A Protease-Activated Pathway Underlying Th Cell Type 2 Activation and Allergic Lung Disease

TLDR

Respiratory allergens that trigger Th2‑dependent allergic lung inflammation fall into two functional classes: type I allergens require remote priming with adjuvants to overcome airway tolerance, whereas type II allergens can induce robust disease without such priming. The study aims to demonstrate that proteolytic activity shared by diverse type II allergens is both necessary and sufficient to overcome airway tolerance and induce pulmonary allergic disease. Using an experimental model, the authors show that active protease acting on endogenous substrates is required for type II allergen–mediated airway tolerance abrogation and allergic lung disease. They found that only active protease on endogenous substrates confers allergenic potency, that adding purified protease to a type I allergen can induce disease, and that exogenous proteases are likely required for type II allergens to overcome airway tolerance, suggesting a potential role in asthma.

Abstract

Abstract The respiratory allergens that induce experimental Th cell type 2-dependent allergic lung inflammation may be grouped into two functional classes. One class of allergens, in this study termed type I, requires priming with adjuvants remote from the lung to overcome airway tolerogenic mechanisms that ordinarily preclude allergic responses to inhaled Ags. In contrast, the other, or type II, allergen class requires neither remote priming nor additional adjuvants to overcome airway tolerance and elicit robust allergic lung disease. In this study, we show in an experimental model that diverse type II allergens share in common proteolytic activity that is both necessary and sufficient for overcoming airway tolerance and induction of pulmonary allergic disease. Inactivated protease and protease-free Ag fragments showed no allergenic potency, demonstrating that only active protease acting on endogenous substrates was essential. Furthermore, induction of airway tolerance could be aborted and allergic lung disease established by simply adding purified protease to a type I allergen. Thus, exogenous proteases are common to type II allergens and may be generally required to overcome the innate resistance of the airway to Th cell type 2 activation and allergic inflammation, raising concern for their potential contribution to diseases such as asthma.