Mast Cell and Basophils: Interaction with Ige and Responses to Toll Like Receptor Activators

Mast Cell and Basophils: Interaction with IgE and Responses to Toll like Receptor Activators

Jean S. Marshall, Michael G. Brown, and Ruby Pawankar

Mast Cells in Host Defense and Innate Immunity

Mast cells have multiple roles, not only as effector cells in allergic disease, but also as sentinel cells in the regulation of early immune responses to infection and initiators of early acquired immune responses [1, 2]. These are fully established as cellular initiators of the symptoms of acute allergic disease and may have more complex immunoregulatory roles through IgE-mediated activation. There is also longstanding evidence, from nematode parasite infection models, that mast cell activation can contribute to host defense [3–6]. Over the past 11 years evidence has accumulated for a critical role for mast cells in host defense to a variety of bacterial pathogens – primarily as a result of enhanced neutrophil recruitment [7–10]. Mast cell production of TNF has been shown to be of particular importance to several of these processes [8, 9]. However, other multiple mast cell mediators, such as cytokines and proteases, are also of importance in regulating or initiating innate immune responses [11–13]. Mast cells have been shown to respond vigorously to fungal products in vitro [14, 15] and there is an increasing evidence of their important role in models of viral infection [16–18]. Bacterial, viral, and fungal infections have been demonstrated to be associated with the initiation or exacerbation of allergic symptoms. For example, Staphylococcus aureus infection in atopic dermatitis (AD) [19] as well as respiratory syncytial virus or other viral infection in asthma [20–22]. With this in mind, dual roles of mast cells and their mediators in allergic disease and host defense need to be carefully considered. Mast cell activation and production of mediators can occur through multiple mechanisms other than classical FcεRI cross-linking. In allergic disease, pathogen-associated mast cell activation may modify sensitization or alter the nature of disease expression. Understanding these processes could provide important opportunities for therapy.

J.S. Marshall and M.G. Brown Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia B3H 1X5, Canada R. Pawankar () Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, Japan

R. Pawankar et al. (eds.), Allergy Frontiers: Classification and Pathomechanisms, 113 DOI: 10.1007/978-4-431-88315-9_8, © Springer 2009 114 J.S. Marshall et al.

Mast Cell Expression of Innate Immune Receptors

Mast cells express a wide variety of receptors, which enable them to fulfill their role as sentinel cells in early host defense and participate in responses to secondary infections or antigen challenge (see Table 1). When considering these, it is important to distinguish between mast cells derived from different species or distinct anatomical sites, since there are wide variations between mast cell subsets in mediator content and responses to specific activators. It is not surprising that another aspect of such heterogeneity is the range of innate receptors expressed on cells from specific tissue sources or derived under particular culture conditions. Toll-like receptors (TLRs) are a major family of innate immune receptors that has received a great deal of attention in view of their pivotal role in host defense. These germ-line encoded pattern recognition receptors can be activated by a wide variety of pathogen products such as lipopolysaccharide (LPS), peptidoglycan (PGN), CpG motifs, and double-stranded RNA, and also by endogenous products produced during tissue injury. Their properties and signaling pathways have been studied in depth and are well reviewed elsewhere [23–26] (see Table 2). However, a number of other innate immune receptors, especially complement component receptors, lectin-like receptors for pathogen products, and adhesion molecules with known roles in innate immune activation are expressed by mast cells and can play an important role in responses to some types of infection [27–30]. TLR1, 2, and 6 have been shown to be expressed by mast cells from a variety of sources although in some cases expression is only observed at the mRNA level. TLR4 is widely expressed on murine mast cells [31–34] and has been described in human- cultured mast cells and ex vivo mast cells from some sites [35, 36], while TLR4 is absent from mast cells from other sites or in alternate conditions [37]. TLR5 has been described as absent from some human mast cells and mast cell lines [14] although reported in cultured peripheral blood stem cell-derived mast cells [38]. TLR3 expression has also been observed in both human and murine mast cells [38–40], while the presence of TLR7 and 9 appears to be highly dependent upon the location of mast cells. A good example of such mast cell source-specific variation in TLR expression within one species comes from studies of fetal mouse skin-derived mast cells (FSMCs) compared with murine bone marrow-derived murine mast cell (BMMC). FSMCs displayed a connective tissue mast cell phenotype based on granule contents and were found to express high levels of mRNA for TLR1, 2, and 7, a moderate level for TLR3, TLR4, and TLR6, and a low level for TLR9, but lacked TLR5 [39]. In contrast, BMMCs expressed high levels of TLR2 and TLR6, moderate levels of TLR4, and low levels of TLR1, TLR3, and TLR7, and lacked both TLR5 and TLR9. In human, comparisons of neonatal foreskin mast cells with those derived from adult lung tissue have proved equally enlightening. Lung mast cells expressed high levels of TLR2, TLR3, moderate levels of TLR4, TLR7, and TLR10, and low levels of TLR5 and TLR9, and lacked TLR1, TLR6, and TLR8. In contrast, foreskin-derived mast cells expressed high levels of TLR3, moderate levels of TLR2, TLR4, and TLR9, and low levels of TLR5, TLR7, TLR10, and were deficient in TLR1, TLR6, and TLR8 [38]. In comparison to cultured human peripheral blood-derived mast cells [36], both of these tissue-derived mast cell preparations exhibited less TLR5, TLR7, Mast Cell and Basophils 115

