Mast Cells, Basophils and Mucosal Immunity

Chapter 43

Mast Cells, Basophils and Mucosal Immunity Harissios Vliagoftis and A.D. Befus University of Alberta, Edmonton, AB, Canada

Chapter Outline Introduction859 Mast Cell and Basophil Development and Characteristics 859 Mast Cell Development 859 Mast Cell Progenitors 860 Progenitor Recruitment to Peripheral Tissues 860 Progenitor Differentiation into Mast Cell Subsets 860 Mast Cell Survival and Turnover 861 Basophil Development 862 Basophil Recruitment to Peripheral Tissues 862 Basophil Survival 863 Mast Cell Characteristics 863 Basophil Characteristics 864 Mast Cell and Basophil Mediators 864

New Tools to Understand the Function of Mast Cells and Basophils865 Mast Cell and Basophil Functions—Role in Disease Processes 866 Mast Cells as the Link between Innate and Acquired Immunity867 Infections867 Mast Cell Activation has Vaccine Adjuvant Effects 868 Allergic Diseases 869 Asthma870 Food Allergy 871 Irritable Bowel Syndrome 872 Inflammatory Bowel Disease 873 Tolerance873 Conclusions874 References874

INTRODUCTION

been extensively debated and, at some level, they ­originate from the same progenitor (common myeloid progenitor or further downstream in development). As mature cells, they have several common receptor systems, notably IgE and IgG receptors, and also a number of commonalities in mediator content, as well as in immune and other functions. Given limitations in space in this chapter and the wealth of excellent, recent reviews on mast cells and basophils, we refer the reader to many of these (Moon et al., 2010; Gurish and Austen, 2012; Galli and Tsai, 2012; Befus et al., 2013; ­Gilfillan and Beaven, 2011; Wernersson and Pejler, 2014).

As the field of mucosal immunology has expanded over the last decade, we have a better understanding of how immune responses at mucosal surfaces can define our immune system. Mucosal immune responses are involved in several immune and inflammatory diseases, affecting organs with or without mucosal surfaces. Mast cells have an important position in mucosal immunology, as they are abundant at mucosal surfaces, express phenotypic plasticity that is specific to microenvironmental settings, and influence a diversity of mucosal functions. We now recognize that basophils are also an important component of mucosal defenses and pathogenic mechanisms of immune diseases. Although basophils primarily circulate in blood, they can localize at mucosal surfaces in many physiological and pathological conditions, exhibit phenotypic plasticity associated with microenvironmental conditions, and affect local immune responses. This chapter discusses the ontogeny and plasticity of both cells, their ability to initiate or influence immune processes, and their involvement in mucosal immunology. The developmental relationship of these cells has Mucosal Immunology. http://dx.doi.org/10.1016/B978-0-12-415847-4.00043-4 Copyright © 2015 Elsevier Inc. All rights reserved.

MAST CELL AND BASOPHIL DEVELOPMENT AND CHARACTERISTICS Mast Cell Development Mast cells are tissue resident cells originating from ­pluripotential hematopoietic progenitors in bone marrow. They undergo part of their differentiation in bone marrow and enter the circulation as committed mast cell progenitors, which are selectively attracted to peripheral tissues, 859

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including mucosal sites, under the influence of selective chemotactic and growth factors and terminally differentiate in situ under the direction of the microenvironment. Early information on bone marrow origin of mast cells came from reconstitution studies in two strains of mice (W/WV and Sl/Sld) that lack mast cells due to spontaneous mutations (Kitamura et al., 1987). Transplantation of bone marrow from normal mice into W/WV mice showed the defect in W/Wv mice to be an intrinsic abnormality of c-kit (CD117) in mast cells, and similar studies demonstrated that the problem in Sl/Sld mice was in the CD117 ligand, stem cell factor (SCF), a cytokine that stimulates mast cell progenitors. CD117 is expressed on hematopoietic progenitor cells, and among mature cells, primarily on mast cells. SCF is produced by fibroblasts, stromal cells, epithelial cells, and macrophages, and it is essential for the development of mast cells (Galli et al., 1994) and for their survival.

Mast Cell Progenitors The nature of mast cell progenitors has been studied in mice and in humans. In mice, an early committed mast cell progenitor is found in blood as a Thy-1loCD117hi cell, contains cytoplasmic granules, and expresses RNA encoding mast cell-associated proteinases, mast cell proteinase (MCP)-2, 4, and carboxypeptidase A (CPA3), but lacks FcεRI (­Rodewald et al., 1996). More details of mast cell ontogeny in mice are provided in the excellent review by Gurish and Austen (Gurish and Austen, 2012), including evidence for a splenic mast cell/basophil common progenitor. Human bone marrow mononuclear cells devoid of T and B lymphocytes, eosinophil, and macrophage progenitors give rise to mast cells when treated with recombinant human IL-3 (Kirshenbaum et al., 1991; Rottem et al., 1994). Elimination of CD34+ progenitor cells from bone marrow eliminated mast cell progenitors (Rottem et al., 1994), and isolated CD34+ cells gave rise to mast cells after culture with fibroblasts (Kirshenbaum et al., 1991, 1992). Human mast cells originate from pluripotential CD34+ progenitors that express CD117 and IL-3 receptors (CD123) and respond to SCF and IL-3 for development into mast cells. Human circulating mast cell progenitors can be defined as CD117+CD34+Ly−CD14−CD17− colony-forming cells (Agis et al., 1993).

Progenitor Recruitment to Peripheral Tissues As early as 1983, it was shown that mast cell precursors can be found in various peripheral organs and in particularly high numbers in the intestine (Crapper and Schrader, 1983). Mast cell precursor numbers increase following antigenic stimulation in the intestine and lymph nodes (Crapper and Schrader, 1983) and in the lung (Abonia et al., 2006). An excellent review summarizes our current knowledge of mast cell progenitor recruitment into peripheral tissues

(­Collington et al., 2011); the exact mechanisms are still not completely understood and discrepancies between in vitro and in vivo experimental data complicate this field. Recruitment of progenitors into tissues involves factors that promote their mobilization from bone marrow, aid their chemotaxis towards specific tissues, and allow them to migrate into the tissue and be retained; these precursors then differentiate locally. The adhesion molecule integrin α4β7 on mast cell progenitors is important for their localization into intestinal tissue through its interactions with the mucosal microvascular addressin MadCAM-1 (Gurish et al., 2001). Furthermore, circulating mast cell precursors must express CXCR2 to localize in the small intestine. Integrin α4β7 and VCAM-1 are required for recruitment of mast cell precursors to the lung (Abonia et al., 2006), and CXCR2 expression by lung cells regulates VCAM-1 expression on the endothelium and is required for antigen-induced recruitment of mast cell progenitors into the lung (Hallgren et al., 2007). The CCL2/CCR2 pathway is also involved in antigen-induced recruitment of mast cell progenitors to the lung (­Collington et al., 2010), although involvement of specific adhesion molecules has not been studied in this system. CXCR3 interactions with its ligands CXCL9 and CXCL10 mediate mast cell recruitment into the synovium in rheumatoid arthritis (Ruschpler et al., 2003) and may also explain the localization of mast cells in airway smooth muscle bundles in asthma (Brightling et al., 2002, 2005). Lipid mediators may be important for recruitment of mast cell progenitors to tissues during inflammation. LTB4 can recruit human and mouse mast cell precursors (Weller et al., 2005), while PGE2, although not able to recruit mast cell precursors, can induce chemotaxis of mast cells at late stages of development (Weller et al., 2007) and may be important for the final localization of mast cells in inflamed tissues. Finally, various immune and inflammatory cells are important in mast cell progenitor recruitment (Alcaide et al., 2007; Jones et al., 2009, 2010), but in many cases, the precise mechanism or the exact chemokines involved are not understood.

