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CHAPTER 15

Mast Cells

Peter A. Nigrovic

KEY POINTS BASIC BIOLOGY OF MAST CELLS


Mast cells arise in the bone marrow, circulate as immature Development and Tissue Distribution
precursors, and develop into functional mast cells after
entering peripheral tissues. Mast cells are distinctive in appearance. Ranging in size
from 10 to 60m and with a centrally located round or oval
The phenotype of mast cells is diverse, plastic, and governed nucleus, their abundant cytoplasm is filled with multiple
by signals from lymphocytes, fibroblasts, and other elements
of the microenvironment.
small granules. They were named Mastzellen in 1878 by the
German pathologist Paul Ehrlich, who believed that they
In healthy tissues, mast cells serve as immunologic sentinels were overfed connective tissue cells (msten, in German,
and participate in innate and adaptive immune responses to means to feed or fatten an animal).1 Electron microscopy
bacteria and parasites. reveals that the plasma membrane of the mast cells exhibits
Mast cells accumulate in injured and inflamed tissue, where multiple thin cytoplasmic extensions, providing a broad
they may amplify or suppress inflammation. interface with the surrounding tissue (Figure 15-1A). The
Mast cells have been implicated in multiple immune- tissue distribution of mast cells is extensive; within tissue,
mediated diseases, including inflammatory arthritis, although mast cells tend to cluster around blood vessels and nerves
their role as a therapeutic target remains uncertain. and near epithelial and mucosal surfaces. They are also
found in the lining of vulnerable body cavities such as the
peritoneum and the diarthrodial joint. Given this localiza-
tion, mast cells are among the first immune cells to encoun-
ter pathogens invading into tissue from the external world
Although mast cells are best known for their role in allergy or via the bloodstream, consistent with their role as immune
and anaphylaxis, the immune function of this bone marrow sentinel cells.
derived lineage far outstrips its participation in immuno- Mast cells are of hematopoietic origin, arising in the
globulin (Ig)E-driven disease. Mast cells are resident broadly bone marrow and depositing in tissues after migrating
in vascularized tissues but cluster near interfaces with the through the bloodstream2,3 (Figure 15-2). Unlike other
external world, in the linings of vulnerable body cavities, myeloid cells, such as monocytes and neutrophils, mast cells
and near blood vessels and nerves. In these locations, mast do not terminally differentiate in the bone marrow but
cells serve as immune sentinels and are equipped with an rather circulate as progenitors, bearing the surface signature
array of pathogen receptors, along with an armamentarium CD34+/c-Kit+/CD13+.4 Further developmental details have
of mediators capable of rapidly recruiting immune effector been worked out most extensively in the mouse. A burst of
cells. Mast cells also accumulate in sites of tissue injury and circulating progenitors late in gestation suggests the possi-
chronic inflammation, although their role in such locations bility that mast cells may populate the tissues primarily
remains uncertain. Other functions for this lineage, con- during early development, with later recruitment restricted
served by evolution for more than 500 million years, con- to the inflammatory context, as appears to be the case for
tinue to be defined. certain populations of murine tissue macrophages.3 After
Circumstantial and experimental evidence implicates entering the tissues, murine mast cells may mature into
mast cells in the pathogenesis of rheumatic diseases. Mast classic granulated cells or remain as ungranulated progeni-
cells reside constitutively in the normal synovium and are tors, awaiting local signals to differentiate fully. Comparison
found in large numbers in inflamed synovial tissue, whereas of murine lung and intestine has demonstrated that these
mast cell mediators are identified in inflammatory joint tissues use distinct pathways to regulate the constitutive and
fluid. Moreover, models have indicated that mast cells can inducible recruitment of mast cell progenitors, illustrating
make an important contribution to the pathogenesis of that mast cell homing is a precisely controlled process.5,6
experimental arthritis. Mast cells have also been implicated Once resident in tissues, mast cells may live for many
in other autoimmune conditions, including multiple sclero- months. Mature mast cells remain capable of mitotic divi-
sis, bullous pemphigoid, and systemic sclerosis. sion, although recruitment of circulating progenitors appears

250
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CHAPTER 15 Mast Cells 251

A B
Figure 15-1 Mast cell morphology. A, An intact mast cell. B, A mast cell that has undergone anaphylactic degranulation. Note how fusion of intra-
cellular granules has resulted in the formation of a labyrinth of interconnected channels by which granule contents may be expelled from the cell.
Arrows indicate remaining granules. N, Nucleus. (Images courtesy Dr. A. Dvorak, Beth Israel Deaconess Medical Center, Boston, Mass. From Dvorak AM,
Schleimer RP, Lichtenstein LM: Morphologic mast cell cycles, Cell Immunol 105:199204, 1987; and Galli SJ, Dvorak AM, Dvorak HF: Basophils and mast cells:
morphologic insights into their biology, secretory patterns, and function. In Ishizaka K, editor: Progress in allergy: mast cell activation and mediator release,
Basel, 1984, S Karger, pp 1141.)

to greatly exceed local replication as a pathway to expand


the number of tissue mast cells. Mechanisms of reducing
mast cell numbers include apoptosis, as demonstrated in
tissue mast cells deprived of the cytokine stem cell factor
(SCF), a critical survival signal for mast cells.7 Under
certain conditions, mast cells can also emigrate via the
Bone
marrow
Circulation lymphatics, appearing in draining lymph nodes much in the
manner of dendritic cells.8 The pathways that license mast
cell accumulation in inflamed tissues are incompletely
Mast cell Tissue defined but include tissue production of factors such as
progenitor interleukin (IL)-4 and IL-33 that attenuate mast cell
apoptosis.9,10
T cell
SCF Mast Cell Heterogeneity: Common Progenitor, Multiple
tissue
environment
Subsets, and Phenotypic Plasticity
Whereas all types of mast cells derive from a common pro-
MCTC genitor lineage, the phenotype of fully differentiated tissue
MCT mast cells is heterogeneous. Human mast cells are conven-
Phenotypic
plasticity
tionally divided into two broad classes on the basis of the
protease contents of their granules (Figure 15-2). MCTC
display rounded granules that contain the enzymes tryptase
and chymase, whereas the smaller, and more irregularly
Figure 15-2 Mast cell origin and differentiation. Mast cells arise in the shaped granules of MCT contain tryptase but not chymase.
bone marrow, circulate as committed progenitors, and differentiate into MCTC also express other proteases, including carboxypepti-
mature mast cells upon entering tissue. Human mast cells may be clas-
sified on the basis of granule proteases into tryptase+ mast cells (MCTC)
dase and cathepsin G. These subtypes differ in tissue dis
and tryptase+/chymase+ mast cells (MCTC), with characteristic tissue local- tribution. MCTC tend to be found in connective tissue,
ization and mediator production. SCF, Stem cell factor. such as in normal skin, muscle, the intestinal submucosa,
and the normal synovium, whereas MCT predominate in