Table 1 Mast cell Basophil Innate receptor type mouse human mouse human TLR1 mRNA + + + Protein TLR2 mRNA + + + + Protein + + TLR3 mRNA + + Protein TLR4 mRNA + + + + Protein + + + TLR5 mRNA + Protein TLR6 mRNA + + + Protein TLR7 mRNA + + Protein TLR8 mRNA + + Protein TLR9 mRNA + + + Protein TLR10 mRNA + + Protein C1qR mRNA Protein + C3aR mRNA + Protein + C5aR mRNA Protein + + FimH R (CD48) mRNA Protein + RNA helicase (RIG-I, Mda-5) mRNA Protein NOD1 mRNA Protein NOD2 mRNA + Protein + CD11b/CD18 (MAC-1) mRNA Protein + + Dectin-1 mRNA Protein + References: Malaviya et al. (1994), Fureder et al. (1995), Ghebrehiwet et al. (1995), Rosenkranz et al. (1998), Malaviya et al. (1999), McCurdy et al. (2001, 2003), Applequist et al. (2002), Sabroe et al. (2002), Varadaradjalou et al. (2003), Kulka et al. (2004), Matsushima et al. (2004), Bonini et al. (2005), Inomata et al. (2005), Thangam et al. (2005), Florian et al. (2006), Komiya et al. (2006), Kulka and Metcalfe (2006), Kubo et al. (2007), Wu et al. (2007) 116 J.S. Marshall et al.

TLR9, and TLR10, with no TLR1, TLR6, and TLR8 mRNA. An additional study investigating the protein expression of TLR on a number of inflammation-associated immune effector cells, including mast cells, in both normal and allergic conjunctiva, indicated that while mast cells expressed both TLR2 and TLR4, they lacked any detectable TLR9 [41]. It has been suggested that mast cells from certain sites, such as the human intestine, may not express a range of functional TLRs at the protein level; this could represent adaptation of mast cells to these sites rich in microflora [42]. However, extended periods of ex vivo culture are required to obtain pure mast cells from this site, which could alter TLR expression. Both pathogen products and the cytokine microenvironment have been demonstrated to profoundly alter TLR expression in other cell types and this is likely also true for mast cells. In the context of ongoing disease, current evidence suggests that mast cells are capable of expressing a wide range of functional TLRs and thereby responding to multiple pathogen-associated signals. Analysis of protein level expression of several TLRs has been hampered by the lack of good monoclonal antibodies and by the primarily intracellular location of some TLRs making functional antibody-blocking studies difficult to interpret. However, from what we have learned, in other cell types even quite low levels of TLR expression can mediate substantial responses to certain pathogen products. Inflammatory cytokine and pathogen product exposure can also lead to alterations in the levels or type of TLR expression.

Mast Cell Responses to TLR 1, 2, 4, 5, and 6 Activators

TLR activators are found commonly in our environment, within our natural microbial flora and are a feature of most pathogens. In addition, substances produced during tissue damage can serve as TLR activators. Some examples of common TLR activators are provided in Table 2. Multiple studies using TLR-deficient animals have demonstrated the importance of this family of receptors in host defense against bacterial and