Progenitor Differentiation into Mast Cell Subsets The maturation phases of mast cell development occur after the committed progenitor enters peripheral tissues, where the microenvironment determines gene expression and the phenotypic plasticity of the mast cells generated. In rodents, two prominent mast cell phenotypes are known, namely mucosal mast cells (MMC) and connective tissue mast cells (CTMC) (Table 1) (Gurish and Austen, 2012; Moon et al., 2010). Evidence indicates that these mast cell subsets come from the same progenitor (Kitamura et al., 1977). In contrast, in humans there are at least three subpopulations of mast cells (Weidner and Austen, 1993; Gurish and Austen, 2012)

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TABLE 1  Rodent Mucosal Mast Cell (MMC) and Connective Tissue Mast Cell (CTMC) Characteristics MMC

CTMC

 Size

∼12 μm

∼18 μm

 Granularity

Few granules

More granules

 Staining

Alcian blue

Safranin

Development

T cell ­dependent

T cell ­independent

Induced

Constitutively ­present

Short life span (2–3 weeks)

Long life span (>6 months)

 Proteoglycans

Chondroitin sulfate

Heparin

 Histamine

1–2 pg/cell

15–20 pg/cell

   Bronchi

MCP-1, -6, -7

MCP-1, -4, -5, -6, -7, CPA3

   Trachea

MCP-1, -4, -5, -6, -7, CPA3

MCP-1, -4, -5, -6, -7, CPA3

   Gut

MCP-1, MCP-2

MCP-4, -5, -6, -7, CPA3

Main lipid mediator

LTC4

PGD2

Characteristics

Granule content

 Proteases (mouse)

MCP, Mast cell proteinase.

based on proteinase content. More details on mast cell phenotypes are discussed below in the section on “mast cell characteristics.” Mast cell development, including proliferation and differentiation of progenitors, is regulated by several cytokines and growth factors, including IL-3, IL-4, IL-6, IL-9, IL-10, IL-11, TGFβ, GM-CSF, nerve growth factor (NGF), prostaglandins, and IgE aggregates (Galli et al., 1994; Galli, 1990; Gurish and Austen, 2012; Befus et al., 2013). The effects of specific cytokines and microenvironmental factors vary in different phases of mast cell development (Moon et al., 2012). SCF primarily influences mast cell development in the context of other cytokines (Rennick et al., 1995) since SCF alone cannot stimulate clonal growth of early progenitors, but needs cytokines such as IL-3, IL-4, and IL-10. Evidence, primarily from murine studies, identified that the requirement for CD117mediated stimulation is more important for the development of CTMC compared to MMC (Arizono et al., 1993) and the same is true for IL-4 (Hamaguchi et al., 1987). Cytokines can also affect the phenotype of the cells and the expression of proteinases as will be discussed elsewhere.

Newer studies have addressed the effects of cytokines on mast cell development in vivo. For example, mice with activating mutations in IL-4 receptor α chain (IL-4Rα) and mice receiving exogenous IL-4 have increased numbers of MMC in the lamina propria of the jejunum and a smaller increase in numbers of intraepithelial MMC (Burton et al., 2013); this increase was the result of the direct effect of IL-4 on mast cell progenitors. Administration of TGFβ1 to mice in vivo decreased the number of mast cells in the peritoneal cavity (Fernando et al., 2013), although it was not clear if this effect was direct on mature mast cells or affected progenitor recruitment. The effect of TGF was present in C57BL/6 mice but not in 129/Sv mice, introducing the idea that genetic background may be a determining factor for the effects of cytokines on mast cells.

Mast Cell Survival and Turnover Mast cell numbers in peripheral tissues are regulated by a balance between cell proliferation, differentiation, and death. There is a fundamental difference in the regulation of CTMC and MMC (Table 1); the former are constitutive and T cell independent, while the latter are induced in mucosal surfaces through T cell dependent pathways. MMC are induced in the intestine of mice following helminthic infections; the mast cells induced by Trichinella spiralis disappear from the villi epithelium within two weeks (Friend et al., 1996). MMC induced in the lung have a similar life span (Gurish and ­Austen, 2012). By contrast, CTMC have a much longer half-life in mice compared to MMC (Fukuzumi et al., 1990). The numbers of mast cells in tissues can be determined by progenitor recruitment and apoptosis. Apoptosis of mast cells can be initiated by diverse stimuli, including Fas–Fas ligand interactions, presence or absence of growth and survival factors, and expression of genes that regulate responsiveness to such factors (Ekoff and Nilsson, 2011). The factors inducing or preventing mast cell apoptosis can be tissue specific. Intestinal fibroblasts can prevent apoptosis of intestinal mast cells through factors different than SCF, IL-3, IL-4, or nerve growth factor (Sellge et al., 2004). Human mast cell infection by Pseudomonas sp. (Jenkins et al., 2006) and interactions with Pseudomonas exotoxin A (Jenkins et al., 2004) lead to mast cell apoptosis, perhaps as a way for Pseudomonas to decrease the protective effect of mast cells on epithelial integrity during infections (Junkins et al., 2014). The role of mast cells in infections will be discussed in detail below. Activating transcription factor 3 (ATF3), a basic leucine zipper transcription factor, allowed mast cell development and function. ATF3 knockout mice lack mast cells in a number of tissues and have functional defects in mast cells (Gilchrist et al., 2010). Sphingosine 1-phosphate receptors can also enhance mast cell survival during hypoxia (Zhang et al., 2007).

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One of the mechanisms used by cytokines/chemokines to regulate mast cell numbers is through inhibition of apoptosis. SCF promotes mast cell survival through activation of the fork head transcription factor FOXO3A and down regulation of a Bcl2 homolog Bim, which is proapoptotic in mast cells (Moller et al., 2005). A number of cytokines that suppress mast cell apoptosis affect the expression of family members of the antiapoptotic gene Bcl2 (Ekoff and Nilsson, 2011). Expression of A1 (Moller et al., 2003) and/ or Bfl-1 (Xiang et al., 2006), induced by cross-linkage of FCεR1, are important for increased mast cell survival. Mast cell survival can also be promoted by ligation of FcεR1 with monomeric IgE in the absence of antigen to cross-link the receptor (Kalesnikoff et al., 2001; Asai et al., 2001). This might be a mechanism that increases mast cells in allergic disease and parasitic infections where there are high levels of circulating IgE. Medications may also affect mast cell survival; glucocorticoids that decrease mast cell numbers in tissues do that by decreasing SCF production (Finotto et al., 1997).

Basophil Development Basophils are readily identifiable in human peripheral blood, and although their numbers in blood are low, they are more accessible for studies than human mast cells that only reside in tissues. Therefore, much of our knowledge about basophilopoiesis comes from human studies (Befus et al., 2013). A basophil/eosinophil progenitor called CFUbaso/eo has been identified from colonies in semisolid cultures (Denburg et al., 1985; Leary and Ogawa, 1984) and can be derived from blood of atopic and normal individuals (Denburg et al., 1985). Lineage commitment of basophil precursors depends on GATA2 and C/EBPα (Iwasaki and Akashi, 2007). There is also evidence of lineage sharing between basophils and mast cells and/or megakaryocytes (Arock et al., 2002; Dy et al., 1999; Gurish and Austen, 2012), but distinct progenitors can also be identified (Befus et al., 2013). There is not a single cytokine that is specific for development of basophils, but IL-3 is the main cytokine involved in human basophil growth and differentiation (Valent et al., 1989). In contrast to mouse mast cells, IL-3 has little effect on mast cell differentiation in humans. Parenteral administration of IL-3 and GM-CSF leads to increased numbers of both basophils and eosinophils in peripheral blood in primates along with the egress of basophil/eosinophil progenitors from bone marrow (Donahue et al., 1988). GM-CSF (Hutt-Taylor et al., 1988), IL-4 (Denburg, 1992), IL-5 through its effects on a common basophil/eosinophil precursor (Denburg et al., 1991), and SCF (Galli et al., 1994) also function as basophilopoietins. There are a number of other factors that can affect basophil growth, including TGFβ (enhances basophil differentiation in the presence

of IL-3), NGF (induces basophil colony growth in humans), IL-6, and TNF (Befus et al., 2013). Recent evidence has indicated an important role for thymic stromal lymphopoietin (TSLP), an epithelial-derived factor, in mouse basophilopoiesis. Administration of recombinant TSLP, or a TSLP expressing cDNA plasmid, leads to significant increase in frequency and total number of basophils in the spleen, blood, lung, and bone marrow of mice (Siracusa et al., 2011). Culture of mouse bone marrow cells with IL-3 gives rise to basophils and mast cells, while culture with TSLP gives rise only to basophils. In addition, mouse basophil precursors isolated from mouse bone marrow express the two chains of the TSLP receptor and can develop into basophils under the influence of TSLP. Administration of TSLP to mice also elicits the development of a distinct population of granulocyte-monocyte progenitor cells that can develop into basophils under the influence of IL-3 or TSLP (Siracusa et al., 2013). Basophils developed under the influence of TSLP have different characteristics than IL-3-induced basophils (Table 2) (Siracusa et al., 2012). Since TSLP is a locally produced epithelial-derived mediator, basophils developed under the influence of TSLP may have a phenotype that is more appropriate for their role in mucosal surfaces in conditions such as asthma or gastrointestinal disorders. Unfortunately, there have not been studies comparing phenotypes from basophils isolated from mucosal surfaces versus other tissues. A multipotent progenitor cell population present in peripheral blood and responsive to IL-25 (called multipotent progenitor type 2) expands in response to helminthic infections and has the capacity to mature into basophils (Saenz et al., 2010); this later basophil progenitor is different from the TSLP-induced progenitor cells discussed above.