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252 PART 2 CELLS INVOLVED IN AUTOIMMUNE DISEASES AND INFLAMMATION

mucosal sites, including the lining of the gut and respiratory also been documented on other lineages including macro-
tract, although in fact both are present in many locations. phages, vascular endothelium, and airway epithelium and is
Beyond the protease signature, other differences between likely a critical pathway by which tissues modulate the local
these subsets include their profile of cytokine elaboration, mast cell population.
as well as cell surface receptor expression; however, tissue-
specific phenotypic differences are noted within each type T Lymphocytes and Other Cells
as well (i.e., neither MCTC nor MCT are homogenous cel-
lular subsets). T lymphocytes exert a profound effect on mast cell pheno-
The relationship between MCTC and MCT mast cells is type. Severe combined immunodeficiency (SCID) mice
controversial. Are they committed subsets, akin to CD4 and that lack T cells fail to develop mucosal mast cells, a defect
CD8 lymphocytes, or are they functional states assumed by that can be corrected by T cell engraftment.21 An analogous
mast cells under the influence of the microenvironment? In observation has been made in humans deficient in T cells
mice, in which an analogous distinction exists between due to congenital immunodeficiency or acquired immuno-
connective tissue mast cells (CTMCs) and mucosal mast deficiency syndrome (AIDS). Intestinal biopsy in these
cells (MMCs), evidence for phenotypic plasticity is strong. patients shows that MMCs (MCT) are strikingly reduced,
Both in culture and in vivo, single CTMCs may differenti- whereas CTMCs (MCTC) are present in normal numbers.22
ate into (or give rise to) MMCs and vice versa.11,12 Mast The pathways by which T cells exert this striking effect are
cells with intermediate protease expression are found, and not defined, although it is clear that T cell cytokines such
serial observations suggest that exposure to an inflammatory as interleukin (IL)-3, IL-4, IL-6, IL-9, and transforming
stimulus can induce progressive change from one class to growth factor (TGF)- may have profound effects on the
another, although whether this change occurs at a single- phenotype of mast cells matured in culture. By contrast,
cell level has not been definitively established.13 Similarly, interferon (IFN)- inhibits mast cell proliferation and may
in murine and human mastocytosis, clonally expanded mast induce apoptosis. These observations imply that cells
cells display divergent phenotypes depending on the tissue recruited to an inflamed tissue may have a profound impact
of residence.14,15 In aggregate, these data favor the hypoth- on the phenotype of local mast cells. The rheumatoid
esis that mast cells assume a particular phenotype under the synovium may well exemplify this phenomenon. The
control of the local signals but can alter this phenotype if synovium is normally populated by MCTC mast cells, but
conditions change. large numbers of MCT mast cells are identified in the
inflamed synovium, typically in regions rich in infiltrating
leukocytes, whereas MCTC mast cells reside in deeper, more
Stem Cell Factor
fibrotic areas of the joint.23 Interestingly, regulatory T cells
One of the most important signals from tissue to local mast (Treg cells) can also have a direct impact on mast cell func-
cells is SCF. The receptor for SCF, c-Kit, is expressed widely tion, including recruitment, receptor expression, degranula-
on hematopoietic lineages early in differentiation, but tion, and cytokine production.24-27
among mature lineages, only mast cells express c-Kit at a Other cells aside from T cells can potentially interact
high level. Stimulation of mast cells by SCF promotes matu- with mast cells in the tissues. In particular, fibroblasts and
ration and phenotypic differentiation, blocks apoptosis, and mast cells commonly demonstrate close physical interac-
induces chemotaxis. It may also activate mast cells directly tions. Beyond SCF, fibroblasts elaborate cytokines such as
to release mediators. In both mice and humans, SCF remains the IL-1 family member IL-33, which can exert effects on
an irreplaceable survival signal for tissue mast cells. Accord- mast cell protease expression, effector phenotype, and sur-
ingly, mice with defects in SCF or c-Kit are strikingly defi- vival.10,28,29 Dendritic cells have also been implicated in the
cient in mature tissue mast cells (examples include W/Wv, recruitment of mast cells into inflamed tissues.30
Sl/Sld, and Wsh mouse strains). Similarly, clonal mast cells
obtained from patients with systemic mastocytosis com- Different Functions for MCT and MCTC Mast Cells
monly exhibit activating mutations in c-kit.
SCF occurs in two alternate forms resulting from differ- The preservation of distinct types of mast cells in multiple
ential mRNA splicing: soluble and membrane bound. The species implies distinct and nonoverlapping roles for these
importance of this latter form is clear from Sl/Sld mice, subtypes. However, the understanding of functional dif
which lack only the membrane-bound isoform yet exhibit ferences between MCT and MCTC remains limited. One
very few tissue mast cells.16 SCF is synthesized by multiple hypothesis is that MCT play a pro-inflammatory role and
lineages, including mast cells themselves. Expression by MCTC specialize in matrix remodeling.31 This hypothesis
fibroblasts is especially important, given the intimate physi- makes sense of (1) the promotion of MCT development by
cal contacts observed between fibroblasts and mast cells in T cells patrolling the tissues; (2) the partition of MCT and
situ. The SCF/c-Kit axis mediates cell-cell adhesion between MCTC mast cells to inflamed and fibrotic areas, respectively;
mast cells and fibroblasts independent of the kinase activity and (3) the preferential expression of the pro-inflammatory
of the receptor.17 Rodent mast cells co-cultured with fibro- mediators IL-5 and IL-6 by MCT and the profibrotic IL-4
blasts demonstrate enhanced survival, connective-tissue by MCTC.32 Not all observations fit comfortably into
phenotypic differentiation, and heightened capacity to this dichotomy, however. For example, the potently pro-
elaborate pro-inflammatory eicosanoids, effects mediated at inflammatory anaphylatoxin receptor C5aR (CD88) is ex-
least in part by direct contact, including interactions pressed on MCTC but not on MCT 33. Ultimately, too little
between SCF and c-Kit.18,19 The extent of similar regulation is known about the actual functional importance of these
in human mast cells is uncertain.20 Expression of SCF has subsets to permit firm conclusions.

