Proteinases as molecular adjuvants in allergic airway disease

Abstract

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(H)2) 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(H)2 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.

Figure 1. Mechanisms of allergenic proteinase-dependent induction of allergic airway disease

Inhaled proteinases or proteinase sources (e.g., fungal spores) initiate a series of molecular events in discrete lung compartments and involving distinct cell types that induce predominant airway T_H2 responses that coordinate both the allergic inflammation and physiological changes that typify allergic respiratory tract disease. Initial innate immune responses induced by proteinases include induction of airway chemokines that favor recruitment of allergic effector cells including T_H2 cells (1). Likely airway cellular targets of proteinases include basophils, airway epithelial cells and possibly airway smooth muscle cells (2). Activation of these cells by cleavage of cell surface receptors such as PAR2 and CD23 potentially leads to activation of these cells to produce pro-allergic cytokines such as TSLP and IL-25, the latter of which is activated by MMP7, an endogenous proteinase also induced by allergenic proteinases. Allergenic proteinases also likely act on soluble substrates such as complement, especially C3 to generate C3a, the ligand for the C3aR. CD25 is another immune receptor present on T cells that can be cleaved by proteinases, potentially to favor T_H2 cytokine secretion. Finally, proteinases act directly on antigen presenting cells such as dendritic cells through an unknown mechanism in secondary lymphoid organs such as lymph nodes to promote their maturation in a manner that favors T_H2 cell differentiation from naïve precursor (T_HP) T cells (3).

Figure 2. Proteinase-activated host defense reactions of insects and plants

Invasion of insects such as Drosophila melanogaster by fungal hyphae initiates a proteinase-activated enzymatic cascade involving the endogenous proteinase Persephone that terminates in the cleavage of Pro-spaetzle to yield spaetzle, the final common ligand for Toll. Activation of Toll induces a broadly effective anti-microbial defensive response against fungi, bacteria and other organisms. Similarly, bacterial proteinases such as AvrPphB can activate plant proteins such as PBS1 and RPS5 to induce a defense response against bacterial invasion.

Figure 3. Possible mechanisms by which allergenic proteinases may induce allergic responses through Toll like receptors

Similar to insect host defense reactions involving Toll, allergenic proteinases may induce enzymatic cascades leading to a common cleavage product that is capable of binding to one or more Toll-like Receptors (TLRs) and initiating essential allergic immune responses such as T_H2 differentiation and IgE secretion (Model 1). Alternatively, allergenic proteinases may cleave and directly activate distinct immune receptors such as CD23, CD25, and PAR2 to induce allergic responses (Model 2).