Chitin Checking — Novel Insights into Asthma
http://www.100md.com
《新英格兰医药杂志》
Westernized countries are in the midst of an asthma epidemic. Despite much effort, therapeutic advances have not kept pace with the dramatic increases in the incidence, prevalence, and severity of allergic asthma that have occurred over the past two decades in such countries. A recent study by Zhu et al. provides new and unexpected insight into the pathogenesis of allergic asthma that could fuel the development of new therapies.1
Allergic asthma is thought to result from maladaptive inflammatory responses to ubiquitous environmental proteins in genetically susceptible persons. More specifically, allergic asthma is a chronic inflammatory disorder of the airways mediated by CD4+ T cells polarized to a type 2 helper (Th2) phenotype. Th2 cytokines, including interleukin-4, interleukin-5, and interleukin-13, drive the cardinal features of the disease: pulmonary eosinophilia, elevated concentrations of serum IgE, airway hyperresponsiveness, and excessive production of mucus in the airways (Figure 1). In particular, the Th2 effector cytokine interleukin-13 has a critical role in mediating airway hyperresponsiveness and mucous metaplasia, the elements of allergic asthma that are most closely linked to disease expression.2 These pathologic immune responses have long been recognized to mirror beneficial immune responses to helminth infection.
Figure 1. Novel Insights into the Mechanisms Underlying the Development of Allergen-Induced Hyperresponsiveness and Inflammation of the Airways.
Allergens and helminths alike induce the polarization of CD4+ T cells to a Th2 phenotype, leading to the production of the Th2 cytokines interleukin-4, interleukin-5, interleukin-9, and interleukin-13. Of these cytokines, interleukin-13 is thought to be the primary effector molecule of the allergic airway response. Recent insights suggest that interleukin-13–mediated induction of an acidic mammalian chitinase by airway epithelial cells and macrophages may underlie the development of airway hyperresponsiveness and airway inflammation after exposure to an allergen. Although the exact mechanisms by which chitinase regulates these pathophysiological features of the disease are unknown, expression of acidic mammalian chitinase in epithelial cells induces the production of monocyte chemoattractant protein 1 (MCP-1) and eotaxin-1, which are thought to play a major role in the recruitment and activation of inflammatory cells such as eosinophils, T cells, and macrophages in lung tissues.
The work of Zhu and colleagues sheds new light on these twinned responses.1 Chitin is a carbohydrate polymer found in nematodes, crustaceans, insects, and fungi, but not mammals. As might be expected, chitinases inhibit the growth of chitin-containing organisms, and a variety of life forms, including plants, insects, and fish, use chitinases as a weapon against chitin-expressing pathogens.3 Mammalian chitinases have recently been identified.4 Although a role of these enzymes in antiparasitic responses remains to be defined, Zhu et al. have implicated one such chitinase in allergic airway responses. They found that the expression of acidic mammalian chitinase (AMCase) by airway epithelia and pulmonary macrophages is dramatically up-regulated both in a mouse model of asthma and in allergic asthma in humans.1 More important, they showed that the enzyme is critical to disease expression in an experimental model of asthma. Neutralization of the chitinase, with either antibodies or the chitinase inhibitor allosamidin, ameliorated airway inflammation as well as airway hyperresponsiveness. Since airway hyperresponsiveness and excessive mucous production have often been experimentally separable from other hallmarks of Th2-driven inflammation, such as eosinophilia and increased IgE concentrations, the involvement of AMCase in the pathogenesis of allergic airway hyperresponsiveness raises the question of whether AMCase has a similar role in allergic mucous metaplasia.
The induction of AMCase is dependent on interleukin-13, and neutralization or inhibition of AMCase does not itself alter the expression of Th2 cytokines. Thus, the available data place AMCase in the effector cascade downstream of interleukin-13 in allergic asthma; perhaps it increases interleukin-13–dependent production of epithelial chemokines (Figure 1).1 Details of the mechanism of action of AMCase in asthma remain to be defined. That allosamidin ameliorates pathological changes suggests that enzyme activity is likely to be important. However, the lack of endogenous mammalian chitins suggests that other, unidentified endogenous substrates or other enzymatic activities are involved.
The implication of chitinases in allergic disease raises some more general points. Several very common allergens derive from chitin-containing organisms, including house-dust mites, cockroaches, and fungi. Although the allergens themselves do not contain chitin, the presence of chitin in the organisms producing the allergens (like the presence of chitin in pathogenic helminths) suggests that the Th2 pattern of immune response to these products may not be all that misguided.
