A. Dean Befus
Judah A. Denburg
Introduction
Hans Selye (1), in his 1965 tome, reviewed the literature on two populations of basophilic leukocytes, namely, mast cells and basophils. These cells have many similarities, but they also exhibit several intriguing differences. Despite an ever-expanding literature, we do not understand the precise nature of their relationship or the factors that determine if one, the other, or both are present and active in inflammatory disorders such as allergic inflammation. Many recent articles and reviews have documented advances in our understanding of these cells, their development, contents, biosynthetic activities, activation, and functions in physiology and pathophysiology (2,3,4,5,6,7,8,9,10,11).
Mast cells and basophils contain electron-dense cytoplasmic granules and stain metachromatically with selected basic dyes. They produce numerous inflammatory mediators, many—such as histamine—that are common to both cells, and others that are cell-specific. Both cells express a tetrameric isoform of the high-affinity receptor for immunoglobin E (IgE) with one α, one β, and two γ chains (αβγ2), whereas human monocytes, dendritic cells, and Langerhan cells express a trimeric isoform (αγ2) of the receptor (12,13,14). When this high-affinity IgE receptor is cross-linked by sensitizing allergen or by anti-IgE antibodies, both mast cells and basophils can be activated, mediator synthesis and secretion induced, and gene expression altered. Through such mechanisms and many other ways of activation, mast cells and basophils are prominent players in allergic inflammation and other immune and inflammatory events.
In a thoughtful review several years ago, Galli et al. (2) provided concise descriptions for mast cells and basophils. Basophils (Fig. 11.1A) are
cells with the kinetics and natural history of granulocytes that mature in bone marrow, circulate in the blood, and retain certain characteristic ultrastructural features, even after migrating into the tissues during inflammatory or immunologic processes. The ultrastructure of mature basophils varies according to species but generally includes electron-dense cytoplasmic granules, prominent aggregates of cytoplasmic glycogen, and short, blunt, irregularly distributed plasma membrane processes. There is no convincing evidence that mature basophils, whether in the circulation or in the tissues, retain mitotic capability, or that basophils metamorphose into mast cells upon entering the tissues.
Mast cells (Fig. 11.1B) are
ordinarily mature outside of the bone marrow or circulation, generally in the connective tissues or serous cavities. Cells in this lineage(s), wherever distributed, apparently retain at least limited or latent proliferative capacity—. [I]mmature and mature granules of mast cells and basophils differ distinctively in ultrastructure. Mast cells also differ from basophils in lacking electrondense aggregates of cytoplasmic glycogen, and in having a plasma membrane surface with uniformly distributed, thin, elongate folds and processes. Mast cell nuclei may appear bilobed in an individual photomicrograph, but they generally lack the pattern of peripherally condensed nuclear chromatin characteristic of basophils and other granulocytes.
Although these descriptions have withstood the test of time well, new information has somewhat complicated our understanding of basophils and mast cells, particularly with regard to (a) their distinct immunomodulatory roles (15,16,17,18), (b) their potential lineage sharing under certain (e.g., leukemic) circumstances (19,20), and, more important, (c) the postulated, but debated (7), capacity of mast cells to be derived from a compartment of multipotential hemopoietic progenitors without having to “pass through” a myeloid commitment first (6). In many ways the original statement by Ehrlich in 1879 (1) that basophils were “blood mast cells,” and the corollary, that mast cells are tissue basophils, although incorrect from a developmental standpoint, is still of some value in thinking about the nature of these two cells types. The striking inverse relationship between the numbers of circulating basophils and the numbers of tissue mast cells has been used for decades to infer similarities in function (1).
In this chapter we provide an overview of the developmental biology of the two cell types, including knowledge about their progenitors and growth factors involved in lineage commitment, differentiation, and maturation. Programmed cell death and factors influencing survival have been increasingly well recognized as important components in the regulation of inflammation and myeloproliferative disorders. Mature basophils and mast cells differ markedly in their surface phenotypes, stored mediators, and in the synthesis of new mediators following activation. Factors that activate and regulate the functions of mast cells and basophils also show fascinating similarities and differences. Lastly, from this background, we will provide a conceptual overview of the functions of mast cells and basophils in physiology, in innate and acquired immunity, and in allergic disease and other clinical settings. There is much to be learned about the developmental biology and cellular and molecular controls of their phenotypes and functions. As we progress early in the 21st century and in exciting new developments in biology and medicine, our exponential learning curve for basophils and mast cells will continue, and will lead to effective strategies to manipulate the complexities of these cells for the betterment of those suffering from allergic and other diseases.
General Morphology, Degranulation, and Recovery
Histochemical staining of blood smears or cytocentrifuge preparations of enriched basophils or mast cells with Wright or May-Grunwald-Giemsa stain shows many similarities in these cell types (Fig. 11.2A,B). The cytoplasm of the cells is generally stains pink, the nucleus is purplish or blue, and the cytoplasmic granules are dark blue to purple or even blackish. Basophils in peripheral blood or tissues range in size from 10 to 15 μm, whereas mast cells in tissue sites may appear irregular in shape and up to 20 μm in a long dimension. Dvorak has published extensively on the morphology of normal mast cells and basophils, as well as on the changes associated with degranulation and recovery of these cells following their activation by different stimuli. The reader is encouraged to review her work, which is only briefly summarized here (21).
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Figure 11.1. A: Human basophils are round and have irregular, short surface projections, cytoplasmic secretory granules, and aggregates of cytoplasmic glycogen. N, nucleus; bar, 1 mum. (Reproduced from Dvorak AM, Warner JA, Fox P, et al. Recovery of human basophils after FMLP-stimulated secretion. Clin Exp Allergy 1996;26:281-294, with permission from the authors and Blackwell Science Ltd.) B: Human skin mast cell with monolobed nucleus with partially condensed chromatin, numerous cytoplasmic granules containing crystalline structures, and regularly distributed, narrow, thin surface projections. Bar, 1 mum. (Reproduced from Dvorak AM. Human mast cells. In: Beck F, Hild W, Kriz W, et al., eds. Advances in anatomy, embryology and cell biology. Leicester, England: Springer-Verlag, 1989, with permission from the author and Springer-Verlag.) |
Ultrastructural analyses also demonstrate many similarities between mast cells and basophils, but also identify some differences (Fig. 11.1A,B). In the blood, basophils are round, whereas in the tissues they can appear in various shapes. Mast cells can appear to be round, oval, or elongate-spindle shaped in the tissues. The surface of basophils exhibits blunt processes of variable shape and size, whereas mast cells often possess long, fingerlike processes that extend from the surface. The nucleus of mast cells can be round or lobed, whereas that of the basophil is generally multilobed. Nucleoli are often not apparent or are absent from normal mast cells and basophils. Basophils have an abundance of condensed chromatin positioned at the periphery of the nucleus, whereas mast cells have little condensed chromatin.
The cytoplasm of normal mature mast cells has few mitochondria and a relatively inconspicuous Golgi apparatus; and ribosomes, rough endoplasmic reticulum, and aggregates of glycogen are rare. In normal basophils, mitochondria and aggregates of glycogen are more abundant in basophils than in mast cells, but as with mast cells, Golgi apparatus, ribosomes, and rough endoplasmic reticulum are rare in normal basophils. The most prominent cytoplasmic elements in both cell types are the membrane-bound, electron-dense granules.
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Figure 11.2. A: Human peripheral blood basophil stained with Wright. (From Lee G, Bithell T, Foerster J, et al., eds. Wintrobe’s clinical hematology, 9th ed. Philadelphia: Lea & Febiger, 1993.) B: Rat peritoneal mast cell stained with May-Grunwald-Giemsa. |
Basophils generally possess fewer granules than mast cells, and the granules exhibit a more homogeneous morphology than those of mast cells. Basophil granules are often homogeneously electron-dense, although dense particles may be interspersed with membrane aggregates and whorls. Charcot-Leyden crystals can be formed in basophils as well. Mast cell granules may be homogeneously electron-dense, or may exhibit electron-dense particles, membrane or complex scroll-like patterns, highly organized crystalline structures, or combinations of these. The relationship of these different granule patterns to the tissue site, phase in development, or mediator content is not clear, although it has been proposed that major histocompatibility (MHC) class II–positive vesicles of 60 to 80 nm, called exosomes, released by mast cells following activation, arise from these structures within the granules (22). Interestingly, Dvorak has reported that mast cell granules, in addition to storing mediators, are also sites of RNA metabolism and protein synthesis activity (23). Additionally, basophils contain numerous electron-lucent vesicles of 50 to 70 nm that often contain contents similar to granules. These may be associated with a form of mediator exocytosis (see later).
In addition to these membrane-bound granules, mast cells and basophils also contain rounded, non-membrane-bound, electron-dense structures called lipid bodies, a rich store of arachidonic acid. Lipid bodies appear to increase in number associated with cell activation and are thought to be derived from membrane catabolism and the rapid synthesis of lipid mediators such as the cyclo-oxygenase and lipoxygenase derivatives of arachidonic acid.
Degranulation
Mast cells and basophils appear to undergo distinct types of mediator secretion from granule stores, depending on the stimuli involved in their activation (21). Anaphylactic degranulation occurs following stimulation through the IgE receptor or following other stimuli such as fragments of the complement cascade. It is less evident when mast cells are activated by microbial ligands of Toll-like receptors (TLR; see later). Anaphylactic degranulation can be extensive, involving the majority of the granules, or it can be more restricted. The numbers of granules involved appear to correlate with the proportion of the total cellular histamine that is released. By contrast, in numerous inflammatory reactions in which mast cell and basophil infiltration can occur, such as in cutaneous delayed hypersensitivity, a less explosive form of mediator secretion, called piecemeal degranulation, can occur.