Table 2 Pathogen products Receptor References PAM3CSK4 (triacylated LP) TLR1 Marshall (2004), Miyake (2007) PGN, zymosan, LTA TLR2 Marshall (2004) dsRNA TLR3 Kulka et al. (2004), Matsushima et al. (2004), Kawai and Akira (2007) LPS TLR4 Malaviya and Georges (2002), Marshall (2004), Kawai and Akira (2007) Flagellin TLR5 McCurdy et al. (2001), Supajatura et al. (2001), Kulka et al. (2004), Kawai and Akira (2007) MALP-2 (diacylated LP), PGN TLR6 Kawai and Akira (2007), Miyake (2007) ssRNA, R-848 TLR7 Dieboldo et al. (2004), Matsushima et al. (2004) ssRNA, R-848 TLR8 Heil et al. (2004) CpG TLR9 Matsushima et al. (2004) Unknown TLR10 Hasan et al. (2005) Mast Cell and Basophils 117 fungal infection. As part of their “sentinel cell” role, mast cells can respond very rapidly to activation with TLR ligands. A critical feature of mast cell responses to TLR activators is their selectivity. In both humans and mice, TLR activation usually leads to the production and release of only a subset of potential mast cell mediators and fre- quently occurs in the absence of degranulation [14, 36, 43]. Specific TLR interactions give rise to different mediator profiles, in keeping with a role for mast cell activation by pathogen products in defining the nature of the early immune and inflammatory response to infection. A number of co-receptors such as CD14 and dectin-1 can play an important role in the TLR-dependent mast cell responses and their activities may modify the mediator profile induced by TLR ligands. Since the early 1990s we have been aware of the ability of rodent mast cells to respond to pathogen products such as LPS and give rise to selective cytokine production in the absence of degranulation [43]. More recent studies of human and rodent mast cells have confirmed a wide range of selective mast cell mediator responses to TLR activators and in several cases the role of specific TLRs have been confirmed using rodent gene deletion models or neutralizing antibodies [31, 32, 36, 44]. TLR2 and TLR4 on murine mast cells have been demonstrated to be critical for mast cell cytokine responses to LPS and bacterial PGN, respectively. There is some controversy surrounding the ability of bacterial PGN or TLR2-activating lipopeptides to induce mast cell degranulation, since there is little evidence to support a calcium signal being generated via TLR-mediated processes [45]. However, PGN is a very effective activator of complement via classical, alternate, and mannose-binding pathways, complement component receptors could lead to an effective degranulation response in vivo even in the absence of TLR2-mediated signals. Recent studies of murine responses to PGN support this concept [30]. Human-cultured mast cells have also been described to selectively respond to some TLR activators without degranulation under some conditions. McCurdy et al. [14] described the selective production of the cytokines IL-1β and granulocyte-macrophage colony-stimulating factor (GM-CSF) by cord blood- derived human-cultured mast cells in response to PGN, the bacterial lipopeptide ana- logue Pam3CysSer Lys4, and the yeast cell wall component zymosan. Both Zymosan and PGN were also able to induce the selective production of LTC4 from such mast cells under conditions, which did not lead to any significant degranulation. The ability of mast cells to produce leukotrienes in response to certain TLR activators has been established [14, 38]. However, while some of these responses are partially TLR2-dependent there is increasing evidence that they are not all mediated via TLR2 receptors, but can involve other members of a TLR2-containing signaling complex or alternate innate receptors. For example, the mast cell LTC4 response to the yeast cell wall component Zymosan has been shown to be dependent on activation of the dectin-1 receptor [46]. This receptor activates Syk kinase [47, 48] and has the ability to induce a calcium signal, which together with TLR signaling, such as MAPK phosphorylation, provides an appropriate set of combined signals for the generation of LTC4 by mast cells. Dectin-1 signaling has also been demonstrated to be important for lipid mediator production by macrophages in response to fungal products [49]. The dependence on co-receptors such as dectin-1 provides additional therapeutic opportunities to inhibit leukotriene generation selectively in response to fungal infection or environmental exposure. 118 J.S. Marshall et al.

Array studies have been performed using several TLR activators and both human and murine mast cells. These have revealed important differences in the range of mediators, particularly cytokines and chemokines, induced by TLR-mediated mast cell activation and those induced by FcεRI cross-linking [44, 50]. The data from such studies is extremely useful as a starting point for elucidating the biological role of mast cell TLR expression and function. In addition, to consider the range of mediators produced, it is also important to recognize that the mast cell can be a particularly rapid source of a number of critical cytokines and chemokines, either because they are found preformed or because the mast cell has specific mechanisms whereby protein level production can be rapidly initiated.

