Th2 sensitization to aeroallergens in asthma

Atopic asthma is an allergic disorder of the airways in which environmental protein antigens trigger Th2 pulmonary inflammation resulting in airway obstruction. The majority of these aeroallergens are inert proteins that are not themselves microbial and therefore would not be expected to initiate adaptive immune responses. Recent advances in the field of Toll-like receptors (TLRs) indicate that the innate immune system is crucial in the initiation of Th1 but not Th2 immunity. Because pathogen-derived TLR signals can result in IL-12 production it was believed that TLR signaling precludes the development of Th2 responses. However, the signals required for initiation of Th2 immunity remained undefined. Therefore, we addressed the central question of how Th2 immunity is generated to these inhaled protein antigens.; We hypothesized that Th2 sensitization to inhaled allergens requires signals from the innate immune system, and specifically TLR4 activation by lipopolysaccharide (LPS). To study the role of TLR4 in Th2 activation we used an Ovalbumin-induced murine model of allergic airway disease. Our conclusion from these studies is that LPS plays a critical role in Th2 sensitization. Not only is it necessary for efficient Th2 priming, but the effect of LPS on the adaptive immune system is dose dependent. The presence of high dose LPS during antigen exposure results in Th1-mediated pulmonary inflammation and is associated with IL-12 production.; Clinically, patients with allergic disorders are identified only after sensitization has occurred. Therefore, we extended the above studies to examine the role of on-going Th2 immune responses on the process of Th2 sensitization. We hypothesized that activated Th2 cells facilitate sensitization to new antigens in the absence of TLR4 signaling. Using a transgenic Th2 adoptive transfer model of asthma, we show that active Th2-mediated pulmonary inflammation initiates Th2 sensitization to bystander antigens and that this process occurs without the aid of TLR4 signaling, but is dependent on IL-4 production by the active Th2 population. The work presented in this thesis helps define the specific rules governing Th2 sensitization to inhaled protein antigens.