Basophil Recruitment to Peripheral Tissues In contrast to mast cells, basophils can enter the peripheral blood from bone marrow as mature cells. However, there are also circulating basophil progenitors, and whether or when extramedullary basophilopoiesis is prominent requires additional study. The life span of mature basophils is estimated to be 60–70 h (Iwasaki and Akashi, 2007), therefore to maintain basophil populations in the periphery, there is a constant differentiation from precursor populations, largely in bone marrow. Mice inhalation of Aspergillus fumigatus leads to rapid increase in basophil numbers in the spleen and blood, but also in the lung (Poddighe et al., 2014); this increase is IL-3 dependent. IL-3 is also important for recruitment of basophils into mediastinal lymph nodes following Nippostrongylus brasiliensis infection (Kim et al., 2010). Viral components, such as dsRNA, can recruit basophils in murine lungs (Ramadan et al., 2013). In humans, allergen challenge recruits basophils to the lung and the airway

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TABLE 2  Mouse Basophil Heterogeneity: IL-3 versus TSLP-derived Basophils

mucosa (Nouri-Aria et al., 2001), but the factors responsible are not clearly defined. Studies with intradermal administration of chemokines in humans have shown that CCL2, but not CCL3, attracts basophils (Gaga et al., 2008), and the same effect is seen with CCL11 and CCL24 (Menzies-Gow et al., 2002).

IL-3

TSLP

Development from bone marrow

+

+

Blood basophilia in vivo

+

+

Basophil Survival

Promotion of survival

+

+

 CD11b

++

+

 CD62L

++

+

 CD69

+

+

 CD123

+

++

 IL-18Rα

+

++

  IL-33R (T1/ST2)

+

++

 CD200R

+

+

Although IL-3 is the main survival and growth factor for basophils, it may not be required for basophil survival in vivo, at least in some parasitic infections (Shen et al., 2008). IL-3 prevents basophil apoptosis by inducing the antiapoptotic molecule Pim-1 (Didichenko et al., 2008). Activation of the Fas–Fas ligand pathway induces basophil apoptosis (Matsumoto et al., 2008; Forster et al., 2013), but the TNF-related apoptosiinducing lignad TRAIL pathway may be more important for apoptosis of neoplastic basophils (Forster et al., 2013). Many other factors, including leptin, IL-18, IL-33, and IL-25 prolong basophil survival (Suzukawa et al., 2011; Kroeger et al., 2009; Wang et al., 2010), but in contrast to human mast cells, FcεRI cross-linking does not seem to prolong human basophil survival in vitro (Xiang et al., 2006).

Phenotype

Protease mRNA (relative abundance)  MCP2

1

3

 MCP7

8

1

++

−

   IL-3

CCL2

IL-4, 6, CCL3, 12

   IL-18

CCL2, 7

IL-4, 6, TNF, CCL3, 4, 9, 12, CXCL2

   IL-33

CCL2, 7

IL-4, 6, CCL3, 4, 12, CXCL2

Gene ­expression ­profiles (gene ­clusters)

Monocyte/DC maturation

Linoleic acid and arachidonic acid metabolism

MMP

Cell ­communication

TNF signaling

Adhesion ­molecules

Classical IgE responses

Cytokine and chemokine responses

Functions   β-hexosaminidase release (IgE stimulus; degranulation)  Cytokine/chemokine production in response to:

TSLP, Thymic stromal lymphopoietin; MCP, Mast cell proteinase; MMP, Matrix metalloproteinase; DC, Dendritic cells.

Mast Cell Characteristics Human and rodent mast cells in different tissues vary in their morphological and histochemical characteristics, mediator content, and responsiveness to growth factors, drugs, and secretagogues. Rodent mast cells can be divided into MMC and CTMC (Table 1). MMC hyperplasia in the intestine after helminth infections is thymus dependent (Olson and ­Schiller, 1978), whereas CTMC hyperplasia in many cases is thymus independent. MMC are smaller (∼12 μm in diameter) than CTMC (average diameter of ∼18 μm), contain fewer granules per cell, have a smooth plasma membrane, lacking microvilli, and possess irregularly shaped or lobulated nuclei (Enerback and Lundin, 1974). Mast cells express the high affinity IgE receptor FcεRI. In addition to FcεRI, mast cells, including those from the intestinal mucosa, also express a variety of IgG receptors, including FcγRI, FcγRII, and FcγRIII (Tkaczyk et al., 2004). Expression of IgG receptors on mast cells is both species and phenotype dependent. For example, human gut mast cells express FcγRI, FcγRIIa, FcγRIIc, and in some cases FcγRIIb, but not FcγRIII (Sellge et al., 2014). Activation of these cells with IFNγ upregulates FcγRI, decreases FcγRIIa, and renders the cells able to degranulate in response to Fcγ activation, while cells not activated by IFNγ can only release LTC4 and not stored mediators. A major difference between CTMC and MMC is in mediator content (Table 1); for example, heparin is the predominant proteoglycan in CTMC, while chondroitin sulfate is the major proteoglycan in intestinal MMC. The nature of the

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proteoglycan accounts for differences in histochemical staining with alcian blue and safranin and fixation with formalin or with Carnoy’s fluid. A valuable way to distinguish mast cell phenotypes in rats, mice, and humans is based on their specific content of proteinases (Trivedi and Caughey, 2010; Caughey, 2011). In rats, MMC produce rat mast cell proteinase-2 (RMCP-2), in contrast with CTMC that express two chymases, RMCP-1 and RMCP-5, as well as CPA3 (Befus et al., 1995). In mice, there is evidence that the proteinase content depends also on the tissue microenvironment, even for mucosal tissues (Xing et al., 2011). Therefore, the panel of proteinases expressed by mast cells depends on the type of cell (CTMC vs MMC) and on the microenvironment; in some tissues, MMC and CTMC have very similar profiles, while in others the differences in their proteinase content are large (Table 1) (Gurish and Austen, 2012). In humans, there are at least three subpopulations of mast cells (Weidner and Austen, 1993) based on proteinase content, MCTC, MCT, and MCC. On the basis of proteinase content, human mast cells histochemically similar to rodent CTMC express chymase and tryptase MCTC, whereas those that are similar to MMC express only tryptase (MCT). MCT and MCTC cells have many differences, including their responses to proapoptotic effects of IL-4 (Oskeritzian et al., 2004). Some cultured human mast cells express only chymase, and although MCC have been identified in vivo, the relevance of these cells is poorly known (Li et al., 1996). Mast cells from human large airways and the nose are primarily MCT, while human skin mast cells are primarily MCTC. A high proportion of human intestinal lamina propria mast cells are MCT, as in the lung (Befus et al., 1987). The proportion of MCT in the human lung ranges from >95% in the central airways to approximately 50% in perivascular tissue (­Andersson et al., 2009). Moreover, these mast cells could be further subtyped based on their site-specific expression of IgE and IL-9 receptors, renin, histidine decarboxylase, vascular endothelial growth factor, fibroblast growth factor, 5-lipoxygenase, and LTC4 synthase. Presumably, the microenvironment dictates remarkable plasticity in gene expression among mast cells in mucosal and other sites, a phenomenon that has been largely unexplored to date in mast cells (Andersson et al., 2009). Intraepithelial lung mast cells in humans are also MCT but exhibit a different phenotype, since in addition to tryptase, they also express CPA3 (Dougherty et al., 2010), something that is not true for MCT from other tissues (Schwartz, 2006). Histochemical studies have also shown that the predominant mast cell type in bone marrow in neoplastic states, such as myelodysplastic syndromes and mastocytosis, is MCT (Horny et al., 2003).

Basophil Characteristics Basophils are the least abundant granulocytes, accounting for less than 1% of leukocytes in blood. They were first

described by Paul Erlich, but it took almost a century before their functions became apparent. In blood, basophils are round, but the shape changes as they migrate into tissues. They generally have a multilobed nucleus and no evidence of nucleoli. Basophils also have an abundance of condensed chromatin around the periphery of the nucleus. They generally contain fewer granules that are electron dense and more homogeneous appearing than mast cell granules. Basophils may also contain Charcot-Leyden crystals. Many markers for basophils have been described and they are quite similar between human and murine basophils (Schroeder, 2009). One of the differences between mast cells and basophils is that proteinases are abundant in mast cells but not in basophils. Mouse basophils express MCP-11, a tryptase, in contrast to mast cells that express mostly the tryptases MCP-6 and MCP-7 (Ugajin et al., 2009); MCP-11 is expressed in mast cells only during early phases of differentiation. Human basophils express both α tryptase and β tryptase, although at two orders of magnitude lower than mast cells (Jogie-Brahim et al., 2004). There is also a significant difference in expression of Fc receptors between the basophils and mast cells. Both cells express high affinity receptors for IgE (MacGlashan, 2005), a receptor that mediates many of their effects in allergic inflammation and parasitic infections, while basophils (Tkaczyk et al., 2004), in contrast to the spectrum of FcγR on mast cells, express only FcγRIIa and FcγRIIb. Interestingly, basophils appear to bind IgD, and there is evidence that this can activate them in a manner that elicits responses that differ from those of IgE activated basophils, including the following: production of antimicrobial peptides, IL-4 and IgM, IgD and IgA class switching, responses deemed to be relevant in protection against respiratory infections (reviewed by Siracusa et al. (2012)).