Mast Cell Responses to TLR 3, 7, 8, and 9

TLRs on innate effector cells such as mast cells help to differentiate between various types of pathogens, directing appropriate responses to a particular pathogen. Evidence in support of this concept is derived from a number of infection models and also from studies of the responses of mast cells to activation of receptors for DNA and RNA sequences associated with infection as compared with responses to bacterial and fungal cell wall components. The nucleic acid sequence receptors TLR3, TLR7, TLR8, and TLR9 have been shown to function primarily intracel- lularly associated with the endoplasmic reticulum and endosomes, and to signal primarily through similar pathways observed for other TLRs [26, 51]. Mast cell activation with polyI:C has been used as a model for examining TLR3 responses. Kulka et al. [36] revealed a potent and selective type 1 interferon response of human mast cells treated in this way that could be blocked by pretreat- ment of mast cells with an antibody to TLR3. This group also observed ablated type 1 interferon responses in BMMC derived from TLR3-deficient animals. This clearly demonstrates a role for TLR3 in the type 1 interferon response. However, it has been suggested that other aspects of the cellular response to polyI:C might be mediated by alternate cellular receptors for double-stranded RNA such as PKR and RIG-I. Treatment of mast cells with a number of viral preparations also gave rise to a type 1 interferon response. A number of other mediators have been demonstrated to be produced by human mast cells following viral infection. For example, dengue virus infection of mast cells is associated with the increased production of IL-1, IL-6, CCL3, CCL4, and most strikingly CCL5, but not CXCL8 [52, 53]. It is not yet known if these effects are TLR3-mediated. Mast cell interactions with the extracellular matrix may also be altered via TLR activation. Following exposure to polyI:C human mast cell adhesion to vitronectin and fibronectin were reduced by an active TLR3-dependent process. In addition, mast cell responsiveness to IgE-mediated activation was inhibited. Such responses may enhance the localization of mast cells to sites of infection and help to focus the mast cell activities towards aiding antiviral responses [38]. In vivo studies of mast cell responses to TLR3 activation are limited, however Orinska et al. [40] observed Mast Cell and Basophils 119 a mast cell-dependent recovery in CD8 T cells following polyI:C treatment or Newcastle disease virus infection, in experiments comparing mast cell-deficient mice with controls. In contrast, granulocyte recruitment to the peritoneal cavity occurred similarly in mast cell-containing and mast cell-deficient animals. As previously indicated, murine skin-derived and bone marrow-derived mast cells have distinct profiles of TLR expression. Both inflammatory cytokine and chemokine secretions by these two mast cell types following stimulation with TLR ligands have been analyzed. TLR3, TLR7, and TLR9 stimulations of fetal skin-derived mast cells with polyI:C, R-848, and CpG respectively resulted in a dose-dependent production of TNF and IL-6. In contrast, BMMC response to these ligands was negligible or absent. Chemokine responses followed a similar pattern, with MIP-1α, MIP-2, and CCL5 produced by poly I:C, R848, and CpG- containing oligonucleotides, while similarly treated mBMMCs produced little of these chemokines [37]. In other studies, using the TLR7 activator imiquimod applied as a cream to the skin, it was shown that mast cells are essential for ensuing inflammatory response, including the mobilization of local Langerhans cell populations by mechanisms that involve mast cell-derived IL-1β and TNF [54]. The adjuvant effect of imiquimod in the generation of peptide-specific cytotoxic T-cell (CTL) responses was also shown to be mast cell-dependent. There is some controversy surrounding the ability of mast cells to respond effectively to CpG-containing oligonucleotides. Early studies of BMMC demonstrated small but significant TNF and IL-6 responses [55], however, TLR9 dependence was not examined. More recent studies of human mast cells also noted modest production of IL-1β, IFN-α, and TNF in response to CpG-oligonucleotide treatment. Interestingly, CpG treatment in animal models of allergic disease has also revealed decreased mast cell accumulation, but it is not known if this is a direct effect on mast cells or is the result of a decreased severity of disease. Evidence is emerging to suggest that certain pathogens have also acquired the ability to utilize TLRs to their benefit. A major example of this process has been described in mast cells treated with CpG-containing oligonucleotides. It has been demonstrated that the HIV virus is able to reactivate from latent infection in mast cells via stimulation through TLR9 [56]. It is not yet known if the mast cell also serves as a reservoir of other types of latent infection.

