Page 355 - Clinical Immunology_ Principles and Practice ( PDFDrive )

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Mast Cells, Basophils, and Mastocytosis

Joshua Boyce, Laura Fanning

Mast cells and basophils are functionally related effector cells of committed precursors that migrate to their ultimate tissue destina-
hematopoietic origin that are implicated in allergy, type 2 immune tions before acquiring the morphological and biochemical
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responses to parasites, and innate immunity. Both cell types characteristics of mature mast cells. Moreover, circulating
derive from bone marrow progenitors and express high-affinity basophils are short-lived and terminally differentiated, whereas
immunoglobulin E (IgE) Fc receptors (FcεRI) on their surface. mast cells can survive for long periods, and retain the capacity
Both release histamine and generate a variety of other inflam- for proliferation and substantial inducible gene expression. This
matory mediators in response to both IgE- and non–IgE-mediated likely explains the high degree of heterogeneity among mast cell
activation. However, there are important differences between subpopulations.
mast cells and basophils in terms of their developmental origins, In mice, committed mast cell progenitors (MCPs) can be
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hi,
morphology, distribution, and mechanisms and responses to identified cytofluorographically as a Kit (CD117) FcεRI , β7
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stimulation (Table 23.1, Fig. 23.1). This chapter will deal with integrin mononuclear cell population. A similar cell population
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the functional characteristics of both cell types in host defense was recently identified in human blood. In ex vivo colony forming
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and disease. assays, both mouse and human CD117 , FcεRI , β7 integrin cells
give rise preferentially to mast cells. In studies of cells sorted from
various organs BALB/c mice, committed basophil precursors
KEY CONCEPTS (BaPs) were found exclusively in bone marrow, whereas committed
Origins of Basophils and Mast Cells mast cell progenitors were most abundant in the small intestine.
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This study identified a splenic population of cells capable of
• Mast cells and basophils represent distinct hematopoietic lineages. giving rise to both mast cells and basophils with ex vivo culture
• Basophils are granulocytes that mature in the bone marrow, circulate
in blood, and can be recruited into peripheral tissues at sites of (bipotent basophil–mast cell precursor [BMCP]). However, neither
inflammatory responses. mature mast cells nor mast cell progenitors show significant
• Mast cell progenitors arise in bone marrow, but mast cells mature in overlap in gene expression profiles with basophils in either mice
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peripheral tissues. or humans. Thus despite some functional similarities, the bulk
• Mast cells are present throughout connective tissues and mucosal of evidence suggests that the developmental pathways of mast cells
surfaces and are particularly abundant near epithelial surfaces exposed and basophils diverge early in hematopoiesis and that the two
to the environment.
• CD117 and its ligand stem cell factor (SCF) are critical for mast cell cell types likely serve correspondingly very different functions.
development and survival. CD117 and its ligand, stem cell factor (SCF), are absolutely
• Basophil development is promoted in the context of T H 2 inflammatory required for mast cell development. SCF exists as both a
responses and regulated by cytokines, including interleukin-3 (IL-3) membrane-bound protein expressed by fibroblasts and other
and thymic stromal lymphopoietin (TSLP). stromal cells, as well as a soluble form. Mice with mutations in
sh
v
sh
d
the loci for CD117 (W/W or W /W mice) or SCF (Sl/Sl mice)
lack mast cells, among other hematopoietic and nonhematopoietic
DEVELOPMENT AND DISTRIBUTION defects. Although loss-of-function mutations in CD117 or SCF
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OF MAST CELLS have not been identified in humans, gain-of-function mutations
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in CD117 are associated with systemic mastocytosis, suggesting
Mast Cell Development and Survival that the SCF-KIT axis is important for human mast cell develop-
Mast cells are evolutionarily ancient, predating the emergence ment as well. Although SCF can stimulate mast cell development
of adaptive immunity. A mast cell–like cell containing histamine from either mouse or human progenitor cells in vitro, mouse
and heparin has been identified in Styela plicata, a urochordate mast cells can be derived in vitro from unfractionated bone
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species that first appeared around 500 million years ago. Studies marrow cells by using interleukin-3 (IL-3) or thymic stromal
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in rodents indicate that mast cells derive from hematopoietic lymphopoietin (TSLP) as the sole exogenous growth factors.
stem cell (HSC)–derived granulocyte–monocyte progenitor cells Mice lacking IL-3 have wild-type levels of mast cells under
(GMPs) in bone marrow, which can give rise to basophils and steady-state conditions but show diminished capacity to develop
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other lineages. In mice, the transcription factors C/EBPα and a reactive mast cell hyperplasia in the intestine in response to
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MITF interact antagonistically and specify basophil versus mast helminth infections. TSLP knock-out mice display modest
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cell fate, respectively, in GMPs. Basophils undergo full differentia- steady-state reductions in mast cell numbers in all organs studied.
tion in bone marrow, whereas mast cells differentiate from Additionally, transgenic overexpression of IL-9 results in marked
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