Linking innate and adaptive immune responses in allergic asthma.

Abstract

Allergic asthma has long been considered an inappropriate response to inhaled allergens mediated primarily by Th2 CD4+ T-cells that secrete IL-4, IL-5 and IL-13. Particulate matter, endotoxin and other bacterial products present in house dust activate innate immune responses and may influence the adaptive response to allergens. How this occurs and whether it is protective from or contributing to the asthmatic phenotype remains unclear. In a clinically relevant model of asthma-like pulmonary inflammation we determined if innate signaling of Gram-negative bacteria through TLR4, CXC-chemokine-mediated neutrophil recruitment and complement activation influenced adaptive responses to allergens. C3H/HeJ mice that are defective in TLR4 signaling were immunized and challenged with house dust collected from the homes of asthmatic children and extracted in sterile PBS. Defective TLR4 signaling resulted in an augmented Th2 cytokine response without effecting Th1 cytokine production. Furthermore CC chemokine levels and eosinophil influx into the airway were also increased in the absence of TLR4 signaling. The concentration of neutrophil chemoattractants KC and MIP-2 were comparable between groups despite defective TLR4 signaling. Fitting with comparable chemoattractant secretion, neutrophil recruitment to the lung was similar in wild-type and TLR4-defective mice. In order to determine the importance of KC and MIP-2 in neutrophil recruitment to the lung, these chemokines were neutralized by antibody depletion. Antibody treated animals had significantly lower neutrophil and lymphocyte levels in the BAL fluid and decreased plasma IgE. These data suggest that CXC chemokines are important in the IL-13-mediated secretion of IgE. Mice deficient in complement factor 5 were immunized and challenged with house dust extract and airway responses were determined. The complement system is an essential part of the innate immune response to pathogens. Here we report mice deficient in complement factor 5 have enhanced airway hyperresponsiveness. Complement factor 5 deficient animals also have an increased concentration of cysteinly-leukotrienes in the BAL fluid. These data suggest that innate response can influence the adaptive response to allergens. The link between the innate and adaptive immune response to allergens may lie in IL-13 since interference with innate pathways altered IgE secretion and leukotriene secretion which are mediated by IL-13.