Interactions Between IgE and TLR Signaling

Since mast cells reside at classical mucosal surfaces and in the skin there are many situations in which mast cells might concurrently be in contact with allergens and TLR activators. Dual activation or modulation of Fc receptor expression by TLR activators could contribute to the regulation of allergic inflammation especially in the context of food allergies where large amounts of intestinal flora are present or atopic dermatitis when S. aureus colonization is common. Recently, Yoshioka 120 J.S. Marshall et al. et al. [57] examined the ability of the TLR2 activator lipotechoic acid (LTA) to modulate FcεRI expression by pulmonary mast cells and a human mast cell line. They observed substantial down-regulation of FcεRI expression in response to LTA treatment and suggest that this could be employed as a method to control allergic disorders. However, the pro-inflammatory effects of TLR activators may limit the usefulness of this approach. Others have suggested a less beneficial role for TLR activators. Qiao et al. [45] observed that antigen cross-linking of FcεRI interacted synergistically with either TLR2 or TLR4 ligands to enhance production of proinflammatory cytokines in murine mast cell lines. Enhanced MAP kinase activation may have contributed to increased cytokine responses that occurred in the absence of enhanced degranulation or leukotriene generation. More recently, Fehrenbach et al. [58] examined the ability of both dipalmitoylated and tripalmitoylated TLR2 activators in enhancing IgE-mediated mast cell activation. They also observed substantial enhancement of cytokine production via a TLR2-dependent pathway. Other opportunities for cross talk between IgE-mediated mast cell activation and TLR-mediated pathways are found when one considered the effects of released mediators in complex tissues. For example, Talreja et al. [59] observed that histamine induces TLR2 and 4 expression in endothelial cells suggesting that the proinflammatory effects of TLR activators at mucosal sites may be enhanced in the context of ongoing allergic disease. In animal studies, while some TLR activators (such as LPS [60]) have been demonstrated to inhibit the development or expression of allergic disease in a mast cell-dependent manner, other bacterial components such as PGN have been shown to enhance responses [61].

TLR Activation on Mast Cells Is Only Part of a Complex Integrated Innate Response

While a number of studies have identified key TLR-mediated processes with profound effects on the outcome of infection in rodent models, in most disease processes multiple TLRs and co-receptors are activated, in addition to a series of other innate immune responses that work in concert with TLR-mediated processes. For example, during viral infection, mast cells and other innate effector cells might respond to viral-derived double-stranded RNA through both TLR-dependent and TLR-independent mechanisms and also respond to specific viral proteins (e.g., F-protein of RSV) by activation of TLR4. In addition, local tissue damage could liberate substances such as fibronectin breakdown products that can further activate innate immunity in part, through mast cell activation [62]. For many TLR activators, TLRs are only one of a number of receptor systems that can be utilized for initiation of host defense. In vivo, there are often antibody responses to LPS and PGN that can contribute to mast cell activation either directly through Fc receptor cross-linking or indirectly through the activation of the classical complement pathway. Mast cells express multiple complement receptors including α β C3, C4 C3a, and C5a receptors, as well as the 1 2 integrin receptor that serves as a receptor for activated C1q [28, 29]. These receptors can contribute substantially to Mast Cell and Basophils 121 responses to active infection or pathogen products, but are often overlooked during in vitro studies of mast cell activation. Recent studies have demonstrated a critical role for complement in the mast cell-dependent early cell recruitment response to PGN [30]. In addition, mast cells express a number of lectin-like receptors that may contribute to host defense such as peptidoglycan recognition proteins and integrins such as MAC-1, which may contribute. NOD1 and NOD2 expressed by some mast cells might also contribute to responses to Gram-positive bacteria.

Mast Cell Activation by Pathogen Products: Effects on Acquired Immunity

Pathogen product activation by mast cells is thought to modulate acquired immune responses. Studies from Duke University [63] have demonstrated that mast cell activation by whole bacteria or other secretagogues is an important inducer of lymph node hypertrophy following infection. Such lymph node activation, which includes blockade of emigration of T cells from the node, increases the opportunity for antigen laden dendritic cells to come into contact with appropriate T cells and provides an appropriate microenvironment to support optimal antigen presentation and the development of an ensuing acquired immune response. This type of mast cell function may not be dependent primarily on TLR function. Jawdat et al. [64] noted that while S. aureus derived peptidoglycan injection into the ear-induced lymph node swelling by a mast cell-dependent mechanism this response was not inhibited in TLR2-, TLR4-, or MyD88-deficient mice. Mast cell activation by either IgE/antigen or pathogen products also has the ability to mobilize dendritic cell populations and cause them to migrate to draining lymph nodes. This has been most effectively demonstrated in the skin where mast cell activation leads to Langerhans cell migration into the draining lymph node. While the role of mast cells in contact hypersensitivity responses remains highly controversial [65–68]. There appear to be some circumstances in which the mast cell can be pivotal for the development of an effective response. A number of T-cell responses have been shown to be mast cell-dependent by mechanisms which often require the mast cell as an early source of TNF. The role that mast cell activation by either TLRs or IgE have on allergic sensitization or effective responses to vac- cination in humans remains to be determined.