What drives Th2-polarized immune responses, whether helpful or harmful? The activation and polarization of T-cell responses are largely under the control of the innate immune system. In the case of responses mediated by type 1 helper (Th1) cells, the innate immune receptors and environmental ligands that drive activation and polarization are known. Engagement of receptors of the toll-like receptor (TLR) family on dendritic cells by the molecular signatures of bacteria, viruses, and protozoa drives T-cell activation and Th1 polarization. Study of the TLRs has not provided similar insights into the receptors and ligands involved in the initiation of immune responses driven by helminths and allergens, leading to the hypothesis that Th2 polarization is a default response that occurs in the absence of TLR signaling that promotes Th1 responses. Since chitin is present in both helminths and organisms that provide a rich source of allergens, could chitin itself drive Th2 polarization? This mechanism is unlikely: chitin particles have been reported to drive Th1 polarization.5 However, the presence of common carbohydrate signatures in nematodes and allergenic organisms suggests that an experimental focus on other carbohydrate signatures held in common may uncover specific environmental cues for Th2 polarization. Since all chitin-containing organisms express chitinases, and several such chitinases are allergens, research on the question of whether exogenous chitinases promote Th2 polarization would seem to be warranted.
In the nearer term, the study by Zhu and colleagues suggests AMCase as a therapeutic target in allergic asthma. Close examination of other molecules induced during Th2-mediated inflammatory processes in both helminth infection and allergy is clearly warranted. Many such molecules have been identified, including trefoil factors and arginases. New therapeutic targets may be derived from them as well.
Source Information
From the Divisions of Immunobiology and Molecular Immunology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati.
References
Zhu Z, Zheng T, Homer RJ, et al. Acidic mammalian chitinase in asthmatic Th2 inflammation and IL-13 pathway activation. Science 2004;304:1678-1682.
Wills-Karp M, Luyimbazi J, Xu X, et al. Interleukin-13: central mediator of allergic asthma. Science 1998;282:2258-2261.
Herrera-Estrella A, Chet I. Chitinases in biological control. EXS 1999;87:171-184.
Boot RG, Blommaart EF, Swart E, et al. Identification of a novel acidic mammalian chitinase distinct from chitotriosidase. J Biol Chem 2001;276:6770-6778.
Shibata Y, Foster LA, Bradfield JF, Myrvik QN. Oral administration of chitin down-regulates serum IgE levels and lung eosinophilia in the allergic mouse. J Immunol 2000;164:1314-1321.(Marsha Wills-Karp, Ph.D.,)
Allergic asthma is thought to result from maladaptive inflammatory responses to ubiquitous environmental proteins in genetically susceptible persons. More specifically, allergic asthma is a chronic inflammatory disorder of the airways mediated by CD4+ T cells polarized to a type 2 helper (Th2) phenotype. Th2 cytokines, including interleukin-4, interleukin-5, and interleukin-13, drive the cardinal features of the disease: pulmonary eosinophilia, elevated concentrations of serum IgE, airway hyperresponsiveness, and excessive production of mucus in the airways (Figure 1). In particular, the Th2 effector cytokine interleukin-13 has a critical role in mediating airway hyperresponsiveness and mucous metaplasia, the elements of allergic asthma that are most closely linked to disease expression.2 These pathologic immune responses have long been recognized to mirror beneficial immune responses to helminth infection.
Figure 1. Novel Insights into the Mechanisms Underlying the Development of Allergen-Induced Hyperresponsiveness and Inflammation of the Airways.
Allergens and helminths alike induce the polarization of CD4+ T cells to a Th2 phenotype, leading to the production of the Th2 cytokines interleukin-4, interleukin-5, interleukin-9, and interleukin-13. Of these cytokines, interleukin-13 is thought to be the primary effector molecule of the allergic airway response. Recent insights suggest that interleukin-13–mediated induction of an acidic mammalian chitinase by airway epithelial cells and macrophages may underlie the development of airway hyperresponsiveness and airway inflammation after exposure to an allergen. Although the exact mechanisms by which chitinase regulates these pathophysiological features of the disease are unknown, expression of acidic mammalian chitinase in epithelial cells induces the production of monocyte chemoattractant protein 1 (MCP-1) and eotaxin-1, which are thought to play a major role in the recruitment and activation of inflammatory cells such as eosinophils, T cells, and macrophages in lung tissues.