In anaphylactic degranulation in mast cells, the granules rapidly exhibit signs of swelling, then demonstrate membrane fusion with adjacent granules, interconnecting chains and channels form that ultimately fuse with the plasma membrane, creating pores or larger openings which granule contents or larger granule structures can be seen outside the cell. Prominent cytoplasmic filaments can be seen close to the granules, and actin complexes appear outside the cell in association with granules or their contents. The process is generally similar for basophils. Electron-dense granules appear to evolve into electron-lucent vacuoles, many of which communicate to other vacuoles and to the cell surface through pores within 5 to 10 minutes. In addition, apparently intact granules can be seen outside the cell. This anaphylactic degranulation does not lead to major cell death but, as will be outlined, the cells recover and can degranulate again.
Piecemeal degranulation also occurs in mast cells and basophils, as well as eosinophils (21,24) and is the most prevalent morphologic expression of mast cell and basophil secretion in nonallergy inflammatory conditions in human biopsy material. This form of mediator secretion can demonstrate a continuum in its extent. It is postulated that intragranular vesiculotubular networks are released from the granules, move to the cell surface, fuse with the plasma membrane, and discharge their contents to the extracellular space. This form of mediator secretion appears to be associated with secretion of only selected mediators, not the entire contents of the granules, and there is increasing evidence for such selectivity with interleukin-4 (IL-4), for example (25). As with anaphylactic degranulation, piecemeal secretion is associated with the ability of mast cells to recover and to function again.
Recovery after Activation
Dvorak (21) summarized the evidence for the ability of mast cells and basophils to recover and regranulate following activation. During this process, mast cells and basophils appear to conserve membranes and other components and to resynthesize granules and other components, such as rough endoplasmic reticulum, Golgi, microtubules, and new granules. This recovery occurs within 1 to 2 days, but may also take longer. Whether death by necrosis or apoptosis is a feature of mast cell or basophil activation in vivo needs to be carefully evaluated.
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Figure 11.3. Change of lineage model of hematopoiesis. A: In the old view, the presence of mast cell–committed progenitors (MCP) was not clear, but mast cells were considered to be the progeny of common myeloid progenitors (CMP) without convincing evidence. Therefore, MCP is shown in brackets. B: In the new view proposed by Chen et al. (6), the presence of MCP is clear, and MCP are directly derived from multipotential progenitors (MPP). The thick line shows the main differentiation route from MPP to mast cell. CLP, common lymphoid progenitor; GMP, granulocyte/macrophage progenitor; MEP, megakaryocyte/erythrocyte progenitor. (Reproduced, with permission, from Kitamura Y, Ito A. Mast cell-committed progenitors. Proc Natl Acad Sci U S A 2005;102:11129–11130, © 2005 National Academy of Sciences, U.S.A. |
Ontogeny and Developmental Biology of Mast Cells and Basophils
The tissue mast cell and the blood basophil are probably not normally derived directly from a common progenitor, but share their origins from a CD34+ hemopoietic stem cell, regulated closely by various marrow and tissue stromal factors (Fig. 11.3A,B). A unique role is played by CD34 itself—which can be found on some mast cell subpopulations—in these processes (26,27). Recent evidence suggests that mast cells are derived from a separate, non–myeloid lineage-committed progenitor (6), and that, for the most part, basophils and mast cells have distinct ontogenic derivations and markers (6,28). Some observations of leukemic cell lines, as well as more recent analyses of transcriptional regulation of these two lineages and clinical conditions, have nonetheless raised the notion of some circumstances in which lineage pathways may be shared by basophils and mast cells (19,20,29,30), basophils and eosinophils, and basophils and megakaryocytes (31,32,33). Phylogenetically, there appears to be an inverse relationship between the presence of basophils and mast cells (1). Although mast cell growth and differentiation is relatively better understood in rodents than in humans, and basophil production has been more fully worked out in the human, major advances in understanding human mast cell growth and differentiation have come from knowledge of rodent models. Exponential growth in knowledge of human basophil and mast cell ontogeny has ensued, including identification and developmental biology of the mast cell hemopoietin and ligand; stem cell factor (SCF) and its receptor, c-kit; and studies of mast cell–deficient mice, resulting from either deficiencies or several mutations of the ligand or its receptor at the W locus (34,35,36,37). Using definition by flow cytometry and culture with recombinant cytokines, the lineage pathways of basophils and mast cells have been investigated, including analysis of signal transduction and specific transcriptional regulation of basophil and mast cell differentiation in hemopoietic stem cells.
Mast Cell Growth and Differentiation
Rodent and human mast cells can be grown in vitro from lineage-committed, unipotent or multipotent progenitors. Although interleukin-3 (IL-3) is known to contribute to murine mast cell and basophil development (38,39), it is unable to induce human mast cell differentiation from cultures of human cord blood or fetal liver. However, IL-3 can promote human basophil development or act as a cofactor in both basophil and eosinophil differentiation (38,40,41,42,43). A “novel” growth factor was thus postulated for human mast cells, shown to be fibroblast-derived, and identified in both rodents and primates as SCF or c-kit ligand (44,45). In general, human mast cell differentiation in vitro is not influenced directly by cytokines that promote mast cell development in rodents, such as IL-4, IL-9, and IL-10, but almost uniquely by SCF (40), with cofactor effects by IL-3 (44), IL-6 (45), thrombopoietin (TPO) (28,46), and nerve growth factor (NGF) (47). SCF is produced by murine and human fibroblasts, epithelial cells, endothelial cells, and tumor cell lines (34), and must bind to c-kit to effect differentiation. Mutations in c-kitcan result in mast cell deficiency in vivo and in vitro (“loss of function”) or, alternatively, in autonomous mast cell growth (“gain of function,” generally leading to auto-phosphorylation) (35,48,49). It is exciting that on the therapeutic horizon, the latter mutations, especially the D-816-V–associated mastocytosis—which can be transferred with similar consequences to the mouse (49)—have received much attention as potential targets of newly designed tyrosine kinase inhibitors (50,51,52). IL-3, in addition to rodent mast cell differentiation-inducing activity, is a differentiation and activation factor for human and primate basophils (41,53). Because it does not bind to human mast cells, its supportive role in human mast cell differentiation may be a result of its ability to induce SCF-responsive progenitors into the cycle (54). Recently, it has been shown that Th1 and Th2 cytokines (IFN-γ, IL-4, and IL-5) exert differential modulatory effects on SCF-dependent mast cell numbers in vitro (55), pointing out the potential complexity of interactions among factors that control human mast cell differentiation and/or function. Table 11.1lists cytokines, growth factors, transcription factors, and signaling molecules that regulate primate/human and rodent mast cell differentiation (56,57,58,59,60,61,62,63,64,65,66,67,68,69).
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Figure 11.4. Mast cell and basophil ontogeny. An orderly sequence of differentiation is depicted, beginning with a primitive CD34+, Fc∊RI-, c-kit- hemopoietic stem cell (HSC), and proceeding through various stages of commitment to either mast cell or basophil/eosinophil lineages. In reality, the differentiation process is stochastic, and multiple cytokines binding to their receptors permit specific, end-stage differentiation to proceed. For more detailed phenotypic analyses of basophil and mast cell progenitors, see Wang et al. (19). |
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Table 11.1 Regulation of Mast Cell Growth and Differentiation |
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Mast Cell Progenitors
Studies of protease content of human mast cells, identifying tryptase-containing (MCT) and tryptase/chymase-containing mast cell (MCTC) subpopulations (see later) have been used to infer lineage commitments of mast cell subtypes—for example, studies of bowel biopsies from patients with T-cell or combined immunodeficiency, and in vitro examination of fetal liver-derived MCT and MCTC (44). In humans and in rodents, mast cell differentiation proceeds from an immature CD34+, CD38+, CD13+, c-kit+, Fc∊RI-, FcγRII/III+ cell, or, as recently shown, from a previously uncharacterized immature cell in mouse marrow (70). More specifically, this is a multipotent, hemopoietic progenitor characterized as Lin-c-kit+Sca-1-Ly6c-Fc-RI-CD27-β7+T1/ST2+. Both mucosal or serosal mast cell phenotypes develop from this progenitor (56,70,71,72,73) (Fig. 11.4). Mast cell differentiation, abundance, and responses are also regulated in vitro and in vivo in rodents by several recently described transcriptional and nucleosomal regulators such as PU.1, M-Ras, and RabGEF1 (59,60,65,66). In human SCF-stimulated cord blood or fetal liver cultures, both MCT and MCTCphenotypes are found. Similarly, various phenotypes of murine mast cells, characterized by their serine protease content, are present in IL-3- and SCF-stimulated bone marrow cultures (71). Various cytokines can regulate these phenotypic changes, which may not necessarily occur in a linear order, but rather exhibit switching and “trans-differentiation” (1,74,75), reflecting stochastic processes in progenitor differentiation. Primitive cord blood CD34+ c-kit- progenitors may respond quite differently to hemopoietic cytokines than more mature Fc∊RI+, c-kit+ cells (5,6,72). Thus, tissue-dependent stages of progenitor commitment may ultimately predict, in the presence of SCF, differences in mast cell differentiation and phenotype in vitro. Mast cell progenitors can be identified in blood, bone marrow, and various other tissues, especially in relation to mast cell-inducing stimuli, such as viruses or nematodes (72,73,76,77).
Leukemic cell lines with basophilic phenotype have been used to study basophil and mast cell progenitors and immunophenotypic markers of lineage commitment, which recently have undergone a major expansion (28,78,79,80). A model of HL-60 basophilic differentiation (78), for example, identified unexpected phenotypic profiles of maturing basophils and possibly mast cells, including CD15 (Lewis X) down-regulation, CD35 (CRI) up-regulation, and transient expression of c-kit. Similar concepts of combined basophil/mast cell commitment in leukemic cells have been raised from studies of KU812, HMC-1, and other cell lines (79,81,82). Although these findings may represent aberrant pathways activated during malignant transformation, the recent identification of a novel antigenic marker of mast cells, basophils, and their progenitors (31,83), and the presence in peripheral blood of basophilic cells that express mast cell proteases (33), has revived earlier postulates (84,85) that these two cell types share some lineage characteristics under conditions of aberrant cell growth (19,20). However, a recent careful study of eosinophil lineage– committed progenitors in mice revealed that these cells do not express basophil/mast cell–related proteases (86).
