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580 ParT FIvE Allergic Diseases

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FIG 41.7 Mechanisms of Allergenic Protease-Dependent Induction of Allergic Airway Disease.
Inhaled proteases or protease 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-helper 2 (Th2) responses that coordinate both the allergic inflammation and physiological changes
that typify allergic respiratory tract disease. Initial innate immune responses induced by proteases
include induction of airway chemokines that favor recruitment of allergic effector cells including
Th2 cells (1). Likely airway cellular targets of proteinases include basophils, epithelial cells, smooth
muscle cells, and macrophages (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 proallergic
cytokines, such as thymic stromal lymphopoietin (TSLP), interleukin-33 (IL-33), and IL-25 that
promote Th2 responses. Allergenic proteinases also likely act on soluble substrates, such as
complement, especially C3 to generate C3a, the ligand for the C3aR, and fibrinogen, creating
fibrinogen cleaved products (FCPs) that signal through Toll-like receptor 4 (TLR4) to coordinate
antifungal immunity and promote Th2 responses. CD25 is another immune receptor present on
T cells that can be cleaved by proteinases, potentially to favor Th2 cytokine secretion. Finally,
proteinases act directly on antigen-presenting cells, such as dendritic cells (DCs), through an
unknown mechanism in secondary lymphoid organs, such as lymph nodes, to promote their
maturation in a manner that favors Th2 cell differentiation from naïve precursor (ThP) T cells (3).
(Modified from Porter PC, Yang T, Luong A, et al. Proteinases as molecular adjuvants in allergic
airway disease. Biochim Biophys Acta 2011;1810:1059–65.)

allergic disorders and hence warrant consideration in the dif-
ferential diagnosis of airway inflammatory disorders. Two of the Hypersensitivity Pneumonitis
most important nonallergic airway obstructive immune disorders Hypersensitivity pneumonitis (HP) is a non–IgE-mediated
are hypersensitivity pneumonitis and chronic obstructive pul- inflammatory lung disease that results from recurrent exposure
monary disease. to a wide variety of inhaled antigenic aerosols containing organic