Annals of the American Thoracic Society

Mast cells (MCs) are among the first cell types associated with allergies and asthma. Studies in human asthma have identified their presence in the lung submucosa and smooth muscle and also in the airway epithelium. As our understanding of the distribution and location of these MCs in the human airway has increased, it is clear that much remains to be understood regarding the presence and subtype of these MCs in relationship to asthma phenotypes, defined both clinically and on the basis of immunologic pathways. Human MCs have traditionally been divided into two major subtypes based on the protease granule content, with tryptase representing total MCs. There is emerging evidence that in the epithelium, MCs of an altered subtype (with tryptase, chymase, and/or carboxypeptidase A3) may play a role in the pathophysiology of poorly controlled, severe, Th2-associated asthma.

Asthma is one of the most common chronic diseases in the United States, affecting 6 to 8% of the population (1) and causing 4,000 deaths annually (2). Loosely and clinically defined as a chronic inflammatory airway disorder with bronchial hyperresponsiveness and airflow obstruction (2), “asthma” affects all ages and racial groups. Severe asthma, seen up to 10% of patients with asthma (1), is characterized by a poor response to standard inhaled and systemic corticosteroid (CS) treatment (3). The American Thoracic Society workshop defined severe asthma as requiring high-dose inhaled CS treatment and/or continuous or near-continuous oral CSs and at least two of seven minor criteria including: regular short-acting β-agonist use, persistent airway obstruction, frequent urgent care asthma visits and/or oral CS bursts, prompt deterioration with reduction in CS dose, or history of a near-fatal asthma event (4).

Severe asthma, as defined above, is strongly associated with a high degree of morbidity. Twenty-three percent of patients with severe asthma in the NHLBI-sponsored Severe Asthma Research Program (SARP) had a history of a near-fatal event, and 54% had one or more urgent care visits per year (5). As early as 1999, severe asthma was recognized as pathologically heterogeneous, with approximately 50% identified to have a persistent eosinophilic (and mast cell [MC]-associated) inflammation despite CS therapy, and associated with a more exacerbation-prone disease (3). Unbiased cluster analysis of patients with severe asthma further identified five distinct clusters, supporting the heterogeneity of asthma (6). Expanding to all asthma, molecular phenotyping supports the presence of a Th2 cytokine- (and MC-) associated subgroup of asthma (79). Classification of asthma in relation to its phenotypes should allow better association of pathobiology and the resulting clinical characteristics. Substantial evidence now exists to support the role of the MC in at least some of these clusters.

The human MC is a resident inflammatory cell expressing CD34, c-kit, and the high-affinity IgE receptor (10). Originating from bone marrow precursors, MC precursors circulate to specific tissue sites where they mature and become “resident.” Unfortunately, human MCs remain difficult to study, as they are not present as circulating blood cells, and human MC lines bear little resemblance to primary cells. Thus, most human MC studies are descriptive, with few mechanistic data available. However, studies in mice and humans suggest that the environment where the MC or its precursor settles may determine its subtype (11, 12). In humans, the tissue environment is believed to contribute to two major MC subtypes, identified by their protease-rich cytoplasmic granule content. The MCT contains tryptase primarily and predominates in alveolar septae, airway epithelium, and submucosa, as well as small intestinal submucosa. It is believed to represent a mucosal MC phenotype (10, 13). Under normal circumstances, the MCT represents the majority of lung MCs. In contrast, the MCTC subtype is identified by both chymase and tryptase. Traditionally, this phenotype predominates in the skin and small intestinal submucosa (10, 11, 13, 14). Although it has been proposed to contain carboxypeptidase A3 (CPA3), hematopoietic prostaglandin D synthase (HPGDS), and cathepsin G, the specificity of these enzymes for the MCTC remains poorly understood (11, 12, 1518). Very little is understood regarding the factors that control either of these MC subtypes. In asthma, MCs of both subtypes have been identified in the airway submucosa, smooth muscle, and epithelium.

MC activation occurs through several paths, but classically through interaction of an antigen/allergen with its specific IgE antibody bound to its high-affinity receptor (FcεRI) on the MC membrane. On activation, degranulation releases a variety of granule-associated inflammatory mediators, including histamine, proteoglycans (heparin and chondroitin sulfate), and the neutral proteases (tryptase, chymase, and carboxypeptidase A [CPA]) (10, 19). MC activation initiates de novo synthesis of leukotrienes and through the action of HPGDS produces prostaglandin (PG) D2. Some of the products released and formed by activated MCs in humans are summarized in Table 1.