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CHAPTER 15 Mast Cells 253

Mast Cell Activation Immunoglobulin G and Immune Complexes

Immunoglobulin E IgE is only one among many pathways of mast cell


activation. One key trigger for mast cell activation in both
The canonical pathway to mast cell activation is via IgE human and mouse is IgG, acting via receptors for the Fc
and its receptor FcRI. With a Ka of 1010/M, this receptor is portion of IgG (FcR). The importance of this pathway
essentially constantly saturated with IgE at typical serum was demonstrated first in mice rendered genetically defi-
concentrations. Such binding not only sensitizes mast cells cient in IgE. Contrary to expectations, these animals remain
to the target antigen but also helps promote mast cell sur- susceptible to anaphylaxis mediated through IgG and
vival and, in some cases, cytokine production. Cross-linking the low-affinity IgG receptor FcRIII.36,37 The human
FcRI-bound IgE by multivalent antigen induces a brisk and counterpart of this receptor, FcRIIa, is equally capable of
vigorous response. Within minutes, granules within the inducing activation of human mast cells.38,39 Human mast
mast cell fuse together and with the surface membrane, cells can also be induced to express the high-affinity IgG
creating a set of labyrinthine channels that allow rapid receptor FcRI, rendering them susceptible to IgG-mediated
release of granule contents (see Figure 15-1B).34 This com- activation.40,41
pound exocytosis event, termed anaphylactic degranulation, These IgG receptors contribute to involvement of mast
is followed within minutes by the elaboration of eicosanoids cells in IgG-driven diseases. Thus, in the mouse, mast cells
newly synthesized from arachidonic acid cleaved from inter- participate in IgG-mediated immune complex peritonitis,
nal membrane lipids. Finally, signals transduced via FcRI the cutaneous Arthus reaction, and experimental murine
induce the transcription of new genes and elaboration of a bullous pemphigoid.42-44 Activation via Fc receptors also
wide range of chemokines and cytokines (Figure 15-3). mediates mast cell participation in antibody-mediated
Upon termination of the stimulation event, the surface murine arthritis.45
membrane closes over the granule-formed channels, which
subsequently bud off within the cytoplasm, re-creating dis- Soluble Mediators and Cell-Cell Contact
crete granules using the original membranes.34 These gran-
ules are then recharged with mediators in a process that Mast cells coordinate with immune and nonimmune cell
occurs gradually over days to weeks.35 lineages via mechanisms beyond antibody response, includ-
Granule contents
ing soluble mediators and surface receptors. Examples of
such signals include the cytokine tumor necrosis factor
Proteases
Tryptase, chymase, (TNF) and the neurogenic peptide substance P, which can
carboxypeptidase-A induce mast cell degranulation.46,47 Physical contact with
Proteoglycans other cells can also induce mast cell activation. For example,
Heparin, chondroitin sulfate CD30 on lymphocytes can interact with CD30L on mast
Mast Vasoactive amines cells to induce the production of a range of chemokines.48
cell Histamine, serotonin Interestingly, ligation of CD30L does not induce release of
IgE Cytokines
IgG TNF, IL-4, bFGF, VEGF, IL-16
granule contents or lipid mediators, illustrating the selectiv-
Complement ity of response of which mast cells are capable.
TLR agonists Lipid metabolites
SCF, cytokines PGD2, LTC4, LTB4, PAF
Cell-cell contact
Danger and Injury
Trauma Newly synthesized mediators
Cytokines Mast cells are equipped to recognize danger in the absence of
IL-1, IL-3, IL-6, IL-8, IL-16, IL-18 guidance from other lineages via a range of pathogen recep-
TNF, SCF, TGF- tors, including multiple toll-like receptors (TLRs) and
CD48, a surface protein recognizing the fimbrial antigen
Chemokines FimH. These receptors are implicated in the response of
MCP-1, MCP-1, MCP-1, mast cells to pathogens and could potentially contribute to
RANTES
Eotaxin, TARC, Lymphotactin
mast cell engagement in diseases such as atopic dermatitis, in
which skin becomes abnormally colonized with bacteria.49,50
Growth factors Mast cells may also be activated through complement,
GM-CSF, M-CSF, including the anaphylatoxins C3a and C5a.39,47 Mast cells
bFGF, PDGF, VEGF can respond directly to physical stimuli including trauma,
Figure 15-3 Mediator production by human mast cells (partial list). temperature, and osmotic stress.51 Finally, mast cells can be
The set of mediators liberated upon activation will vary depending on triggered by danger signals released by injured bystander
the state of differentiation of the mast cell and the nature of the stimulus. cells, such as IL-33 and monosodium urate crystals.52-54
See Reference 91 for a complete mediator list and references. bFGF, Basic Together, these receptors enable mast cell involvement in a
fibroblast growth factor; GM-CSF, granulocyte-macrophage colony-
stimulating factor; IL, interleukin; Ig, immunoglobulin; LTB4, leukotriene broad range of immune and nonimmune processes.
B4; LTC4, leukotriene C4; MCP, monocyte chemoattractant protein; PAF,
platelet-activating factor; PDGF, platelet-derived growth factor; PGD2,
prostaglandin D2; RANTES, released upon activation, normal T-cell Inhibitory Signals for Mast Cells
expressed and secreted; SCF, stem cell factor; TARC, thymus and
activation-regulated chemokine; TGF-, transforming growth factor-;
As with other immune lineages, mast cells are subject to
TLR, toll-like receptor; TNF, tumor necrosis factor; VEGF, vascular endo- both negative and positive regulation. Cytokines that
thelial growth factor. inhibit aspects of mast cell function include TGF- and