Basophil Growth and Differentiation
Most of what is known of basophilopoiesis is derived from human systems, because basophils are readily identifiable in human peripheral blood. Pure or mixed basophil colonies in semisolid cultures can be identified (84,87,88), thus defining a basophil (–eosinophil) progenitor (termed “CFU-baso” or “CFU-baso/eo”). These CFU-baso can be derived from normal, atopic (87), or leukemic human specimens (85,87,89), the latter including blood of patients with chronic myeloid leukemia (CML) or related myeloproliferative disorders, acute myeloid leukemia (AML), and systemic mastocytosis. The phenotype and lineage commitment of the basophil progenitor, including recent notions of lineage sharing with mast cells and/or megakaryocytes (31,32), is depicted in Figure 11.4.
Basophil Differentiation-Inducing Cytokines
Although no single cytokine has been shown to be a specific basophilopoietin, IL-3 is the main cytokine involved in human basophil growth and differentiation (41). Granulocyte-macrophage colony-stimulating factor (GM-CSF) (78,84,87,88), IL-4 (42), IL-5 (89), and SCF (35) may also play roles. IL-5, interestingly, promotes both eosinophil and basophil differentiation (89), because it acts on a common basophil-eosinophil progenitor (Fig. 11.4) (42). Retinoic acid (RA) may influence granulocyte progenitors to a neutrophilic as opposed to basophilic-eosinophilic pathway, as well as down-regulate human mast cell differentiation (78); conversely, a mutation in the RA receptor allows for expression of basophil differentiation (90). Studies on basophil crisis in chronic myeloid leukemia and the in vitro suppressive effects of RA on basophil-eosinophil differentiation in these and normal cultures support this notion (85).
Other factors that modulate basophil-eosinophil or mast cell differentiation include: transforming growth factor-β (TGF-β), which can inhibit late-stage mast cell maturation, suppress eosinophil, and enhance basophil differentiation in the presence of IL-3 (62,91); the bcr-abl gene present in CML as the Philadelphia chromosome or t(9;22) translocation; nerve growth factor (NGF), which can induce basophil colony growth in humans and mast cell phenotype switch in rodents (47); the oncogene v-erb, which in the rodent is associated with the development of lethal mastocytosis as a result of costimulation of mast cell growth by epidermal growth factors and SCF (92); FcγRIIβ, which can down-regulate mast cell growth (56); Stat5, an essential regulator in vivo of mast cell development (63); MMP-9, which controls mast cell progenitor mobilization (58); and T-bet, a Th1-inducing transcription factor that regulates mast cell progenitor homing to tissues (57). In vivo in primates, parenteral IL-3 and GM-CSF administration leads to basophilia and eosinophilia, along with an egress from the marrow of granulocyte and, specifically, basophil/ eosinophil progenitors (53); this is in contrast to SCF induction of mastocytosis in vivo in human skin (93).
Table 11.2 lists the cytokines involved in basophil growth and differentiation (42). Although IL-3 and SCF represent the primary mast cell growth factors in mouse and rat (35,94), IL-3 is a basophil, but not a mast cell, differentiation factor in the human, and SCF has little known effect on basophil differentiation (35,41). Together with GM-CSF, NGF can costimulate human basophil differentiation (46). IL-4 has minimal activity on human basophil differentiation (40,42), even though IL-4 can down-regulate c-kit expression (35). GM-CSF and IL-5 are prominent basophilopoietins, as well as basophil-activation factors, both in vitro and in vivo in several species (40,42,78,84,87,95). Microenvironmental stimuli, including various cytokines such as IL-3, IL-6, SCF, GM-CSF, TGF-β, and tumor necrosis factor (TNF), may regulate the ultimate phenotypic direction and lineage commitment of human basophils and mast cell subtypes (42); these include negative regulatory effects documented for TGF-β (91), IL-4 (96), interferon-γ (IFN-γ) (91,97), and GM-CSF (67). Contrasts between the murine and human systems in the factors that stimulate basophil or mast cell growth and differentiation, or that regulate phenotypic switching, must be recognized in any analysis of basophil and mast cell lineages.
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Table 11.2 Cytokines and Other Factors Involved in Basophil and Eosinophil Growth and Differentiation |
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Clinical Relevance of Basophil and Mast Cell Differentiation
Allergic Diseases
The clinical relevance of basophil–eosinophil or basophil–mast or mast cell progenitor fluctuations—including CD34+ cell subpopulations—in the blood and bone marrow of patients with a variety of allergic disorders, including allergic rhinitis, nasal polyposis, asthma, atopic dermatitis, and drug allergies, has been documented (46,98,99).
Malignancies
In transient leukemias occurring in Down syndrome (trisomy 21), as well as in megakaryoblastic leukemia, there is basophilic differentiation (which could include mast cells) from leukemic cell progenitors (100). Because there are increased numbers of mast cells as well as basophils in various hematologic malignancies (101), the relationship between leukemic processes and basophil or mast cell lineage commitment is underscored. This could involve aberrant stimulation of basophil or mast cell progenitors by certain transcription factors that also regulate erythroid and megakaryocytic lineages, including GATA-1 to GATA-3 (102,103). Using knockout mice and transfection systems, GATA-2 has been shown to be primarily involved in basophil/mast cell lineage commitment (104) and GATA-3 in TH2 cell switching, a pathway supportive of basophil, eosinophil, and mast cell differentiation. Embryonic stem cells or CD34+ progenitors transfected with GATA genes express varying degrees of erythroid/megakaryocytic and basophil/mast cell commitment (102,103), whereas GATA-1 double-knockout mice lack eosinophils (105). Factors such as Gab-2, certain adaptor proteins (61), signaling molecules, Lyn and SHP-1 (64), or the flt3 ligand for this tyrosine kinase receptor, appear to play secondary roles to c-kit and its ligand in signal transduction and transcription factor regulation of basophil and mast cell differentiation (106). In addition, several cytokines, such as IFN-γ and TNF, can modulate mast cell differentiation and migration/ proliferation in tissues (see earlier).
Other hemopoietic malignancies also exhibit dysregulation of development of basophil and mast cell lineages, including CML/myeloproliferative disorders and systemic mastocytosis. In mast cell proliferative diseases (systemic mastocytosis and urticaria pigmentosa), proliferation of mast cells occurs in tissues, but mature mast cells rarely appear in blood (termed mast cell leukemia). However, higher numbers of both basophil and mast cell progenitors can be documented (72,84,107). These observations emphasize the unusual nature of hemopoietic malignancies with regard to clear distinctions between basophil and mast cell lineages. “Gain of function” mutations in both juxtamembrane and intracellular domains of c-kit, particularly an Asp-Val switch at position 816 (D816V), as discussed previously, provide an explanation for many adult mast cell proliferative diseases (associated with hemopoietic malignancy or not), though such mutations are rarely found in the pediatric form of limited, skin-associated mastocytosis termed urticaria pigmentosa. These mutations provide potential therapeutic targets for newly discovered tyrosine kinase inhibitors related to, but not identical with, imatinib, which can dramatically suppress CML but not mastocytosis characterized by the D816V mutation (50,51,52).
Basophilia or basophil crisis heralding terminal blast crisis in CML is well known (107), and bcr-abl may be involved in basophil/mast cell lineage expression during this phase (see earlier). Hyperhistaminemia in CML and myeloproliferative disorders is related to increased numbers of basophils (and, possibly, mast cells) (85); indeed, blood basophilia and increases in basophil progenitors are poor prognostic indicators in CML (85,107). Such phenomena may relate to specific chromosomal abnormalities in forms of leukemia associated with basophilia or eosinophilia—for example, inversion of chromosome 16 (inv 16) associated with atypical eosinophils with basophilic granulation; t(6;9) chromosomal translocation associated with basophilia and leukemia; trisomy 21; and, several translocations associated with increased numbers of basophils in acute promyelocytic and other leukemias, such as t(15;17), del(5)(q31q35), and t(9;14) (100,108,109,110).
Basophils and/or mast cells, sometimes concurrently, can be derived from leukemic clones (111); analysis of leukemic cell lines derived from such patients reveals cells of mixed basophil-mast cell lineage (81,85,112). However, the precise relationship between specific chromosomal aberrations and basophil or mast cell differentiation in vivo is not clear. The biologic significance of increased numbers of mast cells in various hemopoietic and lymphatic malignancies, as well as in refractory anemias (101), may be related to acquisition in the leukemic clone of concomitant c-kit mutations (113); see earlier).
Apart from c-kit/SCF, whether other cytokines are involved in malignant basophil or mast cell proliferation in vivo is not known; for example, dysregulated cytokine genes such as those encoding IL-3, IL-4, IL-5, and GM-CSF in 5q-leukemias (114) may play a role in leukemic cell phenotypic expression.
Characteristics of Mast Cells and Basophils
Surface Phenotype
A wealth of information is available about the surface phenotypes of mast cells and basophils (Table 11.3), including information about immunoglobulin receptors, complement components, cytokine and chemokine receptors, adhesion molecules, Toll-like receptor (TLR), and other molecules with or without CD nomenclature. Numerous groups have contributed to the characterization of these markers on human mast cells and basophils (e.g., 3,4,115–123), but given the heterogeneity of mast cells from various tissue sites and species, and the availability of various mast cell and basophil-like cells lines, one must be cautious about generalizations about surface receptor expression and phenotype. One prominent difference is that mature mast cells can express CD117 or c-kit (Table 11.3), whereas mature basophils do not. As outlined earlier, SCF is an important factor in mast cell development and, in addition to mast cell progenitors, mature mast cells can also express its receptor, CD117, and respond to SCF.