Mast Cell and Basophil Mediators Mast cells and basophils contain a large number of preformed mediators in their granules and also synthesize many mediators upon activation. Mast cells and basophils can express many similar cytokines and inflammatory mediators, but they also have significant differences. Both cells express histamine, LTC4, and PAF, while cytokine and proteinase profiles can be quite different. The mediators are reviewed in recent publications (Hsu and Boyce, 2009; Befus et al., 2013). Moreover, the type of mediators that are secreted depends on the stimuli involved in mast cell and basophil activation (Dvorak, 2005). The granule content of mast cells and the biological functions of many of the granule mediators have been reviewed in 2014 (Wernersson and Pejler, 2014). The secreted products can have many biological effects as discussed below. As outlined above, the proteinase composition of mast cells varies from tissue to tissue, e.g., MMC versus CTMC and intestine versus lung, and there are marked differences

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among species. The diversity of these proteinases and their physiological functions have been reviewed in 2010 (Trivedi and Caughey, 2010). Significant new information on roles of MCPs has been uncovered through the use of knockout strains of mice (see below). Recently, there has been great interest in the secretion of exosomes, 40–100 nm membrane-enclosed vesicles derived from late endosomes from many cell types, including mast cells (Kowal et al., 2014; Carroll-Portillo et al., 2012). Exosomes contain a cornucopia of lipids, proteins, mRNA, and microRNA species and represent a novel mechanism of cell–cell communications, including exchange of genetic information (van Niel et al., 2006; Record et al., 2011). Mast cell exosomes can directly activate other cells (Skokos et al., 2001; Al-Nedawi et al., 2005), transfer mRNA and selective species of microRNA to other cells (Ekstrom et al., 2012), as well as several proteins (Valadi et al., 2007). Mast cell exosomes released during stress responses may be able to protect other cells from similar injury (Eldh et al., 2010), an effect likely mediated by transferred RNA. We are unaware of any descriptions of exosome secretion by basophils, although their cytoplasm contains vesicles that could be associated with exosome secretion (Dvorak, 2005; Merluzzi et al., 2015).

NEW TOOLS TO UNDERSTAND THE FUNCTION OF MAST CELLS AND BASOPHILS Despite their many important contributions to our understanding of mast cell biology (described above), CD117/ SCF mutant mice that are mast cell deficient have hematologic and other defects that complicate interpretation of results and prohibit unequivocal conclusions about the role of mast cells in biologic processes. The first approach to solve this problem was to replenish mature mast cells in specific tissues, or throughout the body, by injecting mast cells or their committed progenitors in these mice. The last few years have seen remarkable advances in the tools available to apply the principles of Koch’s postulates to study mast cells and basophils as newer technologies have provided genetically engineered mast cell and basophil knockout strains that do not have defects in other hematopoietic cells. A 2012 review summarized the characteristics and utility of newer mast cell-deficient mice and demonstrated that data from experiments with these mice force us to rethink the role of mast cells and basophils in many conditions (Rodewald and Feyerabend, 2012). An engineered mast cell knockout mouse, Cpa3cre/+, exhibits complete lack of mast cells in all tissues studied (Feyerabend et al., 2011). Lack of mast cells was attributed to the genotoxicity of the cre recombinase (Naiche and Papaioannou, 2007), which is highly expressed in mast cell precursors in these mice. Cpa3cre/+ mice had also

lower numbers of basophils in the spleen. Cpa3cre/+ mice were refractory to IgE-mediated anaphylactic responses, responses reconstituted when the mice received normal mast cells. Cpa3cre/+ mice were not susceptible to antibodyinduced arthritis, while W/WV mice were, as shown previously (Lee et al., 2002). However, Cpa3cre/+ mice were susceptible to experimental allergic encephalomyelitis (EAE), as shown before for W/Wv mice (Gregory et al., 2005). Another Cpa3-cre mouse line generated independently was crossed with an antiapoptotic factor myeloid cell leukemia sequence (Mcl-1) floxed mouse (Cpa3-cre; Mcl-1fl/fl mouse) (Lilla et al., 2011). The resultant mouse had deficiency in mast cells and basophils in the blood and tissues and deficiencies in IgE-dependent passive cutaneous anaphylaxis, which was corrected with local engraftment of in vitro cultured mast cells. In contrast to the Cpa3cre/+ mice, Mcpt5-cre (­Scholten et al., 2008) and α-chymase promoter-cre mouse lines (Musch et al., 2008) have mast cells and can be used to delete targeted floxed-genes in mast cell populations. The Mcpt5-cre line was crossed with a previously described iDTR (diphtheria toxin receptor) line to generate mast celldeficient animals (Dudeck et al., 2011), using the timely introduction of diphtheria toxin. These mice showed dramatically reduced contact sensitivity, probably as a result of impaired migration of dendritic cells (DC) to the lymph nodes, and they also showed that this effect was not dependent on IL-10 generated by mast cells (Dudeck et al., 2011). The mice have also been used to better understand the role of mast cells in food allergy (see below) (Reber et al., 2013). The α-chymase promoter-cre mouse lines showed transgene expression specifically in MMC and may be an excellent system to understand the role of MMC. Using a different approach, mice lacking mast cells and basophils (Mas-TRECK) (Otsuka et al., 2011; ­Sawaguchi et al., 2012) or only basophils (Bas-TRECK) (­Sawaguchi et al., 2012) were generated. These mice express human diphtheria toxin receptor under the control of mast cell (Mas-TRECK) or basophil-specific (Bas-TRECK) enhancer elements for Il4 gene expression. Using Mas-TRECK, it was shown that mast cell depletion during the sensitization phase attenuates contact hypersensitivity and abrogates maturation and migration of skin DC (Otsuka et al., 2011). Another study using Mas-TRECK and Bas-TRECK mice showed that both cells play a role in allergic airway inflammation, but mast cells are also important for airway hyperreactivity, while basophils do not play a large role (Sawaguchi et al., 2012). Mas-TRECK mice also exhibited defective passive cutaneous and passive systemic anaphylaxis, whereas Bas-TRECK mice had responses similar to wild-type mice. Mast cell proteinase 8 (Mcpt8)-cre mice (Ohnmacht et al., 2011) are deficient in basophils due to cre toxicity the same way that Cpa3cre/+ mice are deficient in mast cells,

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and they have no defect in any other leukocyte lineage, including normal numbers of CTMC in the peritoneal cavity and normal numbers of MMC. Another mouse expressing the human diphtheria toxin receptor under the control of Mcpt8 promoter has been generated, and basophils can be eliminated in this mouse following administration of diphtheria toxin (Wada et al., 2010).

MAST CELL AND BASOPHIL FUNCTIONS— ROLE IN DISEASE PROCESSES For many years, the focus of research on mast cells and basophils was on their roles in parasitic infections and allergic reactions. However, as information emerged about mast cell and basophil heterogeneity/plasticity and about the plethora of receptors the two cell types express, our understanding of their diverse functions in physiologic and pathologic processes has evolved. In recent years, research has focused on their roles in innate immune responses to microbial infections, development and expression of acquired immune responses, effectors functions, injury and initiation

of repair and remodeling, as well as in homeostasis. A summary of the biological functions of mast cells is shown in Figure 1 (Moon et al., 2010; Gilfillan and Beaven, 2011; Galli and Tsai, 2012; Befus et al., 2013; Wernersson and Pejler, 2014). Mast cells, and to a large extent basophils, initiate allergic reactions and play significant roles in the development of Th2 responses in mucosal tissues when they are activated by allergens that bind to surface IgE antibodies. Both cell types can also be activated by pattern recognition and other receptors and participate in other immune and inflammatory responses in these tissues and in their role in protection from viral, bacterial, and parasitic infections. An intriguing, new line of research has focused on their potential role as adjuvants for vaccines. The ability of mast cells and basophils to activate innate immune responses and to link these with the development of adaptive responses is a pivotal property. In the next sections, we will highlight several exciting developments in our understanding of mast cell and basophil functions in mucosal tissues.

FIGURE 1  Mast cell effector functions in homeostasis and disease. Mast cells respond to a variety of stimuli by releasing numerous preformed (­histamine, proteases, some cytokines/chemokines) and newly generated (cytokines/chemokines, lipid mediators) mediators. These mediators influence various cell types to regulate both physiologic and pathologic processes. Reproduced from Moon et al. (2010) with permission of the Nature Publishing Group.