Table 1. Summary of types of products released when human mast cells are activated

Mediator TypePreformedLipid-derivedCytokines and Growth Factors
Selected productsTryptasePGD2IL-1α/β
ChymasePGE2IL-3
CPA3LTB4IL-4
Cathepsin GLTC4IL-5
HistamineIL-13
HeparinGM-CSF
Chondroitin sulfateIFN-α
SCF
TGF-β1
TNF
TSLP
VEGF

Definition of abbreviations: CPA3 = carboxypeptidase A3; GM-CSF = granulocyte/macrophage colony stimulating factor; IFN-α = interferon alpha; LT = leukotriene; PG = prostaglandin; SCF = stem cell factor; TGF = transforming growth factor; TNF = tumor necrosis factor; TSLP = thymic stromal lymphopoietin; VEGF = vascular endothelial growth factor.

These MC mediators have been implicated in inflammatory responses such as bronchospasm and airway hyperresponsiveness in asthma (20, 21). However, MCs can also be activated by osmotic and temperature changes and innate stimuli and can undergo a process known as “piecemeal degranulation,” such that a level of chronic activation can be observed in the absence of acute degranulation (22). Even though MCs have been traditionally defined by the presence of tryptase and chymase, the factors controlling these MC subtypes and the relative expression of these mediators in relation to the specific MC subtypes is not fully understood.

MCs were among the first cells associated the pathogenesis of asthma and allergies through type I IgE-mediated hypersensitivity reactions, likely through activation of epithelial MCs. Early studies of the immediate response to endobronchial instillation of allergen in mild asthma demonstrated marked increases in MC mediators, including tryptase, histamine, leukotriene C4, and PGD2 in lavage fluid (2325). The role of IgE activation of the MC in allergic asthma has now been confirmed by efficacy studies of the humanized monoclonal antibody omalizumab, which recognizes and binds to the Fc portion of the IgE molecule and thereby prevents the ability of IgE crosslinking to activate MCs. Use of omalizumab in mild to moderate allergic asthma reduced both the immediate and late response to allergen challenge, while also decreasing exacerbations chronically in more severe asthma (2630). Despite this strong immunobiologic connection of IgE to MCs and their activation, not all patients with allergic asthma respond to anti-IgE therapy. The reasons for the variability in response are not well understood, but could relate to the heterogeneity of the underlying pathobiology.

Evidence for MCs in the Submucosa and Smooth Muscle

In contrast to the short-term and immediate allergic reactions, the presence and activation of MCs in chronic severe asthma is more complex. MCT have long been appreciated to be increased in both submucosa and smooth muscle in steroid-naive patients with mild asthma (3133). In contrast, the addition of CS therapy appears to profoundly decrease submucosal MCT (33, 34). Despite this general effect of CSs on MCT, therapy-resistant severe asthmatic airways have higher percentages of MCTC than milder asthma (33). In addition, tissue studies of severe asthmatic airways have higher numbers of IgE-bound MCs, and the numbers are highest in those with a high degree of eosinophilic inflammation, consistent with an association of IgE-bound MCs with a Th2 inflammatory process (35). Moreover, the presence of IgE bound to MCs was associated with more severe exacerbations (35). MCs are also increased in the small airway wall and alveolar attachments, with the highest density of MCs present in these distal portions of the lung. The numbers of MCs, particularly MCTC, were substantially higher than the numbers seen in control distal lungs from individuals who did not have asthma (36).

In airway smooth muscle bundles, increased numbers of MCT were found in subjects with asthma compared with subjects with eosinophilic bronchitis and normal control subjects and inversely correlated with the provocative concentration of methacholine causing a 20% fall in FEV1, implying that MCs in airway smooth muscle bundles may be associated with airway hyperreactivity/dysfunction (31). Tryptase, perhaps by degrading the airway neuropeptide bronchodilator vasoactive intestinal peptide, may decrease nonadrenergic neural inhibitory influence mediated by vasoactive intestinal peptide in airway nerves, promoting bronchial hyperresponsiveness (37, 38). This effect on airway hyperreactivity may also be explained by the observation that the number of MCT within airway smooth muscle bundles relates to the intensity of smooth muscle actin expression, suggesting that airway smooth muscle MCs promote a contractile phenotype mediated by tryptase (39). Furthermore, coculture of human airway smooth muscle cells with MCs increased smooth muscle actin expression and transforming growth factor (TGF) β secretion and promoted airway smooth muscle differentiation independently of IgE (39). These airway smooth muscle MCT also appear to be the predominant IL-4– and IL-13–expressing cells (40). Interestingly, however, CXC chemokines, induced by IFN-γ, are believed to be important chemoattractants for MCs to smooth muscle, suggesting non-Th2 interactions as well (41). Moreover, a recent mouse study suggested that IFN-γ could enhance MC responses (42). This suggests that both Th2-dependent and Th2-independent MC processes may exist in asthmatic airways.