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254 PART 2 CELLS INVOLVED IN AUTOIMMUNE DISEASES AND INFLAMMATION

IL-10.55,56 Examples of inhibitory receptors on the surface of ties, although other studies document PAR2-independent
mast cells include the IgG receptor FcRIIb and the phos- tryptase activation of mesenchymal cells.67 In aggregate,
phatidyl serine receptor CD300A. The importance of these these effects suggest an important role for tryptase in matrix
receptors is demonstrated in genetically deficient animals. remodeling. A further contribution to the inflammatory
Mice lacking FcRIIb demonstrate a striking propensity to milieu is suggested by the capacity of tryptase to promote
activation via both IgG and IgE (which binds with low neutrophil and eosinophil recruitment and to cleave C3,
affinity to both FcRIIb and FcRI).57,58 CD300A mediates C4, and C5 to generate anaphylatoxins.68-70 Interestingly,
suppression of mast cell activation by apoptotic debris.59 tryptase can potentially suppress inflammation by cleaving
Modulating the surface expression of inhibitory receptors is IgE and IL-6.71,72
a potentially important mechanism for regulation of the Chymase. Chymase, a chymotrypsin-like neutral prote-
activation threshold of mast cells in tissues. ase, is found in the MCTC subset of human mast cells, pack-
aged within the same granules as tryptase. Like tryptase,
chymase can cleave matrix components and activate
Mast Cell Mediators stromelysin, although it can also activate collagenase
directly, suggesting a role in matrix remodeling.73 Chymase
Granule Contents: Proteases, Amines, Proteoglycans,
can activate angiotensin I, leading to angiotensin-converting
and Cytokines
enzyme (ACE)independent activation of the potent
Mature mast cells package a range of mediators in their vasoconstrictor angiotensin II.74 Chymase can also affect
granules that are ready for immediate release through fusion cytokine function, with the capacity to cleave pro-IL-
with the surface membrane. The most abundant of these 1 to generate active cytokine and to inactivate pro-
mediators are the neutral proteases, named for their enzy- inflammatory cytokines such as IL-6 and TNF, as well as
matic activity at neutral pH, but vasoactive amines, proteo- alarmins, including heat shock protein 70 and IL-33.75
glycans such as heparin, and certain pre-formed cytokines -Hexosaminidase. -Hexosaminidase is an enzyme
play distinct roles in the biologic consequences of mast cell found in lysosomes from many cell types. In mast cells it is
degranulation. The release of these mediators is not all or abundant in secretory granules, where it is released into the
none. In addition to anaphylactic degranulation, mast cells surrounding environment during degranulation. Recent
may release only a few granules at a time in a process termed studies have found that this enzyme is capable of degrading
piecemeal degranulation.60 Further, mast cells can release one bacterial cell peptidoglycan, and release by mast cells plays
type of granule but not another.61 Alternately, mast cells an important role in the defense against experimental
may be induced to elaborate cytokines and chemokines staphylococcal infection in mice.76
without any release of granule contents, as illustrated by Vasoactive Amines. Human mast cells are able to syn-
activation via CD30L.48 Thus, although the mast cell is well thesize and store the biogenic amines histamine and sero-
equipped to release large volumes of pre-formed mediators, tonin, which are implicated in instances of vascular leak.77
it is equally capable of responses tailored to the activating Histamine, which is by far more abundant than serotinin,
stimulus. is a vasoactive amine found in both MCT and MCTC mast
Tryptase. Named for its enzymatic similarity to pancre- cells, although it is not unique to this lineage. Histamine is
atic trypsin, tryptase is the most abundant granule protein involved in the wheal-and-flare response to cutaneous aller-
in human mast cells. It is also an essentially specific marker gen challenge via augmented vascular permeability, tran-
for mast cells. Tryptase is synthesized in scant amounts by sendothelial vesicular transport, and neurogenic vasodilation.
basophils but by no other lineage. The enzyme found in These effects are mediated principally via the H1 receptor.
granules is the isomer, which is the product of two distinct Three other histamine surface receptors, H2, H3, and H4,
genes. It is enzymatically active upon formation of a homo- are distributed widely on immune and nonimmune lineages,
tetramer that relies on the scaffolding function of the pro- with effects as diverse as gastric acid secretion, Langerhans
teoglycan heparin.62 Mast cells also synthesize tryptase, a cell migration, and B cell proliferation.78 Another impor-
protein incapable of forming homotetramers and thus enzy- tant mechanism underlying mast cellinduced vascular leak
matically inactive. Unlike tryptase, the isomer is not is heparin-mediated bradykinin production (see the next
stored in granules but is constitutively released into circula- section).
tion, where its function is unknown. The distinction Heparin and Chondroitin Sulfate E. Heparin and chon-
between tryptase isomers is important for diagnostic reasons: droitin sulfate E are large proteoglycans that enable the
as a marker of degranulation, systemic levels of tryptase ordered packing of mediators within human mast cell gran-
constitute a marker of recent anaphylaxis.63 By contrast, ules.79,80 Negatively charged carbohydrate side chains
trypsin levels reflect total body mast cell load and serve as complex tightly with positively charged proteins, allowing
a useful biomarker in systemic mastocytosis.64 very high concentrations of tryptase and other proteases.
Tryptase cleaves structural proteins such as fibronectin Heparin, which is produced exclusively by mast cells, facili-
and type IV collagen and enzymatically activates stromely- tates the activity of tryptase by making possible proteolytic
sin, an enzyme responsible for activating collagenase.65 self-activation within the granule and stabilizing the active
Fibrinogen is another substrate, potentially implicating tetrameric form of this enzyme. Heparin also has a wide
mast cells in prevention of fibrin deposition and blood range of effects beyond the mast cell. It is potently angio-
coagulation in the tissues.66 Tryptase also promotes hyper- genic. Heparin binding activates antithrombin III, provid-
plasia and activation of fibroblasts, airway smooth muscle ing the basis for use as an anticoagulant, while inhibiting
cells, and epithelium. Cleavage of protease-activated recep- chemokines and both classical and alternative pathways of
tors such as PAR2 may contribute to some of these activi- complement activation, as well as the function of Treg

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CHAPTER 15 Mast Cells 255

cells.81,82 The physiologic role of these extra-cellular activi- inflammatory mediators TNF, IL-1, and IL-6; the Th2 cyto-
ties is uncertain. Of more evident in vivo relevance is that kines IL-4, IL-5, IL-10, and IL-13; the alarmin IL-33;
the negatively charged surface of heparin enables activation chemotactic factors including IL-8, macrophage inflamma-
of factor XII. This zymogen then activates kallikrein, an tory protein (MIP)-1, CXCR1, CXCR2, and RANTES
enzyme that in turn cleaves high-molecular-weight kinino- (regulation upon activation normal T cell expressed and
gen to generate bradykinin, a potent mediator of vascular presumably excreted); and growth factors for fibroblasts,
leak. This mechanism contributes to the antihistamine- blood vessels, and other cells such as bFGF, VEGF, and
resistant edema observed in patients with hereditary angio- platelet-derived growth factor (PDGF).91 IL-17 is detected
edema from lack of C1 esterase inhibitor, an inhibitor of in tissue mast cells and can be generated by mast cells
activated factor XII and kallikrein.83 stimulated in culture.92-94 As noted earlier, some of these
Pre-Formed Cytokines and Chemokines. Mast cells are cytokines may also be stored pre-formed in granules for
able to store certain mediators in their granules for rapid rapid release. The panel of mediators generated depends on
release. The first of these mediators to be documented was the state of differentiation, as well as the activating signal,
TNF.84 In the mouse, this pool of TNF is implicated in the and may occur in the absence of degranulation.
rapid recruitment of neutrophils to the peritoneum during
peritonitis.42,85 Exocytosed granules appear to release TNF ROLE OF MAST CELLS IN HEALTH
gradually into the environment, enhancing the immuno AND DISEASE
stimulatory effect of the cytokine as TNF-containing gran-
ules reach draining lymph nodes, helping to promote The understanding of the role of mast cells in health and
development of the mature immune response.86-88 Other disease has been aided greatly by the availability of mice
cytokines that may be stored in granules include IL-4, IL-16, that lack mast cells entirely or are deficient in mast cell
basic fibroblast growth factor (bFGF), and vascular endo- specific products such as heparin or granule proteases. These
thelial growth factor (VEGF). Stored chemokines include mice are viable, excluding an obligate role for mast cells in
the neutrophil chemoattractants CXCL1 and CXCL2.89 the structure and function of most tissues. Yet when they
are under physiologic stress, such as that imposed by experi-
mental models of disease, multiple differences from wild-
Newly Synthesized Mediators: Lipid Mediators,
type mice become evident. In many cases, these abnormalities
Cytokines, Chemokines, and Growth Factors
may be corrected by engraftment with cultured mast cells,95
Beyond pre-formed mediators stored within granules, acti- directly implicating mast cells in a remarkably broad range
vated mast cells elaborate a range of mediators that are of disease processes (Table 15-1). The extrapolation of such
generated de novo. These mediators are released minutes to experiments to human disease is limited by multiple factors.
hours after stimulation, broadening and extending the Most evidently, mice are not humans, and the experimental
impact of activated mast cells on surrounding tissues. systems used typically model at best only certain aspects of
Lipid Mediators. Within minutes of activation, mast the corresponding human condition. Further, many of these
cells begin to release metabolites of membrane phospholip- mice exhibit off-target phenotypes outside of the mast cell
ids. This process is rapid because the relevant enzymes, lineage, complicating interpretation of the data, especially
beginning with phospholipase A2, which is responsible for when results in one mast celldeficient mouse strain diverge
harvesting phospholipids from the outer leaflet of the from those observed in another. These discrepancies have
nuclear membrane, are already present in the cytoplasm and occasioned considerable controversy in the mast cell
need only to be activated through signals mediated by related literature.96,97 However, together with in vitro exper-
calcium flux and the phosphorylation of intra-cellular mes- iments using human mast cells and careful study of
sengers. The hallmark prostaglandin of human mast cells is individuals in different states of health and disease, animal
prostaglandin D2 (PGD2), which induces bronchoconstric- experiments have contributed greatly to the understanding
tion, vascular leak, and neutrophil recruitment. Smaller of mast cell physiology and pathophysiology.
amounts of other prostaglandins, as well as thromboxane,
are also made. Mast cellderived leukotrienes (LTs) have Mast Cells in Allergic Disease: Anaphylaxis,
similar but generally more potent activity. LTC4 (the major Allergic Disease, and Asthma
LT species generated by human mast cells), together with
its metabolites LTD4 and LTE4, serve as potent inducers of Mast cells are the primary mediator of IgE-mediated sys-
vascular leak. Smaller amounts of the chemotaxins LTB4 temic anaphylaxis. This phenomenon is demonstrated in
and platelet-activating factor (PAF) are also generated. The mast celldeficient mice, in which resistance to anaphylaxis
particular profile of lipid mediators produced by mast cells may be restored by engraftment with mast cells.98 In humans,
can change with local environmental signals and the result- participation of mast cells in anaphylaxis has been docu-
ing state of differentiation. Thus mast cells from skin gener- mented through the detection of elevated serum levels of
ate PGD2 in excess of LTC4, whereas both species are tryptase, a specific marker of mast cell degranulation.63 Of
elaborated in roughly equal proportion by mast cells isolated note, anaphylaxis may be mediated by IgG, a context in
from lung and osteoarthritic synovium.90 which mast cells play only a partial role, while neutrophils
Cytokines, Chemokines, and Growth Factors. Within assume primacy.99 Mast cells accumulate in atopic mucosal
hours of activation, mast cells begin to elaborate newly tissues where they degranulate upon exposure to antigen
synthesized mediators as the end result of induced gene and contribute prominently to tissue edema and the over-
transcription and translation. The range of such mediators production of mucus.100 Mast cells also accumulate in the
is broad (see Figure 15-3). They include the canonical pro- asthmatic airway, including within the smooth muscle

