The broad, long-term objectives of this laboratory are to understand the immunological mechanisms underlying allergic lung disease. This proposal specifically will determine the earliest innate immune signaling pathway activated by allergens that conditions the lung for subsequent allergic lung disease. Further, we will determine the relationship between allergenic proteinases in home environments and the development of childhood asthma. Recent studies indicate that allergic asthma is the result of failure of immune tolerogenic mechanisms that are normally activated to suppress inflammatory responses to inhaled antigens. Commonly used experimental allergens such as ovalbumin are only transiently capable of avoiding tolerance and inducing robust airway inflammation and then only if administered initially remotely from the lung followed by airway antigen challenge. In contrast, we have developed more potent allergens derived from sources implicated in human allergic disease. Without requiring special adjuvants or protocols for administration, these fungal and pollen-derived allergens strongly induce allergic lung inflammation by bypassing airway immune tolerogenic mechanisms. These potent allergens contain strong proteinase activities that account entirely for their ability to induce and sustain chronically the asthma phenotype. Although non-fungal proteinases exist and are implicated in human asthma and other allergic disorders, our data indicate that dust from homes of asthmatic children contains primarily fungal proteinases. We therefore propose the novel hypothesis that proteinases represent an essential environmental adjuvant factor that is responsible for inducing allergic disease, especially in early life. The aims of this proposal are therefore to: 1. To evaluate the association between fungal proteinases and childhood asthma;and 2. To functionally characterize a novel innate signaling pathway of the airway activated by proteolytic allergen. We will conduct a case-control study involving Houston-area children with and without asthma to understand the association between active proteinase in house dust and asthma and, further, prepare allergens from fungi isolated from homes of asthmatic children and determine the innate immune mechanism by which they elicit disease in mice. This proposal links human and animal studies to unravel the fundamental immune mechanisms underlying allergic inflammation with the intent to develop novel therapies for asthma.