Evidence for MCs in the Epithelium

Although MCs were first reported in the human proximal airways epithelium by electron microscopy in 1968 (43), only recently have studies begun to explore the MC phenotype in the asthmatic epithelium and its relation to asthma phenotypes. Recent gene expression profiling studies on freshly brushed human epithelial cells showed that 3 of the 13 differentially expressed genes between CS-naive patients with mild asthma and healthy control subjects were related to MCs (7). The increased expression of tryptase α/β1 and β2 and CPA3 (7) implies that MCs are present in the epithelial compartment of patients with mild asthma, with the increase in CPA3 suggesting they may have a distinct activation profile (Figure 1). Epithelial MCs express both tryptase and CPA3, with MCT appearing to predominate in patients with mild asthma. In contrast, an MCTC subtype, as identified by immunohistochemical staining, predominates in severe asthma (33). Thus, as disease severity increases, in combination with increasing doses of both inhaled and systemic CSs, the presence of an MCTC increases as well. In severe asthma, this increase in epithelial MCTC is associated with increased bronchoalveolar lavage fluid PGD2, suggesting an association of PGD2 with this MC subtype (33).

In vitro studies have long suggested Th2 cytokines can influence MC subtype, and even activity. An MC progenitor isolated from mouse bone marrow cells responds to IL-13 and stem cell factor (SCF) to specifically induce CPA3 (44). In purified human intestinal MCs, the addition of IL-4 to SCF enhanced MC proliferation, induced Th2 cytokine expression, and preferentially increased MCT phenotype expression (4547).

Ex vivo data now strongly support these in vitro findings. MCs are associated with eosinophils as well as a “Th2-like” molecular phenotype in the airway epithelium (3, 9, 33). Two subgroups of CS-naive patients with mild asthma (“Th2-high” and “Th2-low” asthma) have now been defined based on downstream epithelial gene signatures for IL-13. Immunohistochemical staining for MCs showed increased MC numbers in subjects with Th2-high asthma (9). Moreover, these MCs were found to have an unusual subtype (tryptase and CPA3 high and chymase low) (9). These data suggest that the epithelial MCs in asthma may be a specific and novel MC subtype expressing tryptase and CPA3 (9, 33). Similar to the Th2 signature, the presence of MCs in the epithelium predicted clinical response to CSs (9). A recent study of the epithelium from nasal polyps in subjects with chronic rhinosinusitis also supports MCs expressing tryptase and CPA3 with low levels of chymase, suggesting that this novel MC phenotype may also exist in upper airway disease states (48).

One of the primary MC lipid mediators, PGD2, has also been linked with development and maintenance of a Th2 immune process, as one of its receptors, chemoattractant receptor–homologous molecule expressed on TH2 lymphocytes (CRTH2/DP2), is preferentially expressed on Th2 lymphocytes, eosinophils, and basophils, suggesting a close relationship with Th2 immunity (49, 50). PGD2 is generated after activation of HPGDS, converting arachidonic acid to PGG2 and PGH2 by cyclooxygenases (51). It is mainly expressed in MCs, macrophages, dendritic cells, and Th2 cells (4951). Prior studies in nasal polyps, rhinosinusitis, and eosinophilic esophagitis suggest MCs are the predominant source of HPGDS (5254). In samples from human airway epithelial brushings obtained after bronchoscopy, HPGDS mRNA was significantly increased in subjects with severe and mild to moderate asthma compared with healthy control subjects (55). Human airway epithelial brushing HPGDS mRNA correlated strongly with the MC proteases, tryptase, and CPA3, supporting a common MC source in the epithelium. Importantly, elevated mRNA levels were confirmed by HPGDS immunohistochemical studies. HPGDS+ cells by IHC were increased in severe asthma and morphometrically appeared to be MCs (Figure 2) (55).

As anticipated by the immunology, subjects with Th2-high asthma, defined by peripheral blood eosinophilia (>300/mm3) and high fractional exhaled nitric oxide (55, 56), had significantly increased bronchoalveolar lavage fluid PGD2 and HPGDS+ cells in the epithelium (55). These data support the association of an activated HPGDS+ MC in the epithelium in patients with asthma. In addition to an association with Th2 inflammation, the presence of HPGDS+ cells was associated with a poorly controlled, exacerbating asthmatic phenotype, despite the use of inhaled CSs and even oral CSs. Thus, an HPGDS+/tryptase+ MC may play a more prominent role in the severe asthmatic Th2-high epithelium, but further coimmunostaining of the epithelium is needed to confirm this.

Activation of one of the PGD2 receptors, CRTH2, on Th2 cells induces Th2 cytokine production, which could further promote IgE pathway activation of MCs, contributing to elevated PGD2 in severe asthma (33, 55). Recent CRTH2 antagonist studies in patients with asthma (5759) have been mixed, but none have yet studied severe asthma. Further studies are needed to determine whether continued activation of the PGD2/CRTH2 pathway perpetuates a Th2 inflammatory process in certain asthma phenotypes.