Mast Cells in Allergic Diseases

Mast Cells in Allergic Rhinitis and Asthma

Allergic rhinitis (AR) is the most common allergic disease affecting up to 25–40% of the population. The pathophysiology of AR shares many similarities to allergic asthma and the two diseases are often considered manifestations of “one syndrome, 122 J.S. Marshall et al. one airway, one disease” [69]. Mast cells constitutively reside in the nasal mucosa of normal subjects, but are not normally present in the nasal epithelium. Mast cells comprise of two phenotypes: tryptase (MCT)-positive and tryptase/chymase (MCTC)-positive [70]. While both MCT-positive and MCTC-positive mast cells reside within the subepithelium, the phenotypes of mast cells in the allergic nasal epithelium are predominantly of the MCTC [70–72]. Upon allergen exposure, mast cells migrate to, and proliferate within, the epithelium [73, 74]. Although Stem cell factor (SCF) is a strong mast cell chemoattractant and elevated in the nasal lavage fluid of patients with seasonal AR, the levels of SCF in the allergic nasal epithelium are relatively compared with the lamina propria. By contrast, the levels of RANTES (CCL5) are increased in the epithelium and may instead have a more prominent role in the intraepithelial migration of nasal mast cells (NMCs) as compared to SCF or Eotaxin (CCL11) [74]. A low SCF environment is known to decrease mast cell chymase expression, which may explain the selective accumulation of MCT in the nasal epithelium of AR [74, 75]. Mast cell degranulation is characterized by elevated levels of tryptase, histamine, LTB4, LTC4, and PGD2 in the nasal secretion of individuals with AR following nasal allergen challenge [76–79]. These mediators contribute to the characteristic early-phase symptoms of AR namely sneezing, pruritus, rhinorrhea, and nasal con- gestion. Histamine is a major mediator inducing vasodilation, increased vascular permeability, and increased glandular secretion. In addition, histamine acts on the sensory nerve endings of the trigeminal nerve to cause sneezing. However, more recently mast cells are found to be an important source of a variety of cytokines (TNF-alpha, IL-4, IL-5, IL-6, and IL-13) and mast cell activation results in orches- trating of the late-phase reaction, inducing the infiltration of eosinophils through the release of platelet-activating factor (PAF) and LTB4; and the upregulation of VCAM-1 expression on endothelial cells. The survival of eosinophils is promoted through the mast cell release of granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-5. Additionally, histamine upregulates RANTES (CCL5) and GM-CSF, while IL-4, IL-13, and TNF-α upregulate Eotaxin (CCL11) and TARC (CCL17), further contributing to the late-phase eosinophilic/T-cell infiltration. Clinically, this is displayed as an increase in nasal mucosal swelling with increased nasal airway resistance [74, 80]. As regard to nasal hyperresponsiveness it is the result of exaggerated neural reactivity, and the levels of nerve growth factor (NGF) in the nasal lavage fluids from patients with AR are markedly elevated and ampli- fied through nasal allergen challenge [81, 82]. In addition, IL-4, IgE, and NGF increases the expression of FcεRI and c-Kit on mast cells [83, 84]. Furthermore, the FcεRI expression in NMC correlated well with the levels of serum IgE [83]. These findings taken in concert with the observations of Pastorello et al., who demonstrated a strong positive correlation between the levels of serum IgE and clinical symptoms, in symptomatic patients with allergic rhinoconjunctivitis [85], suggest a very important role for NMC in regulating chronic allergic inflammation. Moreover, mast cells can induce IgE synthesis in B cells and IL-4 and IgE can upregulate the FcεRI expression in mast cells. Several studies have demonstrated that local IgE synthesis occurs at sites of allergic inflammation [86–88]. Putting together all these Mast Cell and Basophils 123 observations one can perceive a very important role for the mast cell in perpetuating allergic inflammation via the mast cell-IgE-FcεRI cascade [88]. As in allergic rhinitis, mast cells are primary effector cells in asthma and play crucial roles in the early-phase response, late-phase response, and chronic allergic inflammation [89–92]. Mast cell numbers are increased in the bronchial epithelium of atopic asthmatics [93]. Besides the epithelial compartment, mast cells are widely distributed in specific compartments of the asthmatic airways (i.e., the bronchoalveolar space [94]), beneath the basement membrane, in close proximity to blood vessels, near submucosal glands and in the ASM bundles [95]. In fact a close correlation between mast cell numbers in the bronchial smooth muscle of asthmatics and the degree of airway hyperresponsiveness to methacholine is well established [95]. Mast cells in asthmatics release a variety of mediators (histamine, cysteinyl leukotreine C4 (LTC4), PGD2, tryptase, and chymase), as well as cytokines and chemokines, which induce and sustain chronic inflammation in asthma by regulating the recruitment and function of T cells, macrophages, ASM, and epithelial cells. As mentioned earlier in this chapter increasing evidence suggests that histamine can regulate the activity and cytokine/chemokine release from other cells. Histamine induces lysosomal enzyme release and IL-6 and TNF-α production from human lung macrophages [96] and CysLTs exert a variety of responses on bronchial smooth muscle, human lung macrophages, mast cells, and peripheral blood leukocytes via the CysLTR1 and CysLTR2 [69–72]. Besides the above-mentioned mediators, mast cells in asthmatic airways express a wide spectrum of cytokines (e.g., IL-4, SCF, IL-5, IL-6, IL-8, IL-13, IL-16, trans- forming growth factor-beta [TGF-β], IL-25, TNF-α, and granulocyte-macrophage colony-stimulating factor [GM-CSF] [Pawankar R et al.]) [97]. IL-16 is chemotactic for CD4 + T cells and IL-25 can induce IL-4 and IL-13 gene expression, and this may contribute to mast cell–ASM interactions, as well as in amplifying allergic inflammation via the mast cell-IgE-FcεRI cascade [98]. IL-3, IL-5, and GM-CSF from mast cells can enhance histamine release and IL-4 synthesis in basophils, whereas IL-4 enhances the production of proinflammatory mediators (PGD2 and LTC4) and various cytokines by mast cells [99, 100]. Thus, Th2 (IL-4, IL-5, and IL-3) cytokines can induce changes in the biosynthetic pathways of mast cells at sites of allergic inflammation. SCF, a principal growth differentiating and chemotactic factor for human mast cells is expressed and released by lung mast cells [101]. Several mast cell mediators like histamine, tryptase, LTC4, TNF-α, and TGF-β1 also exhibit fibrogenic activity [102]. Mast cells that are treated with IL-4 express Toll-like receptor 4 (TLR4), which when activated by lipopolysaccharide (LPS) induces the release of Th2 cytokines [103]. Activation of mast cells via TLR2 and TLR3 selectively induce the release of leukotrienes, GM-CSF, and IL-1β [14, 36, 103]. Human-cultured mast cells also express TLR1, TLR2, TLR4, TLR5, TLR6, TLR7, and TLR9 [36]. These findings highlight several novel mechanisms, whereby endogenous, bacterial, and viral proteins can activate human mast cells, thus providing the means by which viruses and bacteria can induce asthma exacerbations. 124 J.S. Marshall et al.