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Table 11.3 Expression of Selected Surface Markers on Human Mast Cells and Basophils |
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Another potentially important difference between mast cells and basophils is in their expression of Fc receptors. Mast cells and basophils both express high-affinity receptors for IgE (12), but to date, the only receptor for IgG that has been identified on basophils is FcγRII (both A and B, CD32), whereas mast cells can express CD16, CD32, and CD64 (124). Further investigation of Fcγ receptors on human mast cells and basophils will be important, because different receptors such as FcγRIIA and B and FcγRIII have been shown to play distinct roles in mediator secretion and phagocytosis or endocytosis (125). Mice deficient in FcγRIIB are highly sensitive to IgG-triggered mast cell degranulation through FcγRIII and exhibit enhanced passive cutaneous anaphylaxis and elevated immunoglobulin levels in response to both thymus-dependent and thymus-independent antigens (126). FcγRIIB down-regulates Fc∊RI signaling and is important in the regulation of mast cell and basophil activities (8,13,14).
Another intriguing difference between mast cells and basophils lies in their expression of selected integrin molecules (Table 11.3). Human basophils, but not mast cells, express CD11a/18, CD11b/18, and CD11c/18, which have as their complementary ligands ICAM-1/2, C3bi, and fibrinogen, respectively. The latter are expressed on endothelial cells and appear to be involved in the migration of basophils into the tissues during inflammation. By contrast, mature mast cells and basophils express a repertoire of adhesion molecules designed to interact with the extracellular matrix components. The ligation of these surface molecules plays a significant role in cell recruitment and activation, and in the future these interactions may be targets for strategies to modulate allergic or other diseases (123).
Recent focus on mast cells in innate immunity and expression of TLR and other molecules (e.g., 3,4) has markedly influenced our view of these cells (see later). Basophils appear to express a smaller repertoire of these types of receptors (121,122) and thus must have roles in innate immunity distinct from mast cells (see later).
Mediators
Mast cells and basophils are storehouses of inflammatory mediators that can be released by IgE-mediated and other stimuli (Table 11.4). Mediators such as histamine, platelet-activating factor (PAF), and arachidonic acid metabolites have been extensively studied and are considered to be important in the pathogenesis of inflammatory diseases such as asthma (e.g., 4,10). A major distinction between the two cell types lies in the proteinases that are abundant in mast cells from humans (127) and other species (128), but are not major markers of basophils. Indeed, proteinases are excellent markers of mast cell heterogeneity, with two major populations separated on their serine proteinase content, namely, those with tryptase only (MCT) and those with both tryptase and chymase (MCTC).
An informative area of research has focused on the cytokines that mast cells and basophils produce (Table 11.4) (4,8,10,129,130). Since initial observations in the 1980s, this field has expanded rapidly, but one must be careful with generalizations. There is literature on cytokine expression in cells from in vivo sites, but many studies have used long-term cell lines, and the relevance of this work to cytokine expression in vivo must be viewed cautiously. Cells from several species have been studied, and initially many results were restricted to expression of mRNA as assessed by the sensitive technique of reverse transcriptase polymerase chain reaction (RT-PCR). However, cytokine protein levels have been defined in numerous studies, and the amounts secreted by mast cells and/or basophils range from small to relatively large quantities. For example, basophils produce large quantities of IL-4 and IL-13 (hundreds of picograms per 106 cells). The cytokine repertoire of mast cells includes a broad spectrum representing those associated with both TH1 and TH2 phenotypes. It may be that in a given population of mast cells, cytokines are differentially expressed in individual cells or at different times, or that individual mast cells truly express several functionally distinct cytokines. In the latter case, one could speculate that there are rigorous control mechanisms regulating production, secretion, and functions of individual cytokines.
Most recent work suggests that cell type–specific regulation of cytokine expression can be under epigenetic control at the level of structural modifications in the DNA (131).
Activation of Mast Cells and Basophils
Numerous stimuli in addition to IgE–antigen interactions activate basophils and mast cells. Not all the factors that activate mast cells or basophils from various experimental animals also activate human cells (3,4,10). Furthermore, marked heterogeneity exists among mast cell populations from different tissue sites within a single species (4,7). Another important consideration is that there are stimulus-specific differences in the mediators released when basophils or mast cells are activated—that is, activation is not an all-or-none phenomenon, an observation that has been re-emphasized with recent studies of TLR–ligand stimulation of mast cells and basophils (3,121,122).
Human basophils and mast cells can be activated by cross-linkage of Fc receptors for IgE or IgG with sensitizing allergens or with antibodies to the receptors or to their immunoglobulin ligands (Table 11.5). Such cross-linkage initiates a complex cascade of biochemical signaling events in the cells (9), resulting in the release of several stored and newly synthesized mediators. A number of other stimuli, including anaphylatoxins C3a and C5a, certain lectins, and the bacterial product formyl methionyl leucyl phenylalanine (fMLP), activate basophils and/or mast cells. Interestingly, with the unexplained exceptions of polyarginine, polycationic substances such as compound 48/80 and numerous basic polypeptides including a spectrum of neuropeptides activate human skin mast cells, but not human mast cells from other sites, or human basophils (132).
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Table 11.5 Factors That Activate Mediator Secretion from Human Basophils and Mast Cells |
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At present, the working model to explain these observations (132) proposes that human skin, and rat peritoneal mast cells, possess a binding site for these polycationic secretagogues, including neuropeptides such as substance P, which involves the direct activation of Gi-like G protein, initiating cell activation. Neurogenic vasodilatation produced by an axonal reflex in human skin appears to involve mast cell activation by neuropeptides released from primary afferent nerves (132). Mast cell-dependent neurogenic inflammation has been described in the respiratory and gastrointestinal tracts (e.g., 133) and appears to be important in at least some inflammatory and infectious diseases.
Recently there has been great interest in observations that basophils and mast cells can be activated by several interleukins, chemokines, and histamine-releasing factors (Table 11.5) (3,4,7). The significance of these pathways of basophil and mast cell activation in vivo in health or disease is becoming increasingly clear, particularly in chronic allergic diseases. The CC chemokines appear to be important in basophil activation, but there is less information for mast cells. SCF appears to be a specific stimulus for mast cells, acting through the receptor CD117 (40). Most recently, Redegeld et al. made the intriguing observation that highly purified immunoglobulin light chain can sensitize mast cells for antigen-specific activation (134), providing a molecular mechanism for earlier observations of antigen-specific but non–antibody-mediated mast cell activation. Currently it is not clear how light chain confers antigen specificity, although the authors reported light-chain binding to the mast cell surface. Additional research on the role of such stimuli for mast cells and/or basophils will shed light on the pathogenesis of inflammatory diseases.
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Table 11.6 Inhibition of Histamine Secretion from Human Basophils and Mast Cells |
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Inhibition of Basophil and Mast Cell Activation
Several antiallergic and anti-inflammatory drugs inhibit the release or activities of histamine and other mediators from human basophils and/or mast cells (Table 11.6) (135,136,137,138,139). Although such drugs are valuable in the treatment of allergies and other inflammatory diseases, their actions can be multiple and varied, and it can be difficult to define their precise mode of action. In turn, it is difficult to attribute to one cell type or another an unequivocal role in these inflammatory diseases. Furthermore, given the heterogeneity of mast cells in different tissue sites, and perhaps even at different times during the evolution of an inflammatory insult (e.g., initial injury, repair, chronicity, or remodeling phases), different agents may vary in the nature or extent of their modulatory effects on basophils and mast cells or their products. One of the promising developments has been with the use of humanized monoclonal anti-IgE antibodies. These antibodies reduce IgE levels and decrease the density of high-affinity IgE receptors on mast cells and basophils, thus limiting sensitivity to allergens. The anti-IgE has been reported to be effective and safe in treatment of allergic asthma, rhinitis, and peanut allergy (140), although the cost-effectiveness has been questioned and further assessment is needed (141,142).
Given the plethora of functions of cytokines in immune and inflammatory responses, it is not surprising that they have become a focal point to study the modulation of allergic and other inflammatory events. Furthermore, despite some notable exceptions, the postulate that distinct profiles of cytokines (Th1 and Th2) orchestrate these responses has stimulated a flurry of studies of cytokine regulation of mast cell and basophil functions. Selected cytokines modulate mast cell activation and mediator secretion and, as would be predicted, the Th1-associated cytokine IFN-γ and the related IFN-α/β, inhibit mast cell degranulation and TNF secretion (143,144). IFN-γ has no effect on basophil cytokine secretion, but IFN-α inhibited IL-4 and IL-13 secretion from human basophils but had no effect on histamine of LTC4 secretion (145). Interestingly, the effects of IFN-γ on mast cell mediator secretion are dependent on exogenous or endogenous nitric oxide (146,147). TGF-β1also inhibits histamine and TNF production by rat mast cells (148). Furthermore, IL-10, often associated with Th2 responses, inhibits TNF and IL-6 production by mast cells (149), but enhances their antigen-induced secretion of histamine (150). This information, taken together with evidence that other mediators such as histamine and arachidonic acid metabolites (118,119,151,152,153) modulate mediator secretion, suggests that several basophil and mast cell mediators may have autocrine-regulatory roles in inflammation.
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Figure 11.5. Summary of the activation of mast cells and basophils, the mediators they produce, and the spectrum of their actions in host defenses and tissue injury. |
Basophil and Mast Cell Functions
Inflammatory Injury and Host Defenses
Investigations of the functions of basophils and mast cells have focused on their roles in allergic and other inflammatory disorders because of the highly visible symptoms of IgE-mediated allergic reactions and life-threatening anaphylaxis. In turn, a great deal has been learned about some aspects of these cells, notably about their activation, inflammatory mediators, and regulation. Numerous drugs are available that inhibit many of their functions, and a wealth of novel approaches are on the horizon that will attempt to exploit numerous pathways to regulate allergic and other inflammatory responses. Nevertheless, several challenges remain, including perhaps the most obvious question: Why do both basophils and mast cells exist, and what functions distinguish them?