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256 PART 2 CELLS INVOLVED IN AUTOIMMUNE DISEASES AND INFLAMMATION

TABLE 15-1 Participation of Mast Cells in Murine Models of lining the airways, and have been implicated by human and
Disease (Partial List) animal data in airway hyper-reactivity and mucosal changes.
Beneficial to Host Harmful to Host
Angiogenesis Anaphylaxis*
Mast Cells in Nonallergic Inflammation
Anxiety control Arthritis*
Pathogen Defense: Mast Cells as Sentinels
Bacterial cystitis Aortic aneurysm*
of Innate Immunity
Bacterial peritonitis* Asthma*
The involvement of mast cells in atopic disease is clear but
Bone remodeling Atherosclerosis*
does not explain their remarkable evolutionary conserva-
Brain trauma Atopic dermatitis tion.101 Rather, mast cells must somehow contribute to the
Dengue fever Atrial fibrillation survival of the organism. The most probable mechanism by
Dermatitis* Autoinflammatory disease
which mast cells convey a survival advantage is in the
defense against infection. This role is suggested by the local-
Envenomation* Bacterial cystitis ization of mast cells near epithelial surfaces, around blood
Glomerulonephritis* Burn vessels, and in other locations of potential invasion by
Graft tolerance* Bullous pemphigoid* pathogens.
Mast cells are competent defensive cells against bacteria.
Intestinal epithelial barrier* Cardiac fibrosis
They express TLRs and other receptors against bacterial
Lung infection, bacterial* Cardiomyopathy antigens, and upon activation are able to phagocytose bac-
Lung infection, viral* Chronic obstructive pulmonary disease teria and generate anti-microbial molecules such as cathe-
Parasites, intestine* Colitis licidin.102,103 However, given their relatively small numbers,
the most important function of mast cells in immune
Parasites, muscle Colon polyps
defense is likely as sentinels, monitoring for early traces of
Parasites, skin Dermatitis, irritant* infection and rapidly mobilizing neutrophils and other
Peptic ulcer disease Dermatitis, sunburn inflammatory cells when needed. Such a role has been
Thromboembolism Gastritis
clearly demonstrated in mouse models of bacterial peritoni-
tis, in which mast celldeficient animals exhibit a high
Tumor suppression* Glomerulonephritis* mortality. This susceptibility correlates with delayed recruit-
Wound healing* Gout ment of neutrophils via TNF and leukotrienes; both neu-
Immune complex peritonitis* trophil influx and survival may be restored by correction of
the mast cell deficit, although in the case of severe infec-
Ischemia-reperfusion injury
tion, mast cell TNF may actually contribute to mortal-
Kidney injury* ity.85,104-106 Clearance of bacteria from the lungs is delayed
Lung fibrosis in mast celldeficient mice and can be similarly restored by
Malaria exogenous mast cells.85 Analogous observations have been
made in other models of bacterial infection. Thus mast cells
Multiple sclerosis*
likely play an important role in the defense of the host
Myositis* against bacterial infection.
Neurogenic inflammation* Mast cells are also implicated in the defense against para-
Obesity*
sites. Mast celldeficient animals exhibit abnormal clear-
ance of multiple parasites from the gut and skin, in a manner
Peritonitis, irritant* promoted by IgE.107,108 The mechanism of this defense
Peritoneal adhesions remains uncertain but may include direct attack upon
Pneumonitis pathogens, recruitment of inflammatory lineages such as
neutrophils and eosinophils, and lysis of tight junctions in
Renal fibrosis*
the mucosal lining to facilitate the expulsion of hel-
Scleroderma minths.107,109,110 More limited data implicate mast cells in
Sepsis* the defense against viruses, including dengue, vaccinia, and
Tumor angiogenesis cytomegalovirus. The role of mast cells in this setting
includes recruitment of CD8 T cells and other cytotoxic
Mast cells are implicated in these processes by virtue of phenotypic lineages, as well as production of type I IFNs to help neigh-
abnormalities in mast celldeficient mice or in mice lacking mast boring cells resist infection.
cell-specific mediators. The asterisk (*) indicates that the phenotype has
been shown to be reversible by engraftment with cultured mast cells,
providing more direct evidence for a role for this lineage. Mast Cells and the Adaptive Immune Response
In addition to recruiting innate effector cells, mast cells
mobilize T and B lymphocytes, the adaptive arm of the
immune system.91 Mast cells may express major histocom-
patibility complex (MHC) II, as well as co-stimulatory mol-
ecules such as CD80 and CD86, rendering them effective
antigen-presenting cells for CD4 T cells. Mast cells can also

