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.
|Millien, Valentine Ongeri; Lu, Wen; Mak, Garbo et al. (2014) Airway fibrinogenolysis and the initiation of allergic inflammation. Ann Am Thorac Soc 11 Suppl 5:S277-83|
|Knight, John M; Lee, Seung-Hyo; Roberts, Luz et al. (2014) CD11a polymorphisms regulate TH2 cell homing and TH2-related disease. J Allergy Clin Immunol 133:189-97.e1-8|
|Porter, Paul C; Lim, Dae Jun; Maskatia, Zahida Khan et al. (2014) Airway surface mycosis in chronic TH2-associated airway disease. J Allergy Clin Immunol 134:325-31|
|Mak, Garbo; Porter, Paul C; Bandi, Venkata et al. (2013) Tracheobronchial mycosis in a retrospective case-series study of five status asthmaticus patients. Clin Immunol 146:77-83|
|Millien, Valentine Ongeri; Lu, Wen; Shaw, Joanne et al. (2013) Cleavage of fibrinogen by proteinases elicits allergic responses through Toll-like receptor 4. Science 341:792-6|
|Shearer, William T; Corry, David B (2012) High prevalence of asthma in HIV-infected adults: new insights. J Allergy Clin Immunol 129:715-6|
|Yang, Tianshu; Ramocki, Melissa B; Neul, Jeffrey L et al. (2012) Overexpression of methyl-CpG binding protein 2 impairs T(H)1 responses. Sci Transl Med 4:163ra158|
|Grünig, Gabriele; Corry, David B; Reibman, Joan et al. (2012) Interleukin 13 and the evolution of asthma therapy. Am J Clin Exp Immunol 1:20-27|
|Porter, Paul; Polikepahad, Sumanth; Qian, Yuping et al. (2011) Respiratory tract allergic disease and atopy: experimental evidence for a fungal infectious etiology. Med Mycol 49 Suppl 1:S158-63|
|Porter, Paul C; Yang, Tianshu; Luong, Amber et al. (2011) Proteinases as molecular adjuvants in allergic airway disease. Biochim Biophys Acta 1810:1059-65|
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