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Mast Cells as the Link between Innate and Acquired Immunity Infections Mast cells have been associated with protection from viral, bacterial, fungal, and parasitic infections, especially in mucosal surfaces, in part because of their role as a primary innate immune cell that orchestrates early detection (sentinel cell) and responses to infectious organisms (Shelburne and Abraham, 2011). In many cases, mast cells interact directly with bacteria and viruses through a variety of surface or internal receptors, including TLR. Mast cells express many TLR that differ depending on the species of origin and tissue localization of the cells (Vliagoftis and Befus, 2005; Sandig and Bulfone-Paus, 2012). These interactions lead to proinflammatory changes that are often host protective, but in some cases also detrimental. Bacteria: As early as 1996, it was shown that mast cell deficiency is associated with susceptibility to bacterial infections (Malaviya et al., 1996; Echtenacher et al., 1996). Mast cell-deficient mice exhibit increased mortality from peritonitis compared to normal mice (Echtenacher et al., 1996), and mast cells are required for clearance of Klebsiella pneumoniae in both the peritoneal cavity and the lung (Malaviya et al., 1996); in both cases, TNF released from mast cells mediated protection, but the particular mast cell receptors detecting infection were not identified. Since these early observations, mast cells have been shown to confer protection from various infections at mucosal surfaces (Xu et al., 2006; Junkins et al., 2014) and other tissues (Siebenhaar et al., 2007). Mast cells can have direct bactericidal effects through the release of antimicrobial peptides (Di Nardo et al., 2003) or through extracellular traps (von Kockritz-Blickwede et al., 2008). Mast cells may also augment mucosal protection through an increase in IgA production; mast cells induce proliferation of activated B cells, and through the release of cytokines and CD40/CD40L interactions, induce differentiation of B cells into IgA producing plasma cells (Merluzzi et al., 2010). It is interesting that mast cells have been shown to be in close contact with IgA plasma cells in inflamed human tissues. However, in addition to their protective functions, mast cells can also increase mucosal injury, as in lung pneumococcal infection, probably through a degranulation-independent mechanism that impairs epithelial barrier function (van den Boogaard et al., 2014). Viruses: Mast cells can also exert antiviral activity, as well as contribute to viral pathogenesis. Mast cell activation by viruses or synthetic TLR3 agonists induced release of IFNα and IFNβ but did not stimulate release of TNF, IL-1β, IL-5, or GM-CSF (Kulka et al., 2004); however, TLR2 or TLR4 ligands did not induce release of type I interferons from these cells. TLR7 activation can also induce release

of type I interferons from mast cells (Witczak et al., 2014). Type I interferons may mediate antiviral effects of mast cells in these cases. Activation of mast cells through interactions with viruses may depend on the source of mast cells (Matsushima et al., 2004), possibly because different mast cells express different sets of TLR receptors (Vliagoftis and Befus, 2005). For example, in vivo developed mast cells are susceptible to infection with viruses that do not seem able to infect in vitro cultured mast cells (Ebert et al., 2014). The effect of mast cells in viral infections is in many cases through the recruitment of other immune cells to the site of infection. Human mast cells activated through interactions with the double-stranded RNA virus, reovirus serotype 3, can mediate recruitment of NK cells through CXCL8 release (Burke et al., 2008), while mouse mast cells activated by Newcastle disease virus can induce the recruitment of CD8 cells both in vivo and in vitro (Orinska et al., 2005). In mouse CMV infection, mast cells release CCL5 that is responsible for recruitment of CD8 cells to the airways (Ebert et al., 2014); in this case, direct infection of mast cells by CMV enhances control of the viral infection. Human mast cells activated by IFNγ express antiviral proteins MX dynamin-like GTPase 1 (Mx1), 2′-5′-oligo adenylate synthetase 1 (Oas1), and retinoic acid-inducible gene-I (RIG-I); expression is further enhanced by LPS activation (Okumura et al., 2003). Mouse mast cells express melanoma differentiation-associated gene 5 (MDA5) and RIG-I, expression that increases following vesicular stomatitis virus infection (Fukuda et al., 2013). Mast cells also synthesize antiviral proteins myxovirus resistance gene A (MxA) and Interferon-induced protein with tetratricopeptide repeats 3 (IFIT3) following infection with Sendai virus (Lappalainen et al., 2013). Mast cell-mediated control of viral infections may result from direct activation of mast cells by the virus, as for vaccinia virus (Wang et al., 2012), or indirect activation through mediators released from other infected cells, as for infection with herpes simplex virus 2 (Aoki et al., 2013). Certain strains of influenza virus can activate mast cells to release cytokines through a RIG-I-dependent pathway and preformed mediators through a RIG-I-independent pathway, but the virus does not replicate in murine mast cells (Graham et al., 2013). The virus infects human mast cells lines and primary cultured mast cells and starts to replicate, but there is no release of infectious particles, perhaps because the cells may lack the machinery to assemble the virus or because of active antiviral mechanisms (Marcet et al., 2013). These observations may reflect the characteristics of the cells or viral strains used, since the murine mastocytosis cell line P815 can support productive replication of influenza A virus, which leads to cytokine production and finally apoptosis of this line (Liu et al., 2014). Interestingly, H5N1 influenza activates mast cells in vitro and in vivo (Hu et al., 2012); H5N1 infection increases the number of mast

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FIGURE 2  Mast cell interactions with influenza virus. Products released from virus-infected epithelial cells, as well as direct virus infection, activate mast cells to generate/release mediators that may control virus infection or increase viral-induced pathology.

cells in the airway mucosa and the mast cells appear degranulated. Increased numbers of mast cells and their mediators is also seen in the airways of influenza-infected dogs and may be responsible for the airway hyperresponsiveness seen in dogs after influenza infection (Miura et al., 1989). In mice lacking mast cells, influenza virus causes less lung pathology than in mast cell-sufficient mice (Graham et al., 2013). The mast cell mediators tryptase and TNF increase in the nasal mucosa, trachea, lungs, and regional lymph nodes in mice infected with H5N1 influenza, and inhibition of mast cell degranulation decreased lung pathology and improved efficacy of antiviral medications (Hu et al., 2012). A model of the interactions between mast cells and influenza virus, based on our data and published literature, is shown in Figure 2 as a representation of potential interactions between mast cells and viruses. Parasites: The involvement of mast cells in parasitic infection has been known for many years. Recent work has shed light on the mechanisms involved and the role of particular mast cell mediators in protection from several parasitic infections. Mast cells are important for control of the protozoan infection, Leishmania major, through local inflammation and their ability to recruit DC to the site of infection (Maurer et al., 2006). Mast cells can also play a protective role in malaria, another protozoan infection, through TNF release (Furuta et al., 2006). Both FcεRI- and FcγRIIImediated mast cell activation accelerates clearance of the

helminth Strongyloides venezuelensis (Matsumoto et al., 2013). Mast cell-deficient mice infected with Heligmosomoides polygyrus bakeri or Trichuris muris produce lower levels of IL-25, IL-33, and TSLP compared to control mice, and the knockout mice have difficulty clearing the parasites (Hepworth et al., 2012). Indeed, mast cell mediators such as histamine, 5HT, and arachidonic acid metabolites are well known to influence epithelial and smooth muscle function, making the mucosal environment hostile to parasite residence and survival (Patel et al., 2009). MCP-6 knockout mice showed that this mast cell tryptase is important in protection from parasitic infections (Shin et al., 2008) through recruitment of inflammatory cells. Collectively, these observations suggest that mast cells have a variety of weapons against parasites and that these defenses are among the fundamental roles of these cells in homeostasis.

Mast Cell Activation has Vaccine Adjuvant Effects One enlightening area of research involves the interactions between mast cells and DC and their role in linking innate and adaptive immunity (a model is shown in Figure 3). This knowledge fostered efforts to use mast cell activating agents as adjuvants for mucosal and systemic vaccination. Direct interactions between mast cells and DC can develop through several mechanisms (Carroll-Portillo et al.,

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FIGURE 3  Model of mast cell and basophil involvement in response to external antigens. Antigens, allergens, and various microbial products cross the epithelium and interact with several cell types, including mast cells and basophils. In turn, these cells can interact with dendritic cells or directly influence the development of TH2 immune responses. These pathways orchestrate the ensuing cellular infiltration and activation and elicit effector functions associated with host defenses or pathogenic processes.