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CHAPTER 15 Mast Cells 257

mobilize and potentiate CD8 T cell responses.111 They can matomyositis, exhibit increased density of mast cells in
migrate from peripheral tissues to lymph nodes carrying inflamed muscle; a similar phenotype is noted in dermato-
antigen and contribute to the recruitment of T cells to myositis skin.130,131 Murine studies suggest that these cells
lymph nodes via mediators including MIP-1 and TNF.8,86,112 may play a role in disease pathogenesis, because experimen-
Indeed, infection-induced lymph node hyperplasia is abro- tal myositis is attenuated in mast celldeficient animals, a
gated in the absence of mast cells. Further, mast cells can defect that corrects partially with mast cell engraftment.131
recruit CD4 and CD8 effector T cells to peripheral tissues The participation of mast cells in arthritis is discussed in
via LTB4, among other mediators.113-115 Finally, mast cells detail later.
contribute to the migration of cutaneous Langerhans cells
and other dendritic cells to lymph nodes via mediators Mast Cells as Anti-Inflammatory Cells
including histamine.116-118 By means of the inducible expres-
sion of CD40L and cytokines, mast cells stimulate B cells Within the past decade, it has become evident that
and induce class switching to IgA or IgE.119,120 The physi- mast cells may also help moderate the immune response.
ologic importance of these effects will vary with circum- One mechanism for this effect is degradation of pro-
stances. For example, under some conditions, delayed-type inflammatory mediators. Mast cell proteases may cleave
hypersensitivity responses in skin are dependent on mast and inactivate the cytokines IL-5, IL-6, IL-13, IL-33, and
cells, whereas under other conditions, mast cells play no TNF, as well as endothelin-1 and the anaphylatoxin
role.91 The potential importance of the mast cell in adaptive C3a.69,75,132-134 Proteases also degrade tissue-derived danger
immunity is highlighted by the recent demonstration that signals, including heat shock protein 70.75 The importance
mast cell activators are effective vaccine adjuvants.87 of this anti-inflammatory activity has been demonstrated
in a murine sepsis model, where mast cells reduced mortal-
ity by restraining excess inflammation in a protease-
Neurogenic Inflammation
dependent manner.134
In addition to their perivascular localization, mast cells More broadly, mast cells can produce mediators such
cluster near and sometimes within peripheral nerves. A as IL-10 that have immunosuppressive activity, and even
discrete function for them in these locations has not yet otherwise pro-inflammatory mediators such as TNF and
been defined, although the potential for bidirectional neu- granulocyte-macrophage colony-stimulating factor (GM-
roimmune interaction is clear. Mast cell mediators such as CSF) can be immunosuppressive under appropriate cir
histamine can directly activate neurons, whereas mast cells cumstances.135,136 Thus mast cells promote immunologic
residing near stimulated neurons can be induced to degranu- tolerance to skin grafts and limit tissue inflammation related
late.121 Indeed, vascular leak and neutrophil infiltration to ultraviolet light injury.72,136-138 Data suggest a role for mast
arising from infiltration of skin with the neurogenic media- cellproduced IL-2 in the promotion of Treg responses that
tor substance P are mediated by mast cells.122,123 Thus limit experimental dermatitis, as well as in the development
neurons might recruit mast cells as local effectors of neuro- of IL-10producing regulatory B cells.139,140 Mast cells may
genic inflammation. play a permissive role in the immunosuppressive activity of
murine myeloid-derived suppressor cells, an activity that
may be beneficial or harmful to the host.141,142
Autoimmune Disease
Reconstitution experiments in mast celldeficient mice
have implicated mast cells in a variety of pathologic condi- Mast Cells and Connective Tissue
tions (see Table 15-1), including murine models of auto Wound Healing and Tissue Fibrosis
immune diseases such as bullous pemphigoid, multiple
sclerosis, scleroderma, and inflammatory arthritis. In mice Mast cells have long been noted to accumulate at the
with pemphigoid, mast cells that are triggered via IgG anti- borders of healing wounds. In healthy human subjects
bodies against a hemidesmosomal antigen recruit neutro- undergoing experimental wounding and recurrent biopsies,
phils, which are responsible for blister formation.44 The role mast cell numbers increase sixfold by day 10 after the initial
of mast cells in murine experimental autoimmune encepha- incision. These mast cells localize preferentially to fibrotic
lomyelitis (EAE) is more complex. Although the resistance areas of the wound and strongly express IL-4, a cytokine
of mast celldeficient W/Wv mice to EAE corrects with capable of inducing fibroblast proliferation and collagen
mast cell engraftment, these cells fail to repopulate the synthesis.143 In vitro studies confirm the stimulatory effects
brain and spinal cord, indicating that mast cells are not of mast cells on fibroblast growth144; candidate fibroblast
obligate local effector cells in this model.124,125 One mecha- mitogens in addition to IL-4 include tryptase, histamine,
nism for this activity appears to be the promotion of the LTC4, and bFGF. Indeed, W/Wv animals exhibit delayed
adaptive immune response, because mast cell engraftment contracture and healing of skin wounds in a manner repa-
into W/Wv animals improves T cell responses to immuniza- rable by local engraftment with cultured mast cells, although
tion with the inciting myelin antigen.126,127 The contribu- other mast celldeficient mice exhibit no defect in wound
tion of mast cells to human scleroderma remains unknown, healing.145,146
although they are recognized to express TGF- in sclero Mast cells also accumulate in sites of pathologic fibrosis,
dermatous skin and to interact closely with local lympho- including the skin and lungs of patients with scleroderma.
cytes and fibroblasts, even to the point of gap junction Because experimental skin fibrosis proceeds in mast cell
formation and therefore cytoplasmic continuity with the deficient mice with few if any differences in intensity or
latter cells.128,129 Humans with polymyositis, but not der kinetics, it is unlikely that mast cells are an obligate effector

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258 PART 2 CELLS INVOLVED IN AUTOIMMUNE DISEASES AND INFLAMMATION

lineage in human scleroderma, although they may contrib-


ute to disease progression.

Bone
Mast cells are also implicated in the remodeling of bone.
Mast cells accumulate in sites of healing fracture, and under
normal circumstances, they may contribute to normal bone
turnover.147,148 However, mast cells accumulate in osteopo-
rotic bone, and systemic osteoporosis is a known complica-
tion of systemic mastocytosis.149,150 Heparin is one potentially
important mediator of bone loss because it directly promotes
differentiation and activation of osteoclasts.151 Mast cell
products such as IL-1, TNF, and MIP-1 have similar
activity.

