Immunobiology of critical pediatric asthma.

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.