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Chapter 72 Mast Cells and Mastocytosis 1171

lies between the TM and TK domains. KIT is expressed on hemato- have shown that certain cytokines or hormonal factors exert inhibi-
poietic stem/progenitor cells and is also essential for gametogenesis tory effects on MCs (e.g., interferon [IFN]-γ), and some cytokine
and melanogenesis. KIT expression is lost when hematopoietic cells pairs counterbalance each other’s effects (e.g., T-helper 2 [Th2]
undergo differentiation. However, the exception is MCs, which retain cytokine interleukin [IL]-4 vs. regulatory T cell cytokine TGF-β1)
persistent and high-level expression of KIT (CD117). This can be on MC homeostasis. Expression of the death receptor tumor necrosis
exploited for the purposes of MC identification by immunohisto- factor–related apoptosis-inducing ligand and inhibitor receptors
chemistry and/or flow immunophenotyping (in conjunction with CD300a and Siglec-8 may also contribute to downregulation of MC
other surface and cytoplasmic markers). activation, survival, and IgE-mediated responses.
The two major splice variants of KIT differ by the presence or
absence of four amino acids (GNNK) at the extracellular JM region.
−
In NIH3T3 cells, the GNNK isoform induced loss of contact MAST CELL ACTIVATION AND FUNCTION
inhibition, anchorage-independent growth, and tumorigenicity in
+
mice, whereas the GNNK isoform did not exhibit most of these MCs commonly reside at the interface between the host and environ-
characteristics. Also, despite similar binding of SCF to KIT, the ment, usually in the skin, or in the mucosa lining the lungs or
−
GNNK isoform displayed more rapid and extensive tyrosine auto- gastrointestinal tract. Migration and homing of MCs to various sites
phosphorylation and faster internalization. Preferential expression of is regulated by the interaction between surface expression of numer-
the GNNK isoform has been noted in small cohorts of patients with ous types of chemokine receptors (e.g., CXC chemokine receptor 2)
SM and germ cell tumors, but larger series are needed to determine and integrins (e.g., α4β7, α4β1) on MCs to tissue-specific endothe-
the relevance of these KIT isoforms to disease pathogenesis. lial binding sites such as mucosal vascular address in cell adhesion
molecule-1 (MAdCAM-1) and vascular cell adhesion molecule-1
(VCAM-1). In addition to playing a primary role in mediating
Stem Cell Factor allergic responses and inflammation, MCs act as one arm of the
adaptive immune system by playing a role in host defense against
SCF (KIT ligand) was identified by three groups in 1990 as the pathogens such as bacteria, fungi, and viruses.
principal growth and differentiation factor for human MCs. In fact, MCs serve as a rich source of a variety of biologically active
+
SCF was found to induce MC differentiation from CD34 cells or molecules (Table 72.1). These include preformed mediators such as
blood/BM mononuclear cells. SCF is produced by fibroblasts and vasoactive amines (histamine), anionic proteoglycans (heparin,
endothelial cells, and promotes the proliferation, differentiation, chrondroitin sulfate), and proteases (tryptase, chymase, and carboxy-
2
survival, and migration of hematopoietic progenitors, melanocytes, peptidase). Activated MCs also contribute to de novo synthesis of
MCs, and germ cells. lipid-derived mediators that constitute the slow-reacting substance of
Loss-of-function mutations at the SI (steel) locus on chromosome anaphylaxis (SRS-A). These mediators include lipoxygenase-derived
10 in mice were found to phenocopy mutations at the W locus. metabolites of arachidonic acid—the cysteinyl leukotrienes LTC4,
Ultimately, the gene product of the SI locus was found to be the
ligand for kit, SCF. In the case of mutations affecting the W (kit)
locus, transplantation of BM cells from congenic +/+ mice into
v
W/W mice corrected MC deficiency and anemia, consistent with an TABLE Human Mast Cell Cell–Derived Mediators
intrinsic progenitor/stem cell defect. In contrast, skin and BM 72.1
engraftment experiments demonstrated that mutations at the SI locus Class Mediators Physiologic Effects
were cell extrinsic (e.g., microenvironmental) in nature. When skin
d
v
from either W/W or Sl/Sl mice was transplanted onto the backs of Preformed Histamine, serotonin, Vasodilation,
congenic +/+ mice, MCs were capable of engrafting the skin from mediators heparin, neutral proteases vasoconstriction,
v
d
W/W mice but not the skin from Sl/Sl mice. In addition, hemato- (tryptase and chymase, angiogenesis, mitogenesis,
d
logic abnormalities in Sl/Sl mice failed to correct with transplanta- carboxypeptidase, pain, protein processing/
tion of BM cells from congenic +/+ animals. These experiments cathepsin G), major basic degradation, lipid/
formally established that SCF is a physiologically relevant ligand of protein, acid hydrolases, proteoglycan hydrolysis,
kit and that development is critically dependent on this ligand- peroxidase, arachidonic acid generation,
receptor interaction. Therefore SCF has also been termed mast cell phospholipases tissue damage and repair,
growth factor. inflammation
Alternative splicing results in two isoforms of membrane-bound Lipid LTB4, LTC4, PGE2, Leukocyte chemotaxis,
SCF with different susceptibility to proteolytic cleavage: a longer mediators PGD2, PAF vasoconstriction,
isoform that retains exon 6 and contains a cleavage site that results bronchoconstriction, platelet
in soluble SCF, and a shorter isoform lacking the cleavage site, which activation, vasodilation
remains membrane-bound and serves as a stem cell homing receptor Cytokines TNF-α, TGF-β, IFN-α, Inflammation, leukocyte
in the BM niche. Both the membrane-bound and soluble form of IFN-β, IL-1α, IL-1β, IL-5, migration/proliferation
SCF (which exists in a homodimeric confirmation) are capable of IL-6, IL-13 IL-16, IL-18
binding to and inducing homodimerization of KIT, which, in turn, Chemokines IL-8 (CXCL8), I-309 Chemoattraction and tissue
leads to autophosphorylation of tyrosine residues located in intracel- (CCL-1), MCP-1 (CCL2), infiltration of leukocytes
lular portions of the molecule. A cascade of signaling events ensues MIP-1αS (CCL3), MIP1β
via downstream effector molecules, including Src kinases, c-Jun (CCL4), MCP-3 (CCL7),
N-terminal kinase (Jnk), mitogen-activated protein (MAP) kinases, RANTES (CCL5), eotaxin
and the Janus-activated kinase (JAK)-signal transducer and activator (CCL11), MCAF (MCP-1)
of transcription and phosphatidylinositol 3-kinase (PI3K)/AKT
pathways. In addition to promoting MC differentiation and survival, Growth SCF, M-CSF, GM-CSF, Growth of various cell types,
SCF can regulate MC adhesion to extracellular matrix proteins as factors bFGF, VEGF, NGF, PDGF vasodilation,
well as mediator release via IgE-dependent and IgE-independent neovascularization,
mechanisms. Likewise, when applied at relatively high concentrations angiogenesis
for 90 min, SCF is capable of directly inducing mediator secretion The mediators in the table are examples only. In addition, many mediators are
from human MCs. Whereas in mice several different cytokines are identified in mouse mast cells, human mast cell lines or primary cultures of
involved in the regulation of growth and activation of MCs, SCF human mast cells and may not be produced in vivo. 2
From Metcalfe DD: Mast cells and mastocytosis. Blood 112:946, 2008.
seems to be a rather specific cytokine for human MCs. Other studies