Both basophils and mast cells are central players in allergic inflammation. They share high-affinity receptors for IgE and produce several mediators in common, each with a wealth of potential in the initiation of inflammatory cascades and in the complex cellular and molecular networks involved in injury and repair (Fig. 11.5). In the early phase of allergic responses, it appears that the pool of circulating mature basophils and the large tissue repository of mast cells can be important. However, basophils and mast cells are not restricted to these sites, because under certain circumstances a large influx of basophils can occur into local tissues [e.g., cutaneous basophilic hypersensitivity (154); asthma (155)], and the numbers of mast cell progenitors in the circulation can be increased (42).
The roles of basophils and mast cells in allergic inflammation also differ in terms of some of the stimuli that are important for the activation of each cell type. Some mast cell populations respond to a number of basic secretagogues, including several neuropeptides. Moreover, given the close anatomic association between mast cells and nerves (156) and abundant evidence for their functional interdependence, it is likely that as a component of allergic and other inflammatory reactions, mast cell-dependent neurogenic pathways are important. There is much less evidence to suggest that neurogenic inflammation is a major pathway in basophil-mediated reactions. It is intriguing that IgE receptors have recently been discovered on neurons (157), and although the clinical significance of this observation is currently unknown, the implications are considerable.
Since early reports of the role of mast cells in innate antimicrobial immunity (158,159) and in the possible role of Toll-like receptors, there has been great interest in expression and function of these receptors on mast cells (3,4) and basophils (121,122). The mechanisms by which engagement of such receptors on mast cells and/or basophils induce cell activation and mediator secretion will be particularly enlightening with regard to their functions (9). There is increasing evidence that the profiles of mediators produced by these pathways differ from those following IgE-mediated activation in allergic reactions; knowledge of such differences will help elucidate the distinct roles of these two cell types in host defense and inflammatory diseases.
The spectrum of mediators produced by the two types of basophilic leukocytes have obvious similarities and differences. Several mediators are common (histamine, LTC4, PAF, and others, etc.), whereas the cytokine and proteinase profiles of the two cells types are distinct. Although the differences in proteinase content likely hold clues to the functional distinctions among the cell types, we are only beginning to identify some of the substrate specificities of mast cell proteinases, and associated functions (160,161). It is intriguing that inhibitors of mast cell-specific tryptase have promising effects in models of allergic asthma (136,138). Perhaps such drugs will help distinguish between the roles of mast cells and basophils in allergic inflammation. Differences in the cytokine profiles of mast cells and basophils, for example, TNF in mast cells and IL-4 and IL-13 in basophils, may help uncover the unique aspects of the functions of these two cells. These functions could include alterations in the cytokine profiles in the microenvironment that influence the development of particular local immune and inflammatory responses (162).
Containment of Injury, Initiation of Repair, Remodeling, and Normal Function
Following the initial insult and injury, the inflammatory response elaborates mediators and pathways that minimize the extent of the tissue damage and begin repair processes. Mast cell and basophil mediators are involved in these phases of the response (Fig. 11.6). Histamine, arachidonic acid metabolites, and several cytokines, particularly IL-1, IL-6, IL-10, TNF, and TGF-β, have several effects on endothelial, epithelial, mesenchymal, and inflammatory cells. Such effects include influences on epithelial integrity and function, regulation of blood flow and vascular permeability, tissue edema, fibroblast proliferation, biochemical phenotype, and others. Unfortunately, these aspects of the functions of basophils and mast cells are poorly known. The relationship between mast cell activation and fibroblasts and angiogenesis in models of tissue repair and remodeling has been studied (163,164), and it is obvious that the pathways involved are multifactorial. As experimental models are developed to address these questions, we will begin to understand the role of mast cells and basophils in this “containment and repair phase” of inflammatory injury.
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Figure 11.6. Model of activities of mast cells and basophils in the sequential responses of tissue injury, containment, repair, and remodeling. |
Once the site of injury is contained and repair processes have begun, mast cells and perhaps basophils are likely to be involved in the remodeling of the tissues and the return to normal function. The numerous proteinases of mast cells have distinct substrate specificities, and among their functions must be restructuring of the connective tissue, extracellular matrix in the local environment. Cytokines such as TGF-β, IL-1, and IL-6 that influence the activities of fibroblasts are likely to be important candidates for this remodeling phase in the responses to injury. Given the life span and normal distribution of mast cells and basophils, an attractive hypothesis is that in this simplified model of tissue injury, containment, and remodeling, basophils play a particularly important role in the injury phase, but their importance in the latter phases is minimal. By contrast, mast cells are undoubtedly important in the injury phase, but also in the containment and remodeling phases. Given the plasticity of mast cell phenotype, it may be that there is a general pattern of expression of functionally linked clusters of mast cell genes that, in a carefully orchestrated manner, facilitate the evolving roles of local mast cell populations in the phases of injury, containment, and repair.
Dynamic Equilibrium and Homeostasis
In addition to the evolving mast cell phenotype in the sequence of injury, repair, and remodeling, some phenotypes of mast cells are involved in normal tissue homeostasis. Neurogenic and endocrine activation of mast cells occurs at subtle physiologic, rather than pharmacologic, levels of activity (165,166,167). This aspect of mast cell function is not well understood, but there is a wide and fascinating literature on these cells in such diverse processes as sexual behavior, implantation, parturition, neuroendocrine signaling (e.g., thyroid and adrenal function), the hypothalamic-pituitary-adrenal axis, gastric acid secretion, metabolism of bone, central nervous system (CNS) functions, myelopoiesis, and so on. Furthermore, given the prominent anatomic association between mast cells and the vasculature, and the effects of mast cell products on blood flow, permeability, and leukocyte adhesion and diapediasis in inflammation (168), it is widely held that one normal physiologic role of mast cells is in the dynamic regulation of tissue perfusion and the chemical and cellular composition of extravascular spaces. To date, little direct evidence exists that basophils exhibit similar functions, although given that they produce several potent mediators known to have such effects, it is possible that they exhibit such effects outside of acute inflammatory injury. However, it is the mast cell literature that suggests these cells are prominent in these more physiologic activities, whereas the basophil appears to be a rapid, circulating response that can be recruited to sites of injury.
It is an exciting time to be involved in biomedical research on basophilic leukocytes. The tools available to ask critically important questions are constantly improving (e.g., 4,7,9,11), and as a result, our conceptual overview of function is improving and our ability to utilize this knowledge to treat allergic and other inflammatory conditions, or myeloproliferation disorders, is improving. The next several years promise to hold exciting advances in the field.
References
1. Selye H. The mast cells. Washington, DC: Butterworths, 1965.
2. Galli SJ, Dvorak AM, Dvorak HF. Basophils and mast cells: morphologic insights into their biology, secretory patterns, and function. In: Ishizaka K, ed. Mast cell activation and mediator release. Prog Allergy 34:1–141. New York: Karger, 1984.
3. Marshall JS. Mast-cell responses to pathogens. Nat Rev Immunol 2004;4: 787–799.
4. Galli SJ, Kalesnikoff J, Grimbaldeston MA, et al. Mast cells as “tunable” effector and immunoregulatory cells: recent advances. Annu Rev Immunol 2005;23: 74–786.
5. Kitamura Y, Ito A. Mast cell-committed progenitors. Proc Natl Acad Sci U S A 2005;102:11129–11130.
6. Chen CC, Grimbaldeston MA, Tsai M, et al. Identification of mast cell progenitors in adult mice. Proc Natl Acad Sci U S A 2005;102:11408–11413.
7. Gurish MF, Boyce JA. Mast cells: ontogeny, homing, and recruitment of a unique innate effector cell. J Allergy Clin Immunol 2006;117:1285–1291.
8. Falcone FH, Haas H, Gibbs BF. The human basophil: a new appreciation of its role in immune responses. Blood 2000;96:4028–4038.
9. Gilfillan AM, Tkaczyk C. Integrated signalling pathways for mast-cell activation. Nat Rev Immunol 2006;6:218–230.
10. Bradding P, Walls AF, Holgate ST. The role of the mast cell in the pathophysiology of asthma. J Allergy Clin Immunol 2006;117:1277-1284.
11. Metcalfe DD, Boyce JA. Mast cell biology in evolution. J Allergy Clin Immunol 2006;117:1227–1229.
12. MacGlashan D. IgE and FcepsilonRI regulation. Clin Rev Allergy Immunol 2005;29:49–60.
13. Kraft S, Novak N. Fc receptors as determinants of allergic reactions. Trends Immunol 2006;27:88–95.
14. Bruhns P, Fremont S, Daeron M. Regulation of allergy by Fc receptors. Curr Opin Immunol 2005;17:662–669.
15. Nakae S, Suto H, Kakurai M, et al. Mast cells enhance T cell activation: importance of mast cell-derived TNF. Proc Natl Acad Sci U S A 2005;102:6467–6472.
16. Hida S, Tadachi M, Saito T, et al. Negative control of basophil expansion by IRF-2 critical for the regulation of Th1/Th2 balance. Blood 2005;106:2011–2017.
17. Lorentz A, Wilke M, Sellge G, et al. IL-4 induced priming of human intestinal mast cells for enhanced survival and Th2 cytokine generation is reversible and associated with increased activity of ERK 1/2 and c-Fos. J Immunol 2005;174: 6751–6756.
18. Gessner A, Mohrs K, Mohrs M. Mast cells, basophils, and eosinophils acquire constitutive IL-4 and IL-13 transcripts during lineage differentiation that are sufficient for rapid cytokine production. J Immunol 2005;174:1063–1072.
19. Wang J, Qi JC, Konecny P, et al. Hemopoietic cells with features of the mast cell and basophil lineages and their potential role in allergy. Curr Drug Targets Inflamm Allergy 2003;2:293–302.
