Proteinases as molecular adjuvants in allergic airway disease

Background: Asthma and related respiratory tract allergic diseases are among the most common chronic diseases of adults and children. Despite their importance, disease course cannot be predicted and treatment remains non-specific and potentially hazardous, with no means for cure. Improved clinical management of asthma will require an improved understanding of the fundamental factors that initiate allergic inflammation, especially T helper type 2 (T _H2) cell induction. Scope of review: In this review, we explore the Proteinase Hypothesis of allergic airway disease, considering specifically how organismal proteinases contribute to the expression of allergic disease and potentially important proteinase signaling pathways. Major conclusions: Proteinases from diverse sources (bacteria, fungi, plants) may cause occupational asthma by acting as immune adjuvant factors that specifically elicit T _H2 cell-dependent allergic inflammation. However, more conventional allergic airway diseases (asthma, allergic sinusitis) are more likely to arise from contained fungal or viral infections of the airway in which proteinases are produced and serve as major virulence factors. Proteinases may elicit allergic disease by disrupting numerous cellular proteins, potentially including Toll like receptor (TLR) 4, but critical proteinase-activated signaling pathways remain largely unknown. General significance: Clarification of how proteinases cause allergic disease, specifically confirming an infectious basis for airway proteinase exposure, will likely radically advance how asthma and related respiratory tract disorders are diagnosed and treated. This article is part of a Special Issue entitled Biochemistry of Asthma.