Angiogenesis Figure 15-4 Mast cells in the rheumatoid synovium. Stained red by an
antibody against tryptase, mast cells are abundant in this synovial biopsy
Another potentially important activity of mast cells on the from a patient with chronic rheumatoid arthritis. Note the proliferation
stroma is the promotion of angiogenesis. Mast cells are not of mast cells in the synovial sublining. (From Nigrovic PA, Lee DM: Synovial
required for the development of the normal vasculature, as mast cells: role in acute and chronic arthritis. Immunol Rev 217:1937,
is evident in the viability of mast celldeficient mice. 2007.)
However, mast cells cluster at sites of early blood vessel
growth in tumors and contribute appreciably to physiologic
angiogenesis under certain experimental conditions.152,153 TABLE 15-2 Joint Diseases with Documented Synovial
Heparin was the first proangiogenic mast cell mediator iden- Mastocytosis
tified; bFGF and VEGF are other potent stimulators of Chronic infection
endothelial migration and proliferation. Gout
Juvenile idiopathic arthritis
Mast Cells in Arthritis Osteoarthritis
The normal synovium is populated by a limited number of Psoriatic arthritis
mast cells. These cells are not found in the immediate lining Rheumatoid arthritis
layer but rather reside in the synovial sublining near blood
vessels and nerves, constituting almost 3% of cells within Rheumatic fever
70M of the synovial lumen.154 In both mice and humans, Traumatic arthritis
their phenotype is principally MCTC, similar to mast cells Tuberculosis
found in most other connective tissue sites.23,155 The several-
fold increased density of mast cells in the immediate vicin-
ity of the synovial lining, compared with more distant
connective tissue, supports the hypothesis that mast cells local replication but rather by recruitment of circulating
contribute to immune surveillance of the articular cavity.23 progenitors.161 Although the signals driving this recruit-
Extrapolating from the activity of mast cells near other ment are unknown, inflammatory cytokines such as TNF
vulnerable body cavities, such as the peritoneum, it is likely enhance expression of the mast cell chemotactic and sur-
that synovial mast cells help monitor the joint for early vival factor SCF on synovial fibroblasts, suggesting one
evidence of infection. mechanism.162 Indeed, degree of inflammation is the best
In the presence of inflammatory arthritis, the population predictor of the number of mast cells within the joint.156,163,164
of synovial mast cells expands remarkably (Figure 15-4). Incompletely identified factors in RA synovial fluid can
More than two-thirds of synovial specimens from patients potently promote mast cell differentiation and growth.165
with rheumatoid arthritis (RA) exhibit abnormal numbers Hyperplasia of the mast cell population is not specific for
of mast cells, averaging in excess of tenfold above normal.156 RA but is observed in a wide range of inflammatory joint
Consistent with these histologic findings, synovial fluid disorders (Table 15-2). Expansion is also noted in osteoar-
from rheumatoid joints contains appreciable quantities of thritis (OA), often to densities observed in RA.166 The
histamine and tryptase.157,158 Unlike the normal joint, in the levels of histamine and tryptase in OA synovial fluid are
RA joint both subtypes of mast cells are present in roughly also comparable. Interestingly, unlike in RA, the expansion
equal numbers, with MCT cells located nearer to the pannus in OA results from an increase in numbers of MCT mast
and infiltrating leukocytes, whereas MCTC cells cluster in cells, the subtype generally associated with T cells and
deeper, more fibrotic areas of the synovium.23 Mast cells inflammation.23,167
have been noted near the junction of pannus and carti- Studies of human synovial mast cells confirm that they
lage.159 Rare mast cells are also identified in synovial fluid.160 can be activated via pathways relevant to arthritis biology,
The absence of mitotic figures and of staining for the pro- including complement, Fc receptors, and TLR ligands.41,168,169
liferation antigen Ki-67 suggests that they arise not from Mast cells are also a potential source of citrullinated

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CHAPTER 15 Mast Cells 259

Histamine,
Endothelium
Leukotrienes, Synovial
Permeability TNF, IL-1 mast cell
Adhesion
molecules ( )
Tryptase, Normal bone
IL-4, TNF,
Leukocyte

Acute arthritis
bFGF
recruitment TNF, IL-1,
and activation Cartilage
Chemokines, Synoviocyte
Eicosanoids activation
PMNs
(fibroblast,
Elastase
PMN Monocyte macrophage)
Lymphocyte
Chondrocyte
activation
bFGF, PDGF, Histamine, IL-1
LTC4, histamine, MMPs
tryptase
Heparin,

Chronic arthritis
Angiogenesis Fibroblast,
bFGF,
VEGF proliferation
Tryptase, Pannus Osteoclast
chymase, differentiation
IL-4 and bone
Heparin, MIP-1,
remodeling
TNF, IL-1

Matrix remodeling
and fibrosis

Figure 15-5 Potential roles of mast cells in acute and chronic arthritis. In the acute phase of joint inflammation, mast cells may contribute to initia-
tion of arthritis by inducing vascular permeability, recruiting and activating circulating leukocytes, and stimulating local fibroblasts and macrophages.
In established arthritis, these activities may be joined by effects on the stroma, including the promotion of pannus formation, angiogenesis, fibrosis,
and injury to cartilage and bone. Potential anti-inflammatory effects of mast cells are not depicted. The mediators listed are representative and do not
represent a complete list. bFGF, Basic fibroblast growth factor; IL, interleukin; LTC4, leukotriene C4; MIP-1, macrophage inflammatory protein-1; MMP,
matrix metalloproteinase; PDGF, platelet-derived growth factor; PMN, polymorphonuclear neutrophil; TNF, tumor necrosis factor; VEGF, vascular
endothelial growth factor. (From Nigrovic PA, Lee DM: Synovial mast cells: role in acute and chronic arthritis, Immunol Rev 217:1937, 2007.)

autoantigens implicated in RA, although their relative these models, mast cells resident in tissue for the purpose
importance in this context is unknown.170 of immune defense become co-opted by autoantibodies to
initiate inflammatory disease (Figure 15-5, top). Mast cells
have also been implicated in monosodium urate crystal
Mast Cells in Acute Arthritis: Insights from
sensing and cytokine production in experimental gout.54
Animal Models
Of note, not all mice lacking mast cells are resistant to
Experimental work in mice has shed light on the role of experimental arthritis.45,176,177 The basis for this discordance
mast cells in inflammatory arthritis. Several mast cell is not fully understood but likely reflects factors that include
deficient strains demonstrate striking resistance to arthritis the intensity of the arthritogenic stimulus and the suscep-
induced by IgG autoantibodies, a defect that may be repaired tibility of the background strain. This suggestion is rein-
by engraftment with cultured mast cells expressing recep- forced by studies in mice lacking specific mast cell proteases,
tors for IgG and C5a.39,45,171-173 A number of mechanisms where partial protection from arthritis is evident, but only
contribute to this arthritogenic activity. First, mast cells in the context of a submaximal arthritis stimulus.67,178 These
induce vascular permeability, facilitating entry of autoanti- data suggest that mast cells represent one potential con-
bodies into the joint.174,175 Second, mast cells release pro- tributor to joint inflammation but that their importance will
inflammatory mediators including IL-1 that help establish vary with context.
inflammation, presumably via effects on endothelium and
other local populations such as macrophages and fibro- Mast Cells in Chronic Arthritis
blasts.45,173 These actions appear to be most critical at the
initiation of disease, constituting a jump start for acute In contrast to the acute phase of joint inflammation, the
inflammation within the joint. This function is in line with role of mast cells in established arthritis is poorly under-
the activity of mast cells in other models of IgG-mediated stood. The sheer numbers of these cells in arthritic synovium
disease, such as IgG-mediated immune complex peritonitis, implies a substantial role. Taking into account the spectrum
murine bullous pemphigoid, and anaphylaxis. In each of of mast cell activity elsewhere, it is likely that mast cells