The work of Zhu and colleagues sheds new light on these twinned responses.1 Chitin is a carbohydrate polymer found in nematodes, crustaceans, insects, and fungi, but not mammals. As might be expected, chitinases inhibit the growth of chitin-containing organisms, and a variety of life forms, including plants, insects, and fish, use chitinases as a weapon against chitin-expressing pathogens.3 Mammalian chitinases have recently been identified.4 Although a role of these enzymes in antiparasitic responses remains to be defined, Zhu et al. have implicated one such chitinase in allergic airway responses. They found that the expression of acidic mammalian chitinase (AMCase) by airway epithelia and pulmonary macrophages is dramatically up-regulated both in a mouse model of asthma and in allergic asthma in humans.1 More important, they showed that the enzyme is critical to disease expression in an experimental model of asthma. Neutralization of the chitinase, with either antibodies or the chitinase inhibitor allosamidin, ameliorated airway inflammation as well as airway hyperresponsiveness. Since airway hyperresponsiveness and excessive mucous production have often been experimentally separable from other hallmarks of Th2-driven inflammation, such as eosinophilia and increased IgE concentrations, the involvement of AMCase in the pathogenesis of allergic airway hyperresponsiveness raises the question of whether AMCase has a similar role in allergic mucous metaplasia.
The induction of AMCase is dependent on interleukin-13, and neutralization or inhibition of AMCase does not itself alter the expression of Th2 cytokines. Thus, the available data place AMCase in the effector cascade downstream of interleukin-13 in allergic asthma; perhaps it increases interleukin-13–dependent production of epithelial chemokines (Figure 1).1 Details of the mechanism of action of AMCase in asthma remain to be defined. That allosamidin ameliorates pathological changes suggests that enzyme activity is likely to be important. However, the lack of endogenous mammalian chitins suggests that other, unidentified endogenous substrates or other enzymatic activities are involved.
The implication of chitinases in allergic disease raises some more general points. Several very common allergens derive from chitin-containing organisms, including house-dust mites, cockroaches, and fungi. Although the allergens themselves do not contain chitin, the presence of chitin in the organisms producing the allergens (like the presence of chitin in pathogenic helminths) suggests that the Th2 pattern of immune response to these products may not be all that misguided.
What drives Th2-polarized immune responses, whether helpful or harmful? The activation and polarization of T-cell responses are largely under the control of the innate immune system. In the case of responses mediated by type 1 helper (Th1) cells, the innate immune receptors and environmental ligands that drive activation and polarization are known. Engagement of receptors of the toll-like receptor (TLR) family on dendritic cells by the molecular signatures of bacteria, viruses, and protozoa drives T-cell activation and Th1 polarization. Study of the TLRs has not provided similar insights into the receptors and ligands involved in the initiation of immune responses driven by helminths and allergens, leading to the hypothesis that Th2 polarization is a default response that occurs in the absence of TLR signaling that promotes Th1 responses. Since chitin is present in both helminths and organisms that provide a rich source of allergens, could chitin itself drive Th2 polarization? This mechanism is unlikely: chitin particles have been reported to drive Th1 polarization.5 However, the presence of common carbohydrate signatures in nematodes and allergenic organisms suggests that an experimental focus on other carbohydrate signatures held in common may uncover specific environmental cues for Th2 polarization. Since all chitin-containing organisms express chitinases, and several such chitinases are allergens, research on the question of whether exogenous chitinases promote Th2 polarization would seem to be warranted.
In the nearer term, the study by Zhu and colleagues suggests AMCase as a therapeutic target in allergic asthma. Close examination of other molecules induced during Th2-mediated inflammatory processes in both helminth infection and allergy is clearly warranted. Many such molecules have been identified, including trefoil factors and arginases. New therapeutic targets may be derived from them as well.
Source Information
From the Divisions of Immunobiology and Molecular Immunology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati.
References
Zhu Z, Zheng T, Homer RJ, et al. Acidic mammalian chitinase in asthmatic Th2 inflammation and IL-13 pathway activation. Science 2004;304:1678-1682.
Wills-Karp M, Luyimbazi J, Xu X, et al. Interleukin-13: central mediator of allergic asthma. Science 1998;282:2258-2261.
Herrera-Estrella A, Chet I. Chitinases in biological control. EXS 1999;87:171-184.
Boot RG, Blommaart EF, Swart E, et al. Identification of a novel acidic mammalian chitinase distinct from chitotriosidase. J Biol Chem 2001;276:6770-6778.
Shibata Y, Foster LA, Bradfield JF, Myrvik QN. Oral administration of chitin down-regulates serum IgE levels and lung eosinophilia in the allergic mouse. J Immunol 2000;164:1314-1321.(Marsha Wills-Karp, Ph.D.,)