20. Sperr WR, Hauswirth AW, Valent P. Tryptase a novel biochemical marker of acute myeloid leukemia. Leukemia Lymphoma 2002;43:2257–2261.
21. Dvorak AM. Ultrastructural studies of human basophils and mast cells. J Histochem Cytochem 2005;53:1043–1070.
22. Raposo G, Tenza D, Mecheri S, et al. Accumulation of major histocompatibility complex class II molecules in mast cell secretory granules and their release upon degranulation. Mol Biol Cell 1977;8:2361–2645.
23. Dvorak AM, Morgan ES, Lichtenstein LM, et al. RNA is closely associated with human mast cell secretory granules, suggesting a role(s) for granules in synthetic processes. J Histochem Cytochem 2000;48:1–12.
24. Melo RC, Perez SA, Spencer LA, et al. Intragranular vesiculotubular compartments are involved in piecemeal degranulation by activated human eosinophils. Traffic 2005;6:866–879.
25. Melo RC, Spencer LA, Perez SA, et al. Human eosinophils secrete preformed, granule-stored interleukin-4 through distinct vesicular compartments. Traffic 2005;6:1047–1057.
26. Drew E, Merzaban JS, Seo W, et al. CD34 and CD43 inhibit mast cell adhesion and are required for optimal mast cell reconstitution. Immunity 2005;22: 43–57.
27. Drew E, Huettner CS, Tenen DG, et al. CD34 expression by mast cells: of mice and men. Blood 2005;106:1885–1887.
28. Krishenbaum AS, Akin C, Goff JP, et al. Thrombopoietin alone or in the presence of stem cell factor supports the growth of KIT(CD117)low/MPL(CD110)+ human mast cells from hematopoietic progenitor cells. Exp Hematol 2005;33: 413–421.
29. Iwasaki H, Mizuno S, Arinobu Y, et al. The order of expression of transcription factors directs hierarchical specification of hematopoietic lineages. Genes Dev 2006;20:3010–3021.
30. Arinobu Y, Iwasaki H, Gurish MF, et al. Developmental checkpoints of the basophil/mast cell lineages in adult murine hematopoiesis. Proc Natl Acad Sci U S A 2005;102:18105–18110.
31. Arock M, Schneider E, Boissan M, et al. Differentiation of human basophils: an overview of recent advances and pending questions. J Leukoc Biol 2002;71: 557–564.
32. Dy M, Pacilio M, Arnould A, et al. Modulation of histidine decarboxylase activity and cytokine synthesis in human leukemic cell lines: relationship with basophilic and/or megakaryocytic differentiation. Exp Hematol 1999;27: 1295–1305.
33. Li L, Li Y, Reddel SW, et al. Identification of basophilic cells that express mast cell granule proteases in the peripheral blood of asthma, allergy, and drug-reactive patients. J Immunol 1998;161:5079–5086.
34. Galli SJ, Tsai M, Wershil BK, et al. The c-kit receptor, stem cell factor, and mast cells. What each is teaching us about the others. Am J Pathol 1993;142: 965–974.
35. Galli SJ, Zsebo KM, Geissler EN. The kit ligand, stem cell factor. Adv Immunol 1994;55:1–96.
36. Kitamura Y, Tsujimura T, Jippo T, et al. Regulation of development, survival and neoplastic growth of mast cells through the c-kit receptor. Int Arch Allergy Immunol 1995;107:54–56.
37. Grimbaldeston MA, Chen CC, Piliponsky AM, et al. Mast cell-deficient W-sash c-kit mutant Kit W-sh/W-sh mice as a model for investigating mast cell biology in vivo. Am J Pathol 2005;167:835–848.
38. Lantz CS, Boesiger J, Song CH, et al. Role for interleukin-3 in mast-cell and basophil development and in immunity to parasites. Nature 1998;392: 90–93.
39. Wright HV, Bailey D, Kashyap M, et al. IL-3-mediated TNF production is necessary for mast cell development. J Immunol 2006;176:2114–2121.
40. Saito H, Hatake K, Dvorak AM, et al. Selective differentiation and proliferation of hematopoietic cells induced by recombinant human interleukins. Proc Natl Acad Sci U S A 1988;85:2288–2292.
41. Valent P, Schmidt G, Besemer J, et al. Interleukin-3 is a differentiation factor for human basophils. Blood 1989;73:1763–1769.
42. Denburg JA. Basophil and mast cell lineages in vitro and in vivo. Blood 1992;79:846–860.
43. Denburg JA. Bone marrow in atopy and asthma: hematopoietic mechanisms in allergic inflammation. Immunol Today 1999;20:111–113.
44. Irani AM, Nilsson G, Miettinen U, et al. Recombinant human stem cell factor stimulates differentiation of mast cells from dispersed human fetal liver cells. Blood 1992;80:3009–3021.
45. Mitsui H, Furitsu T, Dvorak AM, et al. Development of human mast cells from umbilical cord blood cells by recombinant human and murine c-kit ligand. Proc Natl Acad Sci U S A 1993;90:735–739.
46. Mwamtemi HH, Koike K, Kinoshita T, et al. An increase in circulating mast cell colony-forming cells in asthma. J Immunol 2001;166:4672–4677.
47. Matsuda H, Coughlin MD, Bienenstock J, et al. Nerve growth factor promotes human hemopoietic colony growth and differentiation. Proc Natl Acad Sci U S A 1988;85:6508–6512.
48. Piao X, Bernstein A. A point mutation in the catalytic domain of c-kit induces growth factor independence, tumorigenicity, and differentiation of mast cells. Blood 1996;87:3117–3123.
49. Zappulla JP, Dubreuil P, Desbois S, et al. Mastocytosis in mice expressing human Kit receptor with the activating Asp816Val mutation. J Exp Med 2005;202:1635–1641.
50. Gleixner KV, Mayerhofer M, Aichberger KJ, et al. PKC412 inhibits in vitro growth of neoplastic human mast cells expressing the D816V-mutated variant of KIT: comparison with AMN107, imatinib, and cladribine (2CdA) and evaluation of cooperative drug effects. Blood 2006;107:752–759.
51. Gabillot-Carre M, Lepelletier Y, Humbert M, et al. Rapamycin inhibits growth and survival of D816V-mutated c-kit mast cells. Blood 2006;108: 1065–1072.
52. Shah NP, Lee FY, Luo R, et al. Dasatinib (BMS-354825) inhibits KITD816V, an imatinib-resistant activating mutation that triggers neoplastic growth in most patients with systemic mastocytosis. Blood 2006;108:286–291.
53. Donahue RE, Seehra J, Metzger M, et al. Human IL-3 and GM-CSF act synergistically in stimulating hematopoiesis in primates. Science 1988;241: 1820–1823.
54. Metcalf D. Hematopoietic regulators: redundancy or subtlety? Blood 1993;82: 3515–3519.
55. Kulka M, Metcalfe DD. High-resolution tracking of cell division demonstrates differential effects of TH1 and TH2 cytokines on SCF-dependent human mast cell production in vitro: correlation with apoptosis and Kit expression. Blood 2005;105:592–599.
56. Malbec O, Attal JP, Fridman WH, et al. Negative regulation of mast cell proliferation by FcgammaRIIB. Mol Immunol 2002;38:1295–1299.
57. Alcaide P, Jones T, Lord G, et al. Regulation of mast cell progenitor homing to mucosal tissues: unexpected role of transcription factor T-bet. 2006.
58. Heissig B, Rafii S, Akiyama H, et al. Low-dose irradiation promotes tissue revascularization through VEGF release from mast cells and MMP-9-mediated progenitor cell mobilization. J Exp Med 2005;202:739–750.
59. Kalesnikoff J, Rios EJ, Chen CC, et al. RabGEF1 regulates stem cell factor/c-Kit-mediated signaling events and biological responses in mast cells. Proc Natl Acad Sci U S A 2006;103:2659–2664.
60. Tam SY, Tsai M, Snouwaert JN, et al. RabGEF1 is a negative regulator of mast cell activation and skin inflammation. Nat Immunol 2004;5:844–852.
61. Nishida K, Wang L, Morii E, et al. Requirement of Gab2 for mast cell development and KitL/c-Kit signaling. Blood 2002;99:1866–1869.
62. Gebhardt T, Lorentz A, Detmer F, et al. Growth, phenotype, and function of human intestinal mast cells are tightly regulated by transforming growth factor beta1. Gut 2005;54:928–934.
63. Shelburne CP, McCoy ME, Piekorz R, et al. Stat5 expression is critical for mast cell development and survival. Blood 2003;102:1290–1297.
64. O’Laughlin-Bunner B, Radosevic N, Taylor ML, et al. Lyn is required for normal stem cell factor-induced proliferation and chemotaxis of primary hematopoietic cells. Blood 2001;98:343–350.
65. Guo X, Stratton L, Schrader JW. Expression of activated M-Ras in hemopoietic stem cells initiates leukemogenic transformation, immortalization and preferential generation of mast cells. Oncogene 2006;25:4241–4244.
66. Ito T, Nishiyama C, Nishiyama M, et al. Mast cells acquire monocyte-specific gene expression and monocyte-like morphology by overproduction of PU.1. J Immunol 2005;174:376–383.
67. Du Z, Li Y, Xia H, et al. Recombinant human granulocyte-macrophage colony-stimulating factor (CSF), but not recombinant human granulocyte CSF, down-regulates the recombinant human stem cell factor-dependent differentiation of human fetal liver-derived mast cells. J Immunol 1997;159:838–845.
68. Kinoshita T, Koike K, Mwamtemi HH, et al. Retinoic acid is a negative regulator for the differentiation of cord blood-derived human mast cell progenitors. Blood 2000;95:2821–2828.
69. Kirshenbaum AS, Worobec AS, Davis TA, et al. Inhibition of human mast cell growth and differentiation by interferon gamma-1b. Exp Hematol 1998;26: 245–251.
