Galowitz Stacey, Chang Christopher
Division of Allergy and Immunology, Thomas Jefferson University, 1600 Rockland Road, Wilmington, DE, 19803, USA.
Clin Rev Allergy Immunol. 2015 Feb;48(1):84-96. doi: 10.1007/s12016-014-8409-z.
Asthma is a heterogeneous disease with numerous clinical phenotypes. Severe asthma constitutes about 10 % of all cases of asthma. There is significant geographic and regional variation in the incidence and severity of asthma. Other important factors include gender, ethnicity, living environment, lifestyle, socioeconomic class, and pathophysiology. These factors can often be identified as either genetic or environmental influences on asthma severity. The immune system derangements in severe asthma are poorly understood. Many molecules and cell types have been implicated in severe asthma, including neutrophils, airway epithelial cells, thymic stromal lymphopoietin, and even filaggrin. Recently, vitamin D has been thought to have a role in the severity of asthma. Aspirin exacerbated respiratory disease is an example of a phenotype that includes severe asthma as a feature. This suggests a role of leukotrienes or prostaglandins in the pathogenesis of severe asthma. Both the innate and adaptive immune system may play a role in the development of severe asthma. Besides filaggrin, other factors of the innate immune system, including TLR4 and TLR9 have been implicated in asthma. Airway epithelial cells possess pattern recognition receptors that recognize danger or pathogen-associated molecular patterns, and the result of binding of the ligand is the triggering of a signaling pathway that ultimately can lead to an activation of inflammatory mediators through the action of calcineurin and NF-κB. Components of the adaptive immune system, including TH2 and Th17 cells, have been implicated in the pathogenesis of asthma. The fact that so many molecules and cells may be variably involved in asthma patients, coupled with the presence of redundant pathways that lead to secretion of inflammatory mediators, make the development of effective drugs for the treatment of asthma extremely difficult. A better understanding of the heterogeneity and what drives this diversity on a genetic and epigenetic level will help to develop strategies for novel therapeutic agents or methods.
哮喘是一种具有多种临床表型的异质性疾病。重度哮喘约占所有哮喘病例的10%。哮喘的发病率和严重程度存在显著的地理和区域差异。其他重要因素包括性别、种族、生活环境、生活方式、社会经济阶层和病理生理学。这些因素通常可被确定为对哮喘严重程度的遗传或环境影响。人们对重度哮喘中的免疫系统紊乱了解甚少。许多分子和细胞类型都与重度哮喘有关，包括中性粒细胞、气道上皮细胞、胸腺基质淋巴细胞生成素，甚至中间丝相关蛋白。最近，维生素D被认为在哮喘严重程度中起作用。阿司匹林加重性呼吸系统疾病是一种以重度哮喘为特征的表型实例。这表明白三烯或前列腺素在重度哮喘的发病机制中起作用。固有免疫系统和适应性免疫系统可能都在重度哮喘的发展中起作用。除了中间丝相关蛋白外，固有免疫系统的其他因素，包括Toll样受体4（TLR4）和Toll样受体9（TLR9）也与哮喘有关。气道上皮细胞拥有模式识别受体，可识别危险或病原体相关分子模式，配体结合的结果是触发信号通路，最终可通过钙调神经磷酸酶和核因子κB的作用导致炎症介质的激活。适应性免疫系统的组成部分，包括辅助性T细胞2（TH2）和辅助性T细胞17（Th17），都与哮喘的发病机制有关。如此多的分子和细胞可能在哮喘患者中以不同方式参与，再加上存在导致炎症介质分泌的冗余途径，使得开发有效的哮喘治疗药物极其困难。更好地了解哮喘的异质性以及在遗传和表观遗传水平上驱动这种多样性的因素，将有助于制定新型治疗药物或方法的策略。
