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CHaPTEr 41 Immunological Mechanisms of Airway Diseases and Pathways to Therapy 579

proteolytically derived anaphylatoxins, are both essential for the to fungus-sensitized patients with asthma; and (iv) experimental
expression and regulation of asthma in experimental systems. validation that filamentous fungi are infectious for the mouse
C3a signaling through the C3a receptor C3aR is required for airway and readily produce allergic airway disease that is com-
robust Th2 responses, allergic inflammation, and AHR in response parable with asthma. Moreover, fungal airway infection can induce
to airway allergen challenge. In contrast, C5a, which can signal atopy to innocuous bystander antigens, suggesting that fungal
through two receptors, C5aR and C5L2, appears to inhibit Th2 infection could underlie both atopy and respiratory tract allergic
responses, perhaps acting as a physiological antagonist of the disease. However, not all patients with allergic airway disease
allergic disease-promoting activity of C3a. 30 demonstrate fungus-specific immunity; neither are antifungal
Lipid mediators of inflammation of importance to allergic agents effective in all such patients, especially those with CRS.
airway disease include the LTs and prostaglandins (PGs). The Thus fungal airway infections may be etiologically relevant to
cysteinyl leukotrienes (CysLTC4, -D4, and -E4) signal through only a subset of allergic disease patients. 33
at least two major receptors to mediate some of the same allergic Respiratory viruses and particulate matter are also prominently
disease features as IL-13, including airway inflammation and linked to allergic airway disease. Approximately 70–80% of
AHR. Full expression of experimental allergic disease, in fact, children and adults test positive for human rhinovirus (HRV)
appears to require the concomitant expression of both IL-13 during acute disease exacerbations. Other respiratory viruses
and the CysLTs. However, IL-13 appears to be the dominant are likely to contribute to allergic disease pathogenesis, although
34
allergic mediator, perhaps accounting, in part, for why LT the mechanisms remain obscure. Particulate matter in the form
antagonism alone is not as effective as inhaled steroids in asthma. of tobacco smoke, diesel exhaust particles, and other forms of
Noncysteinyl LTs, such as LTB4, also contribute to the expression smoke is strongly linked to asthma exacerbation and enhanced
of allergic airway inflammation by controlling the recruitment atopy, as is exposure to ozone (O 3 ). What links these various
of allergic effector cells, including Th2 cells. 31 forms of air pollution to allergic disease may be the induction
Similarly, PGD 2 is an important mediator of Th2 cell recruit- of oxidative stress, which ultimately leads to enhanced activation
ment and allergic airway inflammation in rodent models, most of nuclear factor kappa B (NF-κB), enhanced Th2 cytokine release,
likely acting cooperatively with LTB4 and chemokines. Most and increased allergic inflammation. 35
other PGs are thought to promote allergic airway disease, Research from experimental systems has shed additional light
especially in aspirin-sensitive rhinitis and asthma. An important on how allergens initiate allergic inflammation and disease.
exception to this is PGE 2 , which exhibits potent antiallergic Although the structural features of allergens do not determine
activity. Other lipid mediators likely contributing to the expression their allergic character, a common biochemical feature that is
of allergic inflammation and airway obstruction are the throm- strongly associated with allergenicity is protease activity. Proteases,
boxanes and lipoxins. Thromboxane A 2 is a potent proinflam- as single molecules, are as effective as any complex allergen or
matory lipid derived from platelets, whereas lipoxins have the fungal infection in inducing allergic airway inflammation and
opposite effect and are antiinflammatory. 32 AHR when administered to rodents or inhaled by humans.
Household proteases are derived largely from fungi, suggesting
Environmental Factors and Allergic Disease Initiation again that airway infection caused by these organisms, which
The earliest immunological events that initiate Th2 responses would result in in situ protease production, may be an important
and the environmental factors that trigger them are incompletely mechanism underlying allergic disease induction. Irritation of
understood. Currently, asthma and to a large extent RS and AR the airways through viral infection, ozone exposure, and other
are believed to represent aberrant immunological responses to mechanisms further increases endogenous airway protease activity,
innocuous inhaled antigens. The very strong association between especially through induction of thrombin activity. 36
asthma and atopy supports this concept, with many allergens Analyses of diverse allergenic proteases suggest that they initiate
being relatively innocuous proteins derived from organisms that a complex, airway epithelial-centered mechanism in which the
are not otherwise harmful or infectious, such as those from dust epithelial cytokines TSLP, IL-33, and IL-25 are induced and lead
mites, cats, dogs, and plants. Atopy is further thought to represent to robust allergic responses. In part, this sequence is initiated
a fundamental underlying condition that leads, in some cases, by the action of exogenous and endogenous proteinases on the
to overt allergic disease, but whether atopy represents primarily terminal coagulation protein fibrinogen, which is secreted by
a genetically or an environmentally controlled condition remains airway epithelial cells into the airway lumen. Cleavage of fibrino-
unclear. Extensive analysis of allergens has revealed no consistent gen by proteases yields fibrinogen-cleaved products (FCPs) that
structural features, suggesting that physical properties are highly signal through Toll-like receptor 4 (TLR4) to initiate both
relevant to atopy and allergic disease expression. antifungal responses and innate allergic inflammation, including
37
A major exception to the intrinsically innocuous nature of ILC2 responses. Proteolytic activation of complement proteins
allergens is, however, the role of filamentous fungi, such as (e.g., C3) is also a crucial early event in the evolution of allergic
30
Aspergillus spp., and other potentially infectious causes of allergic airway disease. Th2 responses arise, in part, through the action
disease. Fungal sensitization is not different from sensitization of proteases on pulmonary dendritic cells (Fig. 41.7).
to any other allergen ubiquitously present in human environments.
However, fungi differ from all other allergen sources in that they NONALLERGIC RESPIRATORY TRACT
are both ubiquitous and able to actively infect and grow within INFLAMMATORY SYNDROMES
the respiratory tract. 33
A fungal infectious basis for allergic disease is also suggested Although the majority of respiratory tract inflammatory disease
by (i) the high rate of isolation of filamentous fungi from the is allergic, additional pulmonary immune-related disorders exist
airways in CRS, especially AFRS, and ABPA; (ii) the universal that are nonallergic and are responsible for considerable morbidity.
presence of fungus-specific immunity in subjects with AFRS The immunological mechanisms, etiological environmental
and ABPA; (iii) the efficacy of antifungal antibiotics when given factors, and therapies for these diseases are distinct from common