2012). IgE-mediated activation of mast cells induces histamine-dependent migration of DC from the skin to draining lymph nodes (Jawdat et al., 2004). Interestingly, although mast cells may not be involved in DC migration to lymph nodes in response to LPS (Jawdat et al., 2004), they play an indispensable role in DC migration following stimulation of mouse skin with bacterial peptidoglycans (Jawdat et al., 2006). Mast cell activation products can also affect trafficking of exogenously administered DC (Ren et al., 2010), indicating that mast cell secretagogues may be useful in immunotherapy for cancer and other conditions where autologous DC primed to antigens in vitro are administered (Kalinski et al., 2013). Trafficking of specific DC subpopulations to lymph nodes shows selective dependence on mast cells and/or specific mast cell products. For example, in a model of peptidoglycan administration to mouse skin, recruitment of CD8+ DC and plasmacytoid DC to the lymph node is mast cell dependent while recruitment of CD11b+ DC is mast cell independent; plasmacytoid DC recruitment is mediated by histamine H2 receptor activation while recruitment of CD8+ cells is not (Dawicki et al., 2010). TNF release from mast cells can facilitate DC migration into the draining lymph nodes (Suto et al., 2006) and also into infected tissues (Shelburne et al., 2009) (Figure 3). From infected tissues, DC then migrate to regional lymph nodes and initiate an adaptive immune response that leads to antibody production and protective immunity. As predicted from such studies, subcutaneous or intranasal administration of mast cell activators can have adjuvant

effects during vaccination (McLachlan et al., 2008), probably through mast cell mediators increasing recruitment of DC to lymph nodes. Indeed, in a mouse model of protection against anthrax, compound 48/80, a mast cell activator, is a safe and effective adjuvant (McGowen et al., 2009). Compound 48/80 is also an effective adjuvant in mucosal vaccination against recombinant viral hemagglutinin, as 48/80 increased both the systemic IgG response to hemagglutinin and the mucosal IgA response that correlated with protection against a pandemic H1N1 influenza strain (Meng et al., 2011). Similarly, adding 48/80 to a botilinum neurotoxin A vaccine given intranasally to rabbits significantly improved induction of antineurotoxin A neutralizing antibodies (­Staats et al., 2011). Another mucosal adjuvant, cholera toxin A1 subunit (CTA1)-DD, which is a fusion protein composed of CTA1, the ADP-ribosylating part of cholera toxin, and DD, two Ig-binding domains derived from Staphylococcus aureus protein A, had mast cell activating potential when complexed with IgG. Its adjuvant activity in mucosal immunization to hapten (4-hydroxy-3-nitrophenyl) acetyl (NP) coupled to chicken gammaglobulin was dependent on mast cells (Fang et al., 2010). The same adjuvant given with human papillomavirus (HPV) type 16 L1 virus-like particles improved anti-HPV antibody titers in the serum and vaginal secretions of mice (Fang et al., 2013). It is interesting that while the vaccination was through the intranasal route, the adjuvant appeared to only activate CTMC found in the nasal submucosa and not MMC. Mast cells activated in mouse footpads release particles/ granules that can be detected two hours later in the draining lymph nodes (Kunder et al., 2009). TNF contained within these granules leads to lymph node enlargement, indicating that it is involved in initiation of immune responses. Interestingly, coadministration of synthetic particles that contain TNF to mimic mast cell granules improves the efficacy of vaccination against influenza infection (St John et al., 2012). Efficacy of mucosal vaccination of mice against Helicobacter pylori in the presence of cholera toxin (Velin et al., 2005) or against influenza in the presence of IL-18 or IL-33 (Kayamuro et al., 2010) is decreased in mast cell-deficient mice. However, the precise nature of mast cell involvement is unclear; there is no evidence in any of these studies whether cholera toxin, IL-18, or IL-33 directly activate mast cells, or whether mast cells are involved in the adjuvant effect through some other mechanism.

Allergic Diseases Allergic disease is the traditional realm assigned to mast cells and basophils, and although it has been studied extensively, there is significant new knowledge. In addition to their role as effector cells, a better understanding has developed on roles of mast cells and basophils in initiating

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immune responses leading to allergy. There is extensive literature on mast cells in immediate hypersensitivity reactions (Galli and Tsai, 2012), and here we will focus on selected issues only.

Asthma The issue of mast cell dependency of allergic sensitization and allergic airway inflammation has long been debated. There are different degrees of mast cell dependency determined by the model used. Williams and Galli (2000) attempted to characterize mast cell dependency of mouse models of asthma using c-kit defective and control mice. Airway hyperresponsiveness and accumulation of eosinophils in the airways were mast cell dependent when mice were immunized to ovalbumin parenterally in the absence of adjuvant, but they were mast cell independent if the mice were immunized using aluminum hydroxide as an adjuvant. The presence and numbers of proliferating epithelial cells and infiltrating inflammatory cells in the airways were dependent on mast cells in both the presence or absence of the adjuvant. Airway hyperresponsiveness and eosinophil infiltration in adjuvant-independent ovalbumin sensitization is dependent on TNF release from mast cells (Nakae et al., 2007; Reuter et al., 2008). In contrast to the results of Williams and Galli, Kobayashi et al. showed that airways hyperresponsiveness to ovalbumin in mice sensitized in the presence of aluminum hydroxide was mast cell dependent (Kobayashi et al., 2000). The two studies differed in many details of sensitization and challenge that may explain the discrepancy. As has been discussed previously (Figure 3), mast cell-mediated promotion of DC mobilization to regional lymph nodes is important in murine models of asthma (Reuter et al., 2010), and mast cells affect the ability of DC to induce Th2 antigen-specific T cells (Mazzoni et al., 2006). Thus, the mast cell dependency of allergic sensitization and components of airways inflammation can vary depending upon the animal model employed. Little is known about mast cell dependency in human asthma and its multiple phenotypes. One characteristic of human asthma is the presence of intraepithelial mast cells in the airways (Laitinen et al., 1985; Dougherty et al., 2010). RNA expression profiling of epithelial brushings from subjects with and without asthma showed that expression of tryptase and CPA3 was higher in asthmatic compared to nonasthmatic subjects. Expression of tryptase was also elevated in subjects with high Th2 immune responses, subjects who also had high expression of several IL-13 signature genes (Dougherty et al., 2010). High levels of expression of tryptase and CPA3 correlated with better improvement in lung function after use of inhaled corticosteroids. Subjects with an asthma phenotype characterized by high Th2 immune responses had up to twofold greater densities of intraepithelial mast cells expressing tryptase

and CPA3 but not chymase, compared to subjects with low profiles of TH2 responses, or healthy controls (­Dougherty et al., 2010). CPA3 may play a role in development of asthma or in disease severity by cleaving molecules such as angiotensins, apolipoproteins, and endothelins (Pejler et al., 2009). CPA3 released from mast cells can also inactivate a variety of snake and honeybee venoms (Metz et al., 2006). In severe asthma, there is a predominance of MCTC cells in the airways, submucosa, and epithelium compared to mild to moderate asthmatics that have primarily MCT cells (Balzar et al., 2011). Numbers of MCTC also correlated with PGD2 levels in the bronchoalveolar lavage, indicating that MCTC may produce more PGD2 in severe asthma. Increased numbers of intraepithelial mast cells are also found in H. pylori gastritis (Caruso et al., 2011), eosinophilic esophagitis (Mulder et al., 2012), and parasitic infections (Friend et al., 1996). However, what regulates the numbers and functions of intraepithelial mast cells in mucosal diseases is not clear. Further studies are needed to identify the relevant molecules that recruit mast cell progenitors and/or mature mast cells into the epithelium and their functions. Interestingly, MCP-4 knockout mice develop greater allergic airway inflammation and smooth muscle thickness after exposure to sensitizing allergen than wild-type mice (Waern et al., 2009). MCP-4 positive mast cells were situated close to the smooth muscle layer in upper bronchi, indicating that MCP-4 may affect smooth muscle remodeling. MCP-4 has several other effects such as protecting against posttraumatic brain inflammation (Hendrix et al., 2013), maintaining tissue homeostasis through activation of pro matrix metalloproteinase-2 (MMP-2) and pro-MMP-9 that can then regulate extracellular protein deposition (Tchougounova et al., 2005), and limiting the toxicity of scorpion venom (Akahoshi et al., 2011). However, not all effects of MCP-4 are protective, as MCP-4 mediates pathogenic effects in experimental bullous pemphigoid (Lin et al., 2011) and contributes to kidney damage in immune complex mediated glomerulonephritis (Scandiuzzi et al., 2010) and to autoimmune arthritis (Magnusson et al., 2009). Recent work in animal models has generated new information on the role of basophils in allergic airway inflammation and other immune responses (Sokol and Medzhitov, 2010a). The precise roles of the basophils vary among models, similar to that found for mast cells. This work requires careful assessment, as some of the observations and associated conclusions may be dependent on whether the authors used mutant mice selectively deficient in basophils, used various more or less selective strategies to deplete basophils, and/or the timing of the depletion. Basophils express MHC class II molecules and can mediate antigen presentation (Nakanishi, 2010), especially of haptens and peptides (Otsuka et al., 2013). However, basophils are not capable of processing and presenting intact protein antigens such as ovalbumin (Otsuka et al., 2013)

