-mediated signal) and environmental (abnormal skewing of Th1 vs Th2) defects likely contribute to the defective mastocytosis and subsequent impairment in immune response against intestinal nematode infection. Less