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260 PART 2 CELLS INVOLVED IN AUTOIMMUNE DISEASES AND INFLAMMATION

participate both in the inflammatory process and in the Mast Cell Protease Inhibition
mesenchymal response (Figure 15-5, bottom).166
An ongoing contribution of mast cells to inflammatory Mast cell proteases make up the bulk of the protein
arthritis is suggested by several observations. First, as noted, content of these cells and are in many cases largely or
prominent among infiltrating synovial mast cells are MCT entirely specific to this lineage, as previously described.
cells, typically associated elsewhere with the elaboration of Targeting these proteins therefore offers a pathway to
cytokines such as IL-6 with documented pathogenic activity selective mast cell antagonism, in particular because mast
in RA. Immunofluorescence staining has identified TNF cell proteases are implicated directly in arthritis pathogen-
and IL-17 in mast cells from inflamed synovium,7,93,179 and esis, both as pro-inflammatory factors and as mediators of
the elaboration of other pro-inflammatory mediators is tissue injury.67,178,185 Protease inhibitors have been gener-
probable. Second, mast cells from RA but not OA synovium ated but are not currently in active clinical development
express the receptor for the anaphylatoxin C5a, a mediator for arthritis.186
readily documented in synovial fluid.168 Immune complexes
within RA joints represent a likely pathway to activation SCF/c-Kit Antagonism
of synovial mast cells.180 Indeed, ultrastructural data support
ongoing degranulation of mast cells in the RA synovium.167 Given the critical importance of the SCF/c-Kit axis for the
Finally, studies of c-Kit inhibitors in murine and human development and survival of mast cells, attention has
arthritis suggest efficacy, although it remains unclear focused on the potential of kinase inhibitors as mast cell
whether these agents functionally antagonize tissue mast antagonists. Although no inhibitors are fully specific to
cells and whether such antagonism explains their efficacy, c-Kit, the tyrosine kinase inhibitors imatinib and mastinib
because these agents have an impact on multiple kinases and the downstream protein kinase C inhibitor midostau-
and affect a broad range of lineages.181,182 rine exhibit relative selectivity for c-Kit and have clinical
The effect of mast cells on the established inflammatory utility in some cases of systemic mastocytosis.187 These
synovial infiltrate is difficult to predict. As in acute arthritis, treatments may be complicated by neutropenia and throm-
activated mast cells may promote the recruitment and acti- bocytopenia, reflecting the importance of c-Kit in other
vation of leukocytes. Alternately, protease cleavage of hematopoietic lineages. Imatinib is effective in murine
inflammatory mediators and the elaboration of cytokines arthritis, in doses that affect in vitro mast cell activation;
such as IL-10 and TGF- could suppress inflammation, similarly, imatinib treatment of human synovial cultures
potentially by promoting Treg function, as has been observed induces apoptosis of mast cells and limits cytokine produc-
in tolerance of skin grafts in mice.137 tion.7,93,181 However, the action of this agent on multiple
Mast cells likely modulate the stromal response to synovial lineages obscures the role of mast cell targeting in
inflammation. Expansion and activation of synovial fibro- these results, even in vitro.181 Interestingly, imatinib is less
blasts is a key pathogenic process within RA, and the effective at antagonizing c-Kit stimulation from immobi-
capacity of mast cells to promote such changes is well estab- lized SCF, as between tissue-resident mast cells and their
lished. Through interaction with osteoclasts, mast cells adjacent fibroblasts.17 Further, both in vitro and in vivo data
could promote both focal erosions and periarticular osteo- suggest that c-Kit signaling can be at least partially replaced
penia. Mast cell tryptase not only promotes inflammation by other survival signals from the inflamed environment,
but can contribute directly to joint injury by activating such as IL-33.10,188 Together, these results suggest that c-Kit
synovial fibroblasts to produce chemokines and by cleaving blockade is unlikely to represent a mast cellspecific thera-
substrates such as cartilage aggregan, both directly and peutic approach, although effects on mast cells may cer-
through proteolytic activation of matrix metalloprotein- tainly contribute to the clinical improvement suggested by
ases.67,178,183-185 Finally, by producing proangiogenic media- series of patients with rheumatic diseases, including RA,
tors, mast cells may enable growth of the vascular supply treated with kinase inhibitors.182,189-191
required for the profound expansion of the thin synovial
layer into thick pannus. Confirmation of these roles awaits Signaling Pathways
further experimental data.
Mast cells share pathways of intra-cellular signaling
with other cells, but disproportionate use of individual
Therapeutic Potential of Mast Cell Antagonism
pathways could offer the potential for pharmacologic
in Rheumatic Disease
specificity. Examples of such pathways include the delta
The broad involvement of mast cells in health and disease isoform of phosphoinositide 3 kinase (PI3K) and Ras
suggests that targeting this lineage could have potential guanine nucleotide-releasing protein-4 (RasGRP4). PI3K
therapeutic value. Multiple strategies for blocking mast cell is involved in intra-cellular signaling in mast cells, includ-
activity are under active consideration.186 In the context of ing downstream of c-Kit, and mice lacking this receptor
atopic disease, targeting IgE and its receptor FcRI offers exhibit a partial deficiency of mast cells in some tissues and
the appealing prospect of antagonizing a pathway of direct a striking reduction of IgE-mediated signaling and anaphy-
disease relevance while retaining most protective mast cell laxis.192,193 Mice lacking RasGRP4, a guanine nuclear
functions. In rheumatic diseases, however, such specificity exchange factor expressed principally in mast cells, exhibit
will be more difficult to achieve because the pathways by impaired mediator production by this lineage and impaired
which mast cells are engaged, and their downstream effector inflammation in models of colitis and arthritis.194,195 Antag-
responses, are typically relevant for immune defense and are onism of targets such as these could hold the promise of
shared by multiple hematopoietic lineages. limiting the contribution of mast cells to human disease,

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CHAPTER 15 Mast Cells 261

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CONCLUSION C57BL/6 mice. J Immunol 185:18041811, 2010.
25. Gri G, etal: CD4+CD25+ regulatory T cells suppress mast cell
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CHAPTER 15 Mast Cells 263.e3

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