Epithelial/Th2 Factors That Could Promote MC Alterations

Although epithelial specific influences on MCs are poorly studied, conditioned media from human airway epithelial cells stimulated with IL-13 (but not IL-13 alone) added to cord blood–derived MCs down-regulated chymase without affecting tryptase or CPA3 expression (9) (Figure 1). As the addition of IL-13 alone to cord blood MCs had no effect, these data suggest that a Th2-activated epithelium may alter the subtype of epithelial MCs in asthma. In severe asthma, it is unclear if MCTC in the epithelium are present despite IL-13 or if the lack of IL-4/IL-13 induces this subtype. Interestingly, although chymase protein is present in asthmatic lung tissue, there is no detectable chymase mRNA transcript (9, 33).

SCF (or c-kit ligand), important for MC adhesion, migration, growth, proliferation, and survival through activation of c-kit receptor (a defining MC feature), is also expressed by airway epithelial cells and reportedly increased by IL-13 (10, 60, 61). Patients with Th2-high asthma had high epithelial SCF gene expression by microarray (9), suggesting SCF could contribute to the migration and survival of MCs in the epithelium. As noted previously, the TGF-β family has also been suggested to impact MC differentiation. TGF-β1 and 2 are highly expressed by asthmatic epithelium in severe asthma, increase in response to IL-13, and through induction of the MC chemoattractant IL-9 could also contribute to enhanced epithelial MCs (6264). Interestingly, in human intestinal MCs, TGF-β1 also up-regulated PGD2 generation and enhanced the percentage of MCTC but reduced MCT and release of other classical MC mediators (histamine) (65). IL-33, constitutively expressed in epithelial cells but activated by MC proteases after its release, can also bind to MC IL1RL1 to enhance their maturation and activation (66). Both eotaxin-2 and 3 mRNA (and eotaxin-2 protein) are increased in airway epithelial brushings from patients with severe asthma (67). Interestingly, the common eotaxin receptor CCR3 has been shown to be present on MCs, particularly those with an MCTC phenotype (68). These studies suggest that epithelial SCF, TGF-β1, IL-4/IL-13, IL-33, and/or eotaxins could recruit or maintain MCs in the epithelium and alter their subtype (Figure 1). Understanding the impact of the epithelial environment to recruit and differentiate MCs is critical to understanding their role in asthma and severe asthma.

Th2-Related Genetic Polymorphisms in Relation to MCs

Polymorphisms in several genes related to several different MC-related processes have been reported to be associated with asthma. One of the first genes linked to asthma was in fact an MC gene. Early studies identified a connection between polymorphisms in the high-affinity receptor for IgE (FceRI) and elevated total and specific IgE (69, 70). Subsequent studies identified an association between IgE receptor polymorphisms and an aspirin-induced asthma phenotype (71, 72). Polymorphisms in the IL4Rα gene, which codes for a chain common to the receptor for both IL-4 and -13, is more common in African Americans. These polymorphisms were associated with increased numbers of MCT and IgE+ MCs in endobronchial biopsies of subjects with asthma and increased exacerbation risk (based on history of ICU admission and/or intubation) (73). Other studies have found an association with sequence variants of the CRTH2 gene with asthma and more recently an association with the CRTH2 single-nucleotide polymorphism, rs533116, in an allergic asthma phenotype with increased circulating eosinophils and Th2 cytokine production (74, 75). These studies suggest that certain single-nucleotide polymorphisms in MC-related genes may contribute to a gain of function and promote MC survival, contributing to asthma pathogenesis.

MCs are believed to be important in the pathogenesis of asthma, specifically in association with a Th2-like phenotype. Increases in total MC number have been observed in the submucosa, smooth muscle, and, more recently, the epithelium in Th2-high asthma. Preliminary data strongly suggest that some MCs are of an altered functional subtype and directed toward specific tissue locations, like smooth muscle and the epithelium. MCT are, in fact, very common tissue cells and can be seen in the epithelium with atopy alone. MCs seen in association with activation of the PGD2/HPGDS pathway associate with Th2-like asthma and poor levels of asthma control and more severe asthma, suggesting the possibility of an altered subtype more strongly associated with disease. The continued expression of chymase in severe asthma suggests that other factors (beyond Th2 influences) may play a role in determining both MC subtypes and asthma phenotypes. Extensive studies combining in vitro and in vivo analysis of human subjects with asthma with targeted therapies are needed to better understand the role that MCs and their subtypes play in asthma and its phenotypes.

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Correspondence and requests for reprints should be addressed to Sally Wenzel, M.D., Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh Asthma Institute at UPMC/ University of Pittsburgh School of Medicine, 3459 Fifth Avenue, NW 628 Montefiore, Pittsburgh, PA 15213. E-mail:

Author disclosures are available with the text of this article at www.atsjournals.org.

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Annals of the American Thoracic Society
10
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