Leal Vinicius Nunes Cordeiro, Genov Isabel Rugue, Mallozi Márcia C, Solé Dirceu, Pontillo Alessandra
Laboratorio de Imunogenética, Departamento de Imunologia, Instituto de Ciências Biomédicas/ICB, Universidade de São Paulo/USP, São Paulo, SP, Brazil.
Laboratorio de Imunogenética, Departamento de Imunologia, Instituto de Ciências Biomédicas/ICB, Universidade de São Paulo/USP, São Paulo, SP, Brazil; Ambulatorio de Alergia, Imunologia clinica e Reumatologia, Departamento de Pediatria, Universidade Federal de Sao Paulo/UNIFESP, São Paulo, SP, Brazil.
Mol Immunol. 2018 Jan;93:64-67. doi: 10.1016/j.molimm.2017.11.006. Epub 2017 Nov 15.
Considering its role in inflammation and recently described "alternative" roles in epithelial homeostasis and Th1/Th2 balance, we hypothesize that inflammasome genetics could contribute to the development of asthma. Selected functional polymorphisms in inflammasome genes are evaluated in a cohort of asthmatic children and their families. Gain-of-function NLRP1 variants rs11651270, rs12150220 and rs2670660 resulted significantly associated to asthma in trios (TDT) analysis; and rs11651270 and rs2670660 also with asthma severity and total IgE level in asthmatic children. NLRP1 activators in humans are still unknown, however we hypothesized that individuals with gain-of-function SNPs in NLRP1 could be more prone in activating inflammasome in the presence of asthma-related cell stressors (i.e. ER stress or ROS), and this activation contribute to exacerbate inflammatory response and asthma development. Gain-of-function IL1A rs17561 resulted significantly associated with a reduced pulmonary capacity in asthmatic children. IL18 rs5744256 which lead to lower serum level of IL-18 appeared to be associated to a worse response to bronchodilators. Concluding, this work provides evidences about the contribution of inflammasome genetics in the development of paediatric asthma, both considering its inflammatory role in alveolar macrophages (i.e.: NLRP1) or its homeostatic role in lung epithelial cells (i.e.: IL1A, IL18).
考虑到炎症小体在炎症中的作用以及最近所描述的其在上皮细胞稳态和Th1/Th2平衡中的“其他”作用，我们推测炎症小体遗传学可能促成哮喘的发生发展。在一组哮喘儿童及其家庭中评估了炎症小体基因中选定的功能性多态性。功能获得性NLRP1变体rs11651270、rs12150220和rs2670660在三联体（传递不平衡检验，TDT）分析中显示与哮喘显著相关；rs11651270和rs2670660还与哮喘儿童的哮喘严重程度和总IgE水平相关。人类中的NLRP1激活剂仍不明确，然而我们推测，在NLRP1中具有功能获得性单核苷酸多态性的个体在存在哮喘相关细胞应激源（即内质网应激或活性氧）时可能更易于激活炎症小体，并且这种激活有助于加剧炎症反应和哮喘的发展。功能获得性IL1A rs17561与哮喘儿童肺功能降低显著相关。导致血清IL - 18水平降低的IL18 rs5744256似乎与支气管扩张剂反应较差相关。总之，这项工作提供了证据，表明炎症小体遗传学在儿童哮喘的发生发展中具有作用，这既考虑到其在肺泡巨噬细胞中的炎症作用（即：NLRP1），也考虑到其在肺上皮细胞中的稳态作用（即：IL1A、IL18）。
