NLRP3介导的细胞焦亡在儿童呼吸道上皮细胞乳头状增生中的作用机制

HPV病毒引发的幼年型复发性呼吸道乳头状瘤(JO-RRP)是儿童呼吸道上皮组织增生性良性病变，其反复发作和病毒的深度扩散给患儿及家庭带来沉重的身心和经济负担。通过多次手术未能彻底终止呼吸道上皮细胞增生。我们前期发现复发患儿免疫减弱呈Th2极性，由于IL21+滤泡T细胞减少而造成B细胞成熟障碍和总IgG下降。针对病毒免疫应答引发的细胞焦亡是机体清除和限制病毒扩散的有效机制。近期研究发现，血浆以及乳头状增生上皮组织内病毒应答因子IFN-g、TNF-a、炎症小体相关蛋白NLRP3、Gasdermin B以及细胞焦亡相关因子IL-1β、IL-18的浓度显著降低。本课题利用国家儿童医学中心JO-RRP样本优势，通过细胞培养，基因敲减以及动物模型等手段，阐明是否NLRP3减低导致了HPV感染上皮细胞中减弱的焦亡反应，从而理解JORRP患者HPV病毒不能有效清除以及上皮组织反复乳头状增生的机理。

Juvenile Onset Recurrent Respiratory Papillomatosis (JO-RRP) is a self-limited benign ailment caused by HPV infection characteristic of frequent papillary epithelial hyperplasia. Multiple surgeries itself is not able to completely eradicate HPV virus and halt the occurrence of excessive epithelial regrowth. Our previous findings revealed that children with JO-RRP exhibited a Th2-biased cytokine profile and a decreased IL21+CD4+ follicle T cells which led to an impaired T-dependent B-cell maturation thus a reduced serum IgG level. Our further study discovered that in serum and papillary epithelial hyperplasia tissue there was a noticeable reduction in the expressions of IFN-g, TNF-a, inflammasome-related factor NLRP3, Gasdermin B as well as pyroptosis associated cytokines IL-1β and IL-18. Cell pyroptosis is proven to be an effective mechanism for virus removal. We hypothesized that in JO-RRP patients, a reduction in NLRP3 expression in virus-infected epithelial cells of respiratory track leads to an inefficient cell pyroptosis that is critical for HPV removal, which consequently induces the epithelial hyperplasia. We will use approaches such as cell culture, gene knock -down and knock-in, as well as animal model to verify this hypothesis so that to understand the underlined formation mechanism of papillary epithelial hyperplasia in JO-RRP patients.