70. Jamur MC, Grodzki AC, Berenstein EH, et al. Identification and characterization of undifferentiated mast cells in mouse bone marrow. Blood 2005;105: 4282–4289.
71. Gurish MF, Ghildyal N, McNeil HP, et al. Differential expression of secretory granule proteases in mouse mast cells exposed to interleukin 3 and c-kit ligand. J Exp Med 1992;175:1003–1012.
72. Rottem M, Okada T, Goff JP, et al. Mast cells cultured from the peripheral blood of normal donors and patients with mastocytosis originate from a CD34+/Fc epsilon RI- cell population. Blood 1994;84:2489–2496.
73. Rodewald HR, Dessing M, Dvorak AM, et al. Identification of a committed precursor for the mast cell lineage. Science 1996;271:818–822.
74. Nakano T, Sonoda T, Hayashi C, et al. Fate of bone marrow-derived cultured mast cells after intracutaneous, intraperitoneal, and intravenous transfer into genetically mast cell-deficient W/Wv mice. Evidence that cultured mast cells can give rise to both connective tissue type and mucosal mast cells. J Exp Med 1985;162:1025–1043.
75. Tsai M, Shih L-S, Newlands GF, et al. The rat c-kit ligand, stem cell factor, induces the development of connective tissue-type and mucosal mast cells in vivo. Analysis by anatomical distribution, histochemistry, and protease phenotype. J Exp Med 1991;174:125–131.
76. Sorden SD, Castleman WL. Virus-induced increases in bronchiolar mast cells in Brown Norway rats are associated with both local mast cell proliferation and increases in blood mast cell precursors. Lab Invest 1995;73:197–204.
77. Denburg JA, Befus AD, Bienenstock J. Growth and differentiation in vitro of mast cells from mesenteric lymph nodes of Nippostrongylus brasiliensis-infected rats. Immunology 1980;41:195–202.
78. Hutt-Taylor SR, Harnish D, Richardson M, et al. Sodium butyrate and a T lymphocyte cell line-derived differentiation factor induce basophilic differentiation of the human promyelocytic leukemia cell line HL-60. Blood 1988;71:209–215.
79. Butterfield JH, Weiler D, Dewald G, et al. Establishment of an immature mast cell line from a patient with mast cell leukemia. Leukemia Res 1988;12: 345–355.
80. Agis H, Willheim M, Sperr WR, et al. Monocytes do not make mast cells when cultured in the presence of SCF. Characterization of the circulating mast cell progenitor as a c-kit+, CD34+, Ly-, CD14-, CD17-, colony-forming cell. J Immunol 1993;151:4221–4227.
81. Nilsson G, Blom T, Kusche-Gullberg M, et al. Phenotypic characterization of the human mast-cell line HMC-1. Scand J Immunol 1994;39:489–498.
82. Samorapoompichit P, Kiener HP, Schernthaner GH, et al. Detection of tryptase in cytoplasmic granules of basophils in patients with chronic myeloid leukemia and other myeloid neoplasms. Blood 2001;98:2580–2583.
83. Buhring HJ, Simmons PJ, Pudney M, et al. The monoclonal antibody 97A6 defines a novel surface antigen expressed on human basophils and their multipotent and unipotent progenitors. Blood 1999;94:2343–2356.
84. Denburg JA, Richardson M, Telizyn S, et al. Basophil/mast cell precursors in human peripheral blood. Blood 1983;61:775–780.
85. Denburg JA, Wilson WEC, Bienenstock J. Basophil production in myeloproliferative disorders: increases during acute blastic transformation of chronic myeloid leukemia. Blood 1982;60:113–120.
86. Iwasaki H, Mizuno S, Mayfield R, et al. Identification of eosinophil lineage-committed progenitors in the murine bone marrow. J Exp Med 2005;201: 1891–1897.
87. Denburg JA, Telizyn S, Messner H, et al. Heterogeneity of human peripheral blood eosinophil-type colonies: evidence for a common basophil-eosinophil progenitor. Blood 1985;66:312–318.
88. Leary AG, Ogawa M. Identification of pure and mixed basophil colonies in culture of human peripheral blood and marrow cells. Blood 1984;64:78–83.
89. Denburg JA, Silver JE, Abrams JS. Interleukin-5 is a human basophilopoietin: induction of histamine content and basophilic differentiation of HL-60 cells and of peripheral blood basophil-eosinophil progenitors. Blood 1991;77: 1462–1468.
90. Tsai S, Collins SJ. A dominant negative retinoic acid receptor blocks neutrophil differentiation at the promyelocyte stage. Proc Natl Acad Sci U S A 1993;90: 7153–7157.
91. Sillaber C, Geissler K, Scherrer R, et al. Type beta transforming growth factors promote interleukin-3 (IL-3)-dependent differentiation of human basophils but inhibit IL-3-dependent differentiation of human eosinophils. Blood 1992;80: 634–641.
92. von Ruden T, Stingl L, Ullrich A, et al. Rescue of W-associated mast cell defects in W/Wv bone marrow cells by ectopic expression of normal and mutant epidermal growth factor receptors. Blood 1993;82:1463–1470.
93. Costa JJ, Demetri GD, Harrist TJ, et al. Recombinant human stem cell factor (kit ligand) promotes human mast cell and melanocyte hyperplasia and functional activation in vivo. J Exp Med 1996;183:2681–2686.
94. Ihle JN, Keller J, Oroszlan S, et al. Biologic properties of homogeneous interleukin 3. I. Demonstration of WEHI-3 growth factor activity, mast cell growth factor activity, p cell-stimulating factor activity, colony-stimulating factor activity, and histamine-producing cell-stimulating factor activity. J Immunol 1983;131:282–287.
95. Sanderson CJ, Warren DJ, Strath M. Identification of a lymphokine that stimulates eosinophil differentiation in vitro. Its relationship to interleukin 3, and functional properties of eosinophils produced in cultures. J Exp Med 1985;162: 60–74.
96. Sillaber C, Strobl H, Bevec D, et al. IL-4 regulates c-kit proto-oncogene product expression in human mast and myeloid progenitor cells. J Immunol 1991;147: 4224–4228.
97. Takagi M, Koike K, Nakahata T. Antiproliferative effect of IFN-gamma on proliferation of mouse connective tissue-type mast cells. J Immunol 1990;145: 1880–1884.
98. Denburg JA, Telizyn S, Belda A, et al. Increased numbers of circulating basophil progenitors in atopic patients. J Allergy Clin Immunol 1985;76: 466–472.
99. Sehmi R, Wood LJ, Watson R, et al. Allergen-induced increases in IL-5 receptor alpha-subunit expression on bone marrow-derived CD34+ cells from asthmatic subjects. A novel marker of progenitor cell commitment towards eosinophilic differentiation. Clin Invest 1997;100:2466–2475.
100. Suda T, Suda J, Miura Y, et al. Clonal analysis of basophil differentiation in bone marrow cultures from a Down’s syndrome patient with megakaryoblastic leukemia. Blood 1985;66:1278–1283.
101. Prokocimer M, Polliack A. Increased bone marrow mast cells in preleukemic syndromes, acute leukemia, and lymphoproliferative disorders. Am J Clin Pathol 1981;75:34–38.
102. Martin DIK, Zon LI, Mutter G, et al. Expression of an erythroid transcription factor in megakaryocytic and mast cell lineages. Nature 1990;344:444–447.
103. Green AR, Lints T, Visvader J, et al. SCL is coexpressed with GATA-1 in hemopoietic cells but is also expressed in developing brain. Oncogene 1992;7: 653–660.
104. Tsai F-Y, Orkin SH. Transcription factor GATA-2 is required for proliferation/ survival of early hematopoietic cells and mast cell formation, but not for erythroid and myeloid terminal differentiation. Blood 1997;89:3636–3643.
105. Yu C, Cantor AB, Yang H, et al. Targeted deletion of a high-affinity GATA-binding site in the GATA-1 promoter leads to selective loss of the eosinophil lineage in vivo. J Exp Med 2002;195:1387–1395.
106. Lyman SD, Brasel K, Rousseau AM, et al. The flt3 ligand: a hematopoietic stem cell factor whose activities are distinct from steel factor. Stem Cells 1994;12(suppl 1):99–110.
107. Soler J, O’Brien M, deCastro JT, et al. Blast crisis of chronic granulocytic leukemia with mast cell and basophil precursors. Am J Clin Pathol 1985;83: 254–259.
108. Le Beau MM, Larson RA, Bitter MA, et al. Association of an inversion of chromosome 16 with abnormal marrow eosinophils in acute myelomonocytic leukemia: a unique cytogenetic-clinicopathological association. N Engl J Med 1983;309:630–636.
109. Gotoh H, Murakami S, Oku N, et al. Translocations t(15;17) and t(9;14) (q34;q22) in a case of acute promyelocytic leukemia with increased number of basophils. Cancer Genet Cytogenet 1988;36:103–107.
110. Pearson MG, Vardiman JW, Le Beau MM, et al. Increased numbers of marrow basophils may be associated with a t(6;9) in ANLL. Am J Hematol 1985;18: 393–403.
111. Bodger MP, Morris CM, Kennedy MA, et al. Basophils (Bsp-1+) derive from the leukemic clone in human myeloid leukemias involving the chromosome breakpoint 9q34. Blood 1989;73:777–781.
112. Nilsson G, Carlsson M, Jones I, et al. TNF-alpha and IL-6 induce differentiation in the human basophilic leukaemia cell line KU812. Immunology 1994;81: 73–78.
113. Beghini A, Cairoli R, Morra E, et al. In vivo differentiation of mast cells from acute myeloid leukemia blasts carrying a novel activating ligand-independent c-kit mutation. Blood Cells Mol Dis 1998;24:262–270.