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or Bet v1 vitro (Eckl-Dorna et al., 2012; Kitzmuller et al., 2012). They can form immunological synapses with T cells (Sokol et al., 2009) and mediate MHC II-dependent Th2 cell differentiation in vivo and in vitro in the absence of DC (Sokol et al., 2009); transfer of antigen-loaded basophils into MHC II-deficient mice was sufficient to induce Th2 differentiation. Basophils can also initiate Th2 responses by capturing IgE-allergen complexes (Yoshimoto et al., 2009). Basophils can interact directly with B cells and induce IgE synthesis (Gauchat et al., 1993), but the significance of this observation has not been assessed. Basophils, particularly TSLP-dependent basophils, appear to play a similar antigen-presenting role in development of Th2 responses in helminthic infections (Perrigoue et al., 2009; Giacomin et al., 2012) and in development of humoral responses to bacteria (Figure 3) (Denzel et al., 2008). An intriguing puzzle in Th2 immune diseases is the nature of the “innate” immune cell that generates IL-4 required for Th2 differentiation of T cells. Historically, many cells have been given this role with the latest cell type assigned being the innate lymphoid cell (Spits et al., 2013); in many cases, basophils appear to be the source of this IL-4 (Sokol and Medzhitov, 2010b). Administration of papain to mice induces accumulation of basophils in the draining lymph nodes that is required for the development of Th2 immunity (Sokol et al., 2008), and basophils are also important for development of Th2 immunity against inhaled A. fumigatus (Poddighe et al., 2014). This basophil accumulation is dependent on release of cytokines from T cells (Liang et al., 2012). Interactions between basophils and DC migrating to the lymph nodes following antigen exposure is also important for basophil activation and Th2 differentiation (Tang et al., 2010). In some settings, T cell-basophil cognate interactions may decrease the ability of basophils to induce Th2 polarization (Nakagawa et al., 2011). However, the role of basophils in Th2 differentiation is not universal, as administration of house dust mite extracts to mice also leads to accumulation of basophils in draining lymph nodes, but elimination of basophils has little effect on development of Th2 responses to these allergens (Hammad et al., 2010). Accumulation of Th2 cells, eosinophilia, and IgE and IgG increases induced by ovalbumin immunization and challenge or by infection with N. brasiliensis are independent of basophils (Ohnmacht et al., 2011), but basophils are required for protection against secondary infection with N. brasiliensis. These observations indicate that the role of basophils in the development of allergy and host defense is complex and likely depends on the specific model studied. Recent evidence that antibiotic-induced modifications of the microbial flora are associated with elevated IgE levels, increased circulating basophil populations, and pronounced basophil-mediated Th2 responses, and allergic inflammation opens new avenues of research on the control of allergic sensitization through commensal flora (Hill et al., 2012).

This study shows that factors derived from commensal bacteria limit proliferative capacity of bone marrow-resident basophil progenitors and may be responsible for decreased Th2 responses.

Food Allergy It has been widely accepted that MMC play a critical role in food allergy with earlier literature often focused on the role of their mediators in epithelial and smooth muscle activities (Crowe and Perdue, 1993; Yu and Perdue, 2001). Recently, with new models of food allergy and of mast cell and basophil deficiency, researchers have begun to dissect the role of these and other cells in the induction of symptoms of anaphylaxis following food allergen challenge in sensitized mice. Two groups have used a mouse model of peanut-induced anaphylaxis to understand the role of mast cells and basophils in the effector phase of food allergy (Arias et al., 2011; Reber et al., 2013). Mice were sensitized through gavage of peanut proteins with cholera toxin adjuvant and then challenged intravenously or intraperitoneally with peanut protein. Several cells, including mast cells, basophils, and macrophages were partially responsible for the signs of anaphylaxis following challenge with peanut protein, and elimination of any of these cells prevented the most significant consequence of anaphylaxis—death (Arias et al., 2011). Simultaneous elimination of mast cells and macrophages nearly abrogated all signs of anaphylactic response, and the effect of mast cells in anaphylaxis was dependent on FcεRI and FcγRII/III signaling (Arias et al., 2011). Reber et al. (2013) used the Mcpt-cre iDTR, inducible mast celldeficient mice to eliminate the possibility that other abnormalities in c-kit mutant mice may affect the outcome of the studies and distinguish between effects of CTMC and MMC. Mcpt5-cre iDTR mice, mice which lack CTMC but not MMC, exhibited less hypothermia following intraperitoneal peanut challenge compared to cre negative control mice, but the response was not completely inhibited, indicating that MMC also play a role in this outcome. The relevance of this model to human food allergy, where antigen challenge is generally through the oral route and therefore where MMC would be expected to have a bigger role than CTMC, is unclear. This study also showed that depletion of basophils had an effect on anaphylaxis, but the reaction was not completely abolished in the absence of basophils. Reber et al. (2013) also showed that Cpa3-cre; Mcl-1fl/fl mice that are deficient in both mast cells and basophils have reduced, but not completely abolished, signs of anaphylaxis, indicating again that other cells play a role; the authors speculate that residual signs of anaphylaxis result from a platelet-­ activating factor that is produced in knockout mice. Interestingly, lack of mast cells and/or basophils did not affect the ability of mice to become sensitized to peanut

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proteins. Chu et al. (2014) established that sensitization was independent of mast cells, basophils, NKT cells, γδ T cells, and innate lymphoid cells, and was only dependent on IL-4 produced from CD4+ T cells following OX40L-­dependent interaction with DC. TSLP, an epithelial cell mediator important for mast cell function and basophil plasticity, was also dispensable in this model of sensitization to peanut proteins (Blazquez et al., 2010). The relevance to human disease of these observations using murine models of food allergy requires careful scrutiny as the models use a strong mucosal adjuvant, cholera toxin, in addition to peanut protein to induce allergic sensitization of mice and then use a systemic route (intravenous or intraperitoneal) for allergen challenge with peanut. In another model of food allergy with systemic sensitization of mice to ovalbumin and oral challenge, mice developed a dramatic increase in MMC number in the epithelium throughout the colon, along with diarrhea (Yamamoto et al., 2009, 2014); colonic MMC degranulated in mice challenged with ovalbumin. PI3K knockout mice that lack MMC (Fukao et al., 2002) did not develop signs of food allergy or mast cell hyperplasia in the colon, although they were sensitized normally to ovalbumin (Yamamoto et al., 2014). Interestingly, food allergy herbal formula-2, a herbal medication that decreases the number of mast cells in the peritoneal cavity and basophils in mouse blood, protected peanut allergic mice from anaphylaxis (Song et al., 2010). Consistent with the role of S1P in mediating migration of mast cells towards antigen (Olivera et al., 2006), interruption of the S1P pathway had protective effects in this model of food allergy by decreasing recruitment of CD4+ T cells and mast cells in the gut and decreasing the development of diarrhea (Kurashima et al., 2007). Intestinal epithelial barrier function is increased in mast cell knockout mice in vivo, and this appears to be attributable to loss of mast cell chymase MCP-4 (Groschwitz et al., 2009). These mice have a significant increase in crypt depth associated with decreased expression of claudin-3 in crypt epithelium, but they have no defect in inflammation-induced alterations of barrier function. Inflammationinduced increase in paracellular permeability of the gut epithelium in parasitic infections is mediated by MMC activation and in particular by release of MCP-1 (McDermott et al., 2003); mice that lack MCP-1 also had a defect in expulsion of T. spiralis. Lack of MCP-1 also delays the time course of mast cell accumulation in the crypts after parasitic infections (Wastling et al., 1998). Given the well-known relationship between mast cells and nerves (Forsythe and Bienenstock, 2012), especially in the intestine, observations that vagal activation can inhibit the signs of food allergy, including mast cell hyperplasia, through α7 nicotinic acetylcholine receptors is noteworthy (Yamamoto et al., 2014). Indeed, there is a growing literature on a cholinergic, antiinflammatory pathway dependent on

α7 nicotinic acetylcholine receptors (Andersson and Tracey, 2012). MMC express inhibitory α7 nicotinic acetylcholine receptors and MMC in mouse colon are in close proximity to cholinergic nerve fibers that exhibit immunoreactivity for choline acetyltransferase (Yamamoto et al., 2014). The same α7 nicotinic acetylcholine receptor is activated following lipid-rich enteric feeding and mediates inhibition of LPS-induced MMC activation (de Haan et al., 2013). These observations indicate that allergic and other intestinal responses can be modified by cholinergic innervation of the GI tract through α7 nicotinic acetylcholine receptors and may identify new therapeutic opportunities through interruption of MMC activation.

Irritable Bowel Syndrome Irritable Bowel Syndrome (IBS) is a common gastrointestinal disorder believed to be the result of disturbances in the brain–gut axis. Patients with IBS complain of abdominal pain in association with diarrhea and/or constipation. Many cells and processes, including enteroendocrine cells, the systemic and enteric nervous systems, immune cells, the microbiome, inflammation, visceral perception, mucosal integrity, nutrition, and psychosocial status are involved in the development and expression of this disease (Camilleri, 2014). Mast cells are situated close to blood vessels, the epithelium, muscle layers, and nerve endings and influence gut motility and secretion through multiple mechanisms (De Winter et al., 2012). Jejunal mucosal biopsies from patients with diarrhea-predominant IBS show higher numbers of mast cells compared to biopsies from normal individuals, although dyspeptic symptoms and severity of IBS did not correlate with the number of mast cells (Guilarte et al., 2007). Patients with IBS also had higher levels of mast cell tryptase in jejunal fluid compared to controls. Another study showed that patients with IBS have lower numbers of mast cells in the descending colon and unchanged numbers in the ascending colon, but the number of mast cells in the small intestine was not evaluated (Braak et al., 2012). More information is needed on the activation status of mast cells in different parts of the GI tract and on the presence or absence of important mediators that affect gut motility and secretion in IBS before we can better understand mast cell involvement in the disease. One factor implicated in IBS pathophysiology is psychological stress, which can activate mast cells through various mechanisms, including the corticotropin releasing hormone (CRH) (Lytinas et al., 2003). CRH directly activates mast cells leading to VEGF release in the absence of overt degranulation and in the absence of histamine, tryptase, or TNF release (Cao et al., 2005). CRH can also increase in situ mast cell development from progenitors in human hair follicles (Ito et al., 2010), but whether the same can happen in mucosal surfaces is not known.