Structural alterations of the airways, defined as “tissue remodeling,” account for a progressive and irreversible loss of lung function in chronic asthma. The positive correlation between the thickness of the tenascin and laminin layers and mast cell density in asthmatics suggests that mast cells may have a role in tissue remodeling [104]. Mast cells, which are closely associated with blood vessels and are increased at angiogenic sites, can contribute to various aspects of angiogenesis [105]. Mast cells synthesize and release various pro-angiogenic factors (histamine, tryptase, TGF-β, IL-8, and vascular endothelial growth factor [VEGF] and the production of VEGF by mast cells is increased by PGE2 and other cAMP-elevating agents) [106–108].

Implications of Mast Cells in Rhinitis and Asthma

The unique microlocalization of mast cells in specific nasal and lung tissue compartments, the ability of these cells to migrate to the epithelial compartment where they are easily activated by allergens or pathogens, the powerful effector repertoire, the recognition of their different microbial-related activating ligands, and their plasticity in response to various signals suggest that mast cells have a central role in allergic airway diseases like rhinitis and asthma. However, mast cells at different stages of maturation, might have different, or even, in some cases, protective roles in the appearance of the asthmatic phenotype. The extent to which each effector cell contributes toward each phase of allergic inflammation and tissue repair remains to be fully elucidated.

Mast Cells in Allergic Conjunctivitis

Ocular allergy occurs in 45% of the allergic population [109, 110]. The location of mast cells in close proximity to the external environment in the mucosa of the eye allows for exposure of these cells to allergen, thereby facilitating cross-linking of membrane-bound IgE, which leads to degranulation and release of inflammatory mediators. Although there are several types of ocular allergy, seasonal and peren- nial allergic conjunctivitis represent the majority of allergy cases [111]. In normal individuals, mast cells are abundant in the conjunctival stroma with an estimated 50 million cells residing at this environmental interface [112]. In symptomatic allergic patients, an increase in mast cells with evidence of degranulation is seen in conjunctival biopsies [113]. In addition to the increase in mast cells within the conjunctiva, the number of mast cells expressing IL-4 message is increased three- fold in seasonal allergic conjunctivitis [114]. Further, use of a mast cell stabilizer (nedocromil sodium) reduces the amount of histamine and PGD2 by more than 70% after challenge, thereby supporting a major role for mast cells in allergic conjunctivitis [115]. In addition to common mast cell mediators such as histamine and cytokines, chemokines released from activated mast cells mediate late-phase Mast Cell and Basophils 125