114. Le Beau MM, Lemons RS, Espinosa R III, et al. Interleukin-4 and interleukin-5 map to human chromosome 5 in a region encoding growth factors and receptors and are deleted in myeloid leukemias with a del(5q). Blood 1989;73: 647–650.
115. Agis H, Fureder W, Bankl HC, et al. Comparative immunophenotypic analysis of human mast cells, blood basophils and monocytes. Immunology 1996;87: 535–543.
116. Florian S, Sonneck K, Czerny M, et al. Detection of novel leukocyte differentiation antigens on basophils and mast cells by HLDA8 antibodies. Allergy 2006;61:1054–1062.
117. Scott K, Bradding P. Human mast cell chemokines receptors: implications for mast cell tissue localization in asthma. Clin Exp Allergy 2005;35:693–697.
118. Kanaoka Y, Boyce JA. Cysteinyl leukotrienes and their receptors: cellular distribution and function in immune and inflammatory responses. J Immunol 2004;173:1503–1510.
119. Gauvreau GM, Plitt JR, Baatjes A, et al. Expression of functional cysteinyl leukotriene receptors by human basophils. J Allergy Clin Immunol 2005;116: 80–87.
120. Sloane DE, Tedla N, Awoniyi M, et al. Leukocyte immunoglobulin-like receptors: novel innate receptors for human basophil activation and inhibition. Blood 2004;104:2832–2839.
121. Bieneman AP, Chichester KL, Chen YH, et al. Toll-like receptor 2 ligands activate human basophils for both IgE-dependent and IgE-independent secretion. J Allergy Clin Immunol 2005;115:295-301.
122. Komiya A, Nagase H, Okugawa S, et al. Expression and function of toll-like receptors in human basophils. Int Arch Allergy Immunol 2006;140(suppl 1):23–27.
123. Bochner BS, Schleimer RP. Mast cells, basophils, and eosinophils: distinct but overlapping pathways for recruitment. Immunol Rev 2001;179:5–15.
124. Tkaczyk C, Metcalfe DD, Gilfillan AM. FcγRI and other Fc receptors on human mast cells. Alternative paradigms for the regulation of mast-cell activation. ACI Int 2002;14:109–116.
125. Nimmerjahn F, Ravetch JV. Fcgamma receptors: old friends and new family members. Immunity 2006;24:19–28.
126. Takai T, Ono M, Hikida M, et al. Augmented humoral and anaphylactic responses in Fc gamma RII-deficient mice. Nature 1996;379:346–349.
127. Caughey GH. New developments in the genetics and activation of mast cell proteases. Mol Immunol 2002;38:1353–1357.
128. Miller HR, Pemberton AD. Tissue-specific expression of mast cell granule serine proteinases and their role in inflammation in the lung and gut. Immunology 2002;105:375–390.
129. Wakahara S, Fujii Y, Nakao T, et al. Gene expression profiles for Fc epsilon RI, cytokines and chemokines upon Fc epsilon RI activation in human cultured mast cells derived from peripheral blood. Cytokine 2001;16:143–152.
130. Nakajima T, Inagaki N, Tanaka H, et al. Marked increase in CC chemokine gene expression in both human and mouse mast cell transcriptomes following Fcepsilon receptor I cross-linking: an interspecies comparison. Blood 2002:100: 3861–3868.
131. Monticelli S, Lee DU, Nardone J, et al. Chromatin-based regulation of cytokine transcription in Th2 cells and mast cells. Int Immunol 2005;17:1513–1524.
132. Foreman J. Non-immunological stimuli of mast cells and basophil leucocytes. In: Foreman J, ed. Immunopharmacology of mast cells and basophils. London: Academic Press, 1993:57–69.
133. Pothoulakis C, Castagliuolo I, LaMont JT. Nerves and intestinal mast cells modulate responses to enterotoxins. News Physiol Sci 1998;13:58–63.
134. Redegeld F, van der Heijden MW, Kool M, et al. Immunoglobulin-free light chains elicit immediate hypersensitivity-like responses. Nat Med 2002;8: 694–701.
135. Marone G, Genovese A, Granata F, et al. Pharmacological modulation of human mast cells and basophils. Clin Exp Allergy 2002;32:1682–1689.
136. Ennis M. New targets for modifying mast cell activation in asthma. Curr Allergy Asthma Rep 2006;6:247–251.
137. Peachell P. Regulation of mast cells by beta-agonists. Clin Rev Allergy Immunol 2006;31:131–142.
138. Santos J, Alonso C, Guilarte M, et al. Targeting mast cells in the treatment of functional gastrointestinal disorders. Curr Opin Pharmacol 2006;6:541–546.
139. Schlutz BL. Pharmacology of ocular allergy. Curr Opin Allergy Clin Immunol 2006;6:383–389.
140. Chang TW, Shiung YY. Anti-IgE as a mast cell-stabilizing therapeutic agent. J Allergy Clin Immunol 2006;117:1203–1212.
141. Walker S, Monteil M, Phelan K, et al. Anti-IgE for chronic asthma in adults and children. Cochrane Database Syst Rev 2006;(2):CD003559.
142. Holgate ST, Polosa R. The mechanisms, diagnosis, and management of severe asthma in adults. Lancet 2006;368:780–793.
143. Swieter M, Ghali WA, Rimmer C, et al. Interferon-αβ inhibits IgE-dependent histamine release from rat mast cells. Immunology 1988;66:606–610.
144. Bissonnette EY, Befus AD. Inhibition of mast cell-mediated cytotoxicity by IFN-α/β and -γ. J Immunol 1990;145:3385–3390.
145. Chen YH, Bieneman AP, Creticos PS, et al. IFN-alpha inhibits IL-3 priming of human basophil cytokine secretion but not leukotriene C4 and histamine release. J Allergy Clin Immunol 2003;112:944–950.
146. Coleman JW. Nitric oxide: a regulator of mast cell activation and mast cell-mediated inflammation. Clin Exp Immunol 2002;129:4–10.
147. Sekar Y, Moon TC, Munoz S, et al. Role of nitric oxide in mast cells—controversies, current knowledge, and future applications. Immunol Res 2005;33: 223–239.
148. Bissonnette EY, Enciso A, Befus AD. TGF-β1 inhibits the release of histamine and tumor necrosis factor-α from mast cells through an autocrine pathway. Am J Respir Cell Mol Biol 1997;16:275–282.
149. Marshall JS, Leal-Berumen I, Nielsen L, et al. Interleukin (IL)-10 inhibits long-term IL-6 production but not preformed mediator release from rat peritoneal mast cells. J Clin Invest 1996;97:1122–1128.
150. Lin T-J, Befus AD. Differential regulation of mast cell function by interleukin-10 and stem cell factor. J Immunol 1997;159:4015–4023.
151. Bissonnette EY. Histamine inhibits TNF-alpha release by mast cells through H2 and H3 receptors. Am J Respir Cell Mol Biol 1996;14:620–626.
152. Hogaboam CM, Bissonnette EY, Chin BC, et al. Prostaglandins inhibit inflammatory mediator release from rat mast cells. Gastroenterology 1993;104: 122–129.
153. Abdel-Majid RM, Marshall JS. Prostaglandin E2 induces degranulation-independent production of vascular endothelial growth factor by human mast cells. J Immunol 2004;172:1227–1236.
154. Dvorak AM, Dvorak HF. Cutaneous basophil hypersensitivity—a twenty-year perspective, 1970 to 1990. In: Foreman J, ed. Immunopharmacology of mast cells and basophils. London: Academic Press, 1993:139–152.
155. Schroeder JT, Lichtenstein LM, Roche EM, et al. IL-4 production by human basophils found in the lung following segmental allergen challenge. J Allergy Clin Immunol 2001;107:265–271.
156. Stead RH, Colley EC, Wang B, et al. Vagal influences over mast cells. Auton Neurosci 2006;125:53–61.
157. Andoh T, Kuraishi Y. Expression of Fc epsilon receptor I on primary sensory neurons in mice. Neuroreport 2004;15:2029–2031.
158. Echtenacher B, Männel DN, Hültner L. Critical protective role of mast cells in a model of acute septic peritonitis. Nature 1996;381:75–77.
159. Malaviya R, Ikeda T, Ross E, et al. Mast cell modulation of neutrophil influx and bacterial clearance at sites of infection through TNF-α. Nature 1996;381:77–80.
160. Huang C, De Sanctis GT, O’Brien PJ, et al. Evaluation of the substrate specificity of human mast cell tryptase beta I and demonstration of its importance in bacterial infections of the lung. J Biol Chem 2001;276:26276–26284.
161. Karlson U, Pejler G, Fröman, et al. Rat mast cell protease 4 is a β-chymase with unusually stringent substrate recognition profile. J Biol Chem 2002;277: 18579–18585.
162. Romagnani S. Induction of TH1 and TH2 responses: a key role for the “natural” immune response? Immunol Today 1992;13:379–381.
163. Garbuzenko E, Nagler A, Pickholtz D, et al. Human mast cells stimulate fibro-blast proliferation, collagen synthesis and lattice contraction: a direct role for mast cells in skin fibrosis. Clin Exp Allergy 2002;32:237–246.
164. Puxeddu I, Ribatti D, Crivellato E, et al. Mast cells and eosinophils: a novel link between inflammation and angiogenesis in allergic diseases. J Allergy Clin Immunol 2005;116:531–536.
165. Befus D. Reciprocal interactions between mast cells and the endocrine system. In: Freier S, ed. The neuroendocrine-immune network. Boca Raton, FL: CRC Press, 1990:39–52.
166. Maurer M, Theoharides T, Granstein RD, et al. What is the physiological function of mast cells? Exp Dermatol 2003;12:886–910.
167. Silverman AJ, Asarian L, Khalil M, et al. GnRH, brain mast cells and behavior. Prog Brain Res 2002;141:315–325.
168. Gaboury JP, Niu X-F, Kubes P. Nitric oxide inhibits numerous features of mast cell-induced inflammation. Circulation 1996;93:318–326.