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Acute experimental physical stress increased water flux into the jejunum as well as gastrointestinal permeability in healthy volunteers (Alonso et al., 2012). In rats, crowding stress induced reversible colonic inflammation characterized by granulocyte infiltration, increase in myeloperoxidase and mast cell activation, and IBS-like dysfunction (Vicario et al., 2012). CRH-receptor-1 expression is also increased with stress. In healthy human volunteers, public speaking increased intestinal permeability measured by 2 h lactulose-mannitol urinary excretion, but only in subjects that showed evidence of stress as measured by salivary cortisol levels (Vanuytsel et al., 2014). Parenteral administration of CRH also increased intestinal permeability. Both stress-induced and CRH-induced increases in permeability were prevented by pretreatment of the volunteers with disodium chromoglycate, a mast cell stabilizer.

Inflammatory Bowel Disease Biopsies of patients with ulcerative colitis and Crohn’s disease have increased number of mast cells that stain for β-tryptase (Gelbmann et al., 1999). Biopsies from patients with ulcerative colitis also release more β-tryptase ex vivo compared to biopsies from normal individuals (Raithel et al., 2001). Even patients with ulcerative colitis in remission have higher numbers of mast cells in the sigmoid mucosa in close proximity to nerve endings and a higher percentage of degranulating mast cells compared to controls (van Hoboken et al., 2011). There was a weak correlation between mast cell numbers and pain perception in patients with ulcerative colitis, and there is evidence that mast cell activation elicits widespread pain hypersensitivity (Levy et al., 2012). Dextran sodium sulfate (DSS)-induced colitis in the mouse has several characteristics similar to inflammatory bowel disease (IBD). Mast cells in colonic mucosa, submucosa, and serosa express the proteinase MCP-6. Mice that lack MCP-6 are resistant to DSS-induced colitis and show decreased expression of inflammatory mediators, such as IL-6, IL-1β, and CXCL1 and CXCL2, compared to mice expressing MCP-6 (Hamilton et al., 2011). This function of MCP-6 in induction of colitis cannot be substituted by the other tryptase expressed by gut mast cells, MCP-7. The consistent finding of mast cell hyperplasia in the GI tract of humans and animals with IBD indicates that mast cells may play an important role in pathogenesis. It is also interesting that drugs that are effective in IBD can either inhibit mast cell activation (Bissonnette et al., 1996) or antagonize the effects of mast cell mediators (Ben-Horin et al., 2014).

Tolerance There has been a growing literature on mast cells in immunological tolerance and the induction of Treg (de Vries and Noelle, 2010). Tolerance to allografts is mast cell dependent

(Lu et al., 2006; de Vries et al., 2011), in part because GMCSF released by mast cells enhances survival of DC in allografts (Figure 3). IL-9 produced by Treg cells in these models of tolerance increases the number and activation status of mast cells in transplanted tissues (Lu et al., 2006). Moreover, systemic or even extensive intragraft mast cell activation can break tolerance in the same model (de Vries et al., 2009). Interestingly, MCP-6 knockout mice do not develop tolerance, and the effect may be dependent on increased levels of IL-6, a cytokine associated with graft rejection and a substrate for MCP-6 (de Vries et al., 2010); MCP-6 is expressed by both CTMC and airway MMC (Gurish and Austen, 2012). TGFβ1 produced by mast cells can induce Treg cells, another way that mast cells may induce tolerance (Zhang et al., 2010), although this pathway has not been validated in vivo. Contrasting in vitro studies have shown that mast cells can also inhibit the ability of Treg to suppress Teff activation and proliferation (Piconese et al., 2009). In experimental models, the lack of mast cells is associated with lower numbers of Treg in the CNS and increased severity of EAE (Li et al., 2011); reconstitution with mast cells increases the numbers of Treg in the CNS and improves disease. In contrast, in a model of food allergy, the presence of mast cells impaired Treg development and promoted allergic sensitization instead of tolerance (Burton et al., 2014). This indicates that the interactions between mast cells and Treg are complex and may depend on the stimulus that activates mast cells or possibly the mast cell phenotype. Since mast cells are involved in the development of systemic tolerance, a critical question is whether they are also involved in oral tolerance. Perhaps surprisingly, oral tolerance developed normally in two strains of mast cell-deficient (c-kit mutation) mice (Tunis et al., 2012) following oral administration of ovalbumin or peanut butter. Furthermore, tolerance was not impaired by mast cell activation due to allergic sensitization to another allergen, indicating that mast cell activation products do not interfere with the mechanisms of oral tolerance. Thus, although the literature is limited, mast cells do not appear to be involved in induction or breaking of oral tolerance, in contrast to the effects of mast cells on allograft tolerance. Another relevant clinical setting is in the mechanisms that underlie induction of allergic desensitization and/ or tolerance in food allergic individuals treated with oral immunotherapy. Basophils from humans undergoing oral immunotherapy for peanut allergy become hyporesponsive to IgE-mediated activation, while they maintain their ability to be activated through other pathways (Thyagarajan et al., 2012). Unfortunately, this study did not provide direct evidence of a link between basophil hyporesponsiveness and symptomatic desensitization, but in another study of milk allergic individuals, subjects with hyporesponsive basophils had developed tolerance to milk (Wanich et al., 2009). It is

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not clear whether mast cells are similarly hyporesponsive following oral immunotherapy but this must be determined. A study that used a similar oral desensitization protocol in mice sensitized to egg proteins showed that mice were desensitized locally and had decreased symptoms following oral exposure to allergen, but they had not developed immunological tolerance because they still reacted to a parenteric challenge with the same allergen (Leonard et al., 2012). Further studies are needed to better understand the mechanisms of oral tolerance and to develop more effective therapeutic interventions.

CONCLUSIONS Research during the past few years has generated some exciting ideas regarding the role of mast cells and basophils in mucosal immune processes. This work has generated some themes that, along with new ideas that will arise, will dominate research over the next few years. Important subjects for research include the following: the role of mast cells and basophils in resolution of inflammatory conditions and maintenance of homeostasis in various organs, their role in protection from infectious diseases, and the interactions of these cells with nerves and their involvement in interactions between the CNS and peripheral inflammatory diseases. It is clear that we must acquire new knowledge on the phenotypic plasticity of both these cell types and better understand the specific characteristics that are expressed only by cells found in particular tissues. This knowledge will be a great starting point to understand their role in the pathophysiology of many tissue-specific inflammatory diseases, such as why atopic individuals develop allergic diseases that manifest only in particular organs and not systemically. Understanding unique pathways regulating mast cell and basophil recruitment and terminal differentiation in mucosal tissues may allow us to develop new therapeutic approaches for diseases that initiate at or affect mucosal surfaces. New knowledge of the role of mast cells and basophils in protection from infectious diseases may alter the way we employ mucosal vaccination to prevent infectious diseases. We are beginning to understand the role of gut commensal bacteria in inflammatory diseases, and recently, emphasis has been put into understanding the role of the airway microbiome as well. New information is appearing on the interactions of mast cells and basophils with the microbiome and how the effects of the microbiome on inflammation can be mediated through activation of these cells. Our understanding of the long-term impacts of antibiotics, as they relate to mast cell and basophil development and functions, could become increasingly relevant to prevention or management of chronic inflammatory diseases.

Although we have learned a tremendous amount about mast cells and basophils in inflammatory and other conditions in the past 10–15 years, our translation of this knowledge into prevention and management of human disease has been limited. The dual role that these cells can play in inflammatory diseases, alternating between protective and pathogenic roles, has to be validated in human disease. This has been difficult, especially since there are no known human deficiencies in mast cells or basophils, cases that would provide phenotypes useful to help understand the biology of these cells. In conclusion, mast cells and basophils play important roles in tissue homeostasis but are also involved in many mucosal inflammatory and immune processes in addition to their traditional role in allergic inflammation. The development of new murine transgenic models to study the role of mast cells and basophils in health and disease has fostered an improved understanding of these innate immune cells. However, there is a long scientific journey ahead before we will be able to knowingly manipulate mast cells and basophils for therapeutic benefit in many diseases.

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878  SECTION | B  Inductive and Effector Cells and Tissues of the Mucosal Immune System

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882  SECTION | B  Inductive and Effector Cells and Tissues of the Mucosal Immune System

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