reactions by recruitment of additional inflammatory cells. Mast cells residing within the conjunctiva express CCR3 and the use of a CCR3 antagonist in a mouse model of allergic conjuctivitis ablated both the early- and late-phase reactions [116]. In this model, the CCR3 antagonist leads to mast cell stabilization and inhi- bition of immediate hypersensitivity, but also impaired neutrophil and eosinophil influx during the late-phase response [116].

Mast Cells in Atopic Dermatitis

Mast cells are increased in lesions of patients with atopic dermatitis (AD) [117, 118]. They reside in the papillary dermis and undergo migration through where they may influence keratinocyte activation and stimulation of endothelial growth with neoangiogenesis [119]. Although histamine has an established role in other atopic diseases, the effect of histamine in AD is questionable, given that levels are not increased compared with control subjects. Tryptase and activation of proteinase- activated receptor-2 (PAR-2) may contribute to the pruritus seen in AD, as tryptase is reported to be increased up to fourfold in AD patients and PAR-2 expression is markedly enhanced on primary afferent nerve fibers in skin biopsies from patients with AD [120]. On the other hand, chymase may play a role by weakening the skin barrier, in turn allowing an enhanced permeability to allergens and microbes [121]. An association between a promoter polymorphism (rs1800875) of the mast cell chymase gene (CMA-1) and AD has been reported [122]. Significantly elevated levels of total IgE are found in about 80% of patients with AD. Beyond traditional signaling through the FcεRI receptor on mast cells, a novel IgE-independent mast cell activation pathway has been proposed for AD involving CD30 and mast cells were shown to be the predominant CD30 ligand-positive cell in AD lesions and activation through CD30 induced a de novo. As in AR, mast cell–nerve interactions may also play a role in promoting inflammation in AD [123]. Contacts between mast cells and nerves are increased in both lesional and non-lesional samples of AD when compared with normal controls [124]. Inflammation appears to be mediated by neuropeptides such as substance P, calcitonin gene-related peptide, vasoactive intestinal peptide, and NGF [84, 125–127].

Mast Cells in Anaphylaxis

Anaphylaxis is an acute, severe, systemic reaction to a foreign stimulus that is often thought to be associated with mast cell activation. The strongest evidence of a role of mast cells in anaphylaxis is in that serum levels of tryptase, resulting mainly from mast cell degranulation, peaks 1–2 h following the onset of IgE-mediated anaphylaxis [128–130]. Besides, the classical IgE-dependent anaphylaxis can occur due to IgE-independent mechanisms namely through IgG and complement receptors 126 J.S. Marshall et al.

[131–134]. Although anaphylaxis is considered a systemic event, the presence and activation of mast cells in specific organs may play a critical role in the severity. Within the cardiac mast cells are located between myocardial fibers, around blood vessels and in the arterial intima, activation of these critically positioned mast cells may directly contribute to cardiopulmonary failure. PAF is thought to be a critical factor in the development of anaphylactic shock through its ability to induce hypo- tension and cardiac dysfunction [135–137]. The overall number of mast cells may also be relevant in anaphylaxis in that in those with recurrent anaphylaxis tend to have more dermal mast cells than those without anaphylaxis.

Closing Comments

The mast cell has therefore a central and versatile role in the pathogenesis of allergic diseases, and more recently has been shown to be involved in innate immunity in response to bacterial and parasitic infections [168]. Toll-like receptors and other innate immune receptors on mast cells may participate in effective host immunity and in the exacerbation of allergic inflammation at sites of infection. By better understanding these receptor systems and their function on mast cells we will obtain better tools with which the function of mast cells can be locally modified to enhance appropriate immune responses while limiting adverse inflammatory effects. In allergic disease, certain TLRs may hold promise as effective regulators of the development of allergic disease or as modifiers of ensuing mast cell-mediated responses. More in vivo animal studies and studies of human material are required to come to grips with the complexity of the multiple signals provided to local mast cells at sites of infection. As sentinel cells, the mast cell’s range of mediator production and rapid selective responses are extremely important in dictating the nature of inflammatory and immune response. Harnessing these responses holds enormous promise as a strategy to modify local inflammatory responses and immune responses. As our understanding of the various roles of mast cells in disease pathogenesis evolves, novel therapeutic targets will continue to be identified.

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