Download Mast cells and basophils in acquired immunity

Mast cells and basophils in acquired immunity
Jochen Wedemeyer* and Stephen J Galli**
Departments of *Pathology and 'Microbiology and Immunology, Stanford University Medical
Center, Stanford, California, USA
In this review we describe the basic biology of mast cells and basophils and discuss
their proposed effector and immunoregulatory roles in acquired immunity,
particularly the IgE-associated immune responses. While mast cells and basophils
share a number of similarities, they also differ in many aspects of natural history
and function. Both mast cells and basophils express the high affinity receptor for
immunoglobulin E (FCERI) on their surface and can be activated to secrete diverse
preformed, lipid and cytokine mediators after crosslinking of FceRI-bound IgE with
bi- or multivalent antigen. Thus, both cell types can represent important effector
cells, as well as potential immunoregulatory cells, in IgE-mediated acquired
immunity. However, mature mast cells are long-term residents of vascularized
tissues, whereas basophils are granulocytic leukocytes that circulate in mature form
and must be recruited into tissues that are sites of inflammatory or immune
responses. The similarities and differences in the natural history, mediator content
and other features of mast cells and basophils not only strongly indicate that these
cells represent distinct hematopoietic lineages that can express complementary or
overlapping functions, but also offer insights into the specific roles of these cells in
acute, late phase' and chronic aspects of adaptive or pathological IgE-associated
acquired immune responses.
While mast cells and basophils are widely regarded as important effector
cells in IgE-associated immune responses, such as those that contribute
to asthma and other allergic diseases and to host resistance to certain
parasites, these cells also may express immunoregulatory function in
such settings1"6. Mast cells contribute importantly to the expression of
many acute allergic reactions, such as anaphylaxis or the acute wheezing
provoked by allergen challenge in subjects with atopic asthma2-3*5'6.
Basophils probably also contribute to the expression of some acute IgEassociated responses, particularly anaphylaxis5. By contrast, there is less
agreement about the importance of mast cells and basophils in late
Correspondence to:
Dr Stephen J. Galli, phase reactions or chronic allergic inflammation. Before discussing
Department of Pathology
recent evidence, much of it derived from in vivo studies in mice, that
L-23S, Stanford University indicates that mast cells can indeed contribute importantly to late phase
Medical Center, 300
reactions and chronic allergic inflammation, we will first review the
Pasteur Drive, Palo Alto,
CA 94305-5324, USA basic biology of these two cell types.
British Medical Bulletin 2000; 56 (No. 4): 936-955
C The British Council 2000
Mast cells and basophils in acquired immunity
Basic basophil biology
Basophilic granulocytes (basophils) derive their name from the affinity of
their cytoplasmic granules for certain basic dyes. Like the other granulocytes (i.e. neutrophils and eosinophils) basophils are of hematopoietic
origin and typically mature in the bone marrow and then circulate in the
peripheral blood, from where they can then be recruited into the tissues1-7.
They are the least frequent of the granulocytes, in humans ordinarily
accounting for less than 0.5% of circulating leukocytes17. The basophil's
prominent metachromatic cytoplasmic granules allow unmistakable
identification in Wright Giemsa- or May-Griinwald Giemsa-stained films
of blood or bone marrow. Under physiological conditions, basophils have
a short life-span of several days. Interleukin-3 (IL-3) promotes the
production and survival of human basophils in vitro and can induce
basophilia in vivo1'2. Findings in wild type and EL-3^~ mice (that can not
produce IL-3) indicate that IL-3 is not necessary for the development of
normal numbers of bone marrow or blood basophils, but is mandatory
for the striking bone marrow and blood basophilia associated with certain
Th-2 cell-associated immunological responses1-7'9.
Mediators stored preformed in the cytoplasmic granules of basophils
include chondroitin sulphates, proteases and histamine1-7. Chondroitin
sulphates probably contribute to the storage of histamine and neutral
proteases, and basophils are the source of most of the histamine found
in normal human blood. Upon antigen crosslinking of IgE, aggregation
of FCERI can induce 'degranulation' and the extracellular release of the
preformed granule mediators. Furthermore, such FceRI-dependent
activation of basophils can induce the de novo production and secretion
of leukotriene C4. Although the ability of basophils to produce cytokines
has been less extensively explored than has mast cell cytokine production, several reports have demonstrated that mature human
basophils can release substantial amounts of IL-4 and IL-13 in response
to FceRI-dependent activation10"12. It is possible, although not yet
proven, that the release of IL-4 and IL-13 by basophils may play a role
in enhancing IgE production or driving Th-2 differentiation1-7-10"12.
The extent of the biochemical and functional similarities between
basophils and mast cells continue to be explored. Li et al., in confirmation
of earlier studies, found that the basophils in the peripheral blood of
normal individuals expressed the basophil marker Bsp-1, but little or no
surface kit or cell-associated tryptase, chymase, or carboxypeptidase A
(CPA)13. However, the metachromatic cells in the peripheral blood of
subjects with asthma, allergies, or drug reactions not only were increased
in number, but many of them expressed surface kit, as well as tryptase,
chymase, and CPA13. These findings indicate that the cytoplasmic granule
content of human basophils and mast cells may exhibit even more overlap
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Allergy and allergic diseases: with a view to the future
than had been previously supposed. As noted by Li et al., their findings
could reflect consequences of the cytokine-dependent regulation of
basophil phenotype during allergic disorders.
Basic mast cell biology
Mast cells, like basophils, are derived from CD34+ hematopoietic
progenitor cells but, unlike basophils, mature mast cells ordinarily do
not circulate in the blood. Mast cells typically complete their differentiation in vascularized tissues (and, especially in rodents, in serosallined cavities). However, unlike mature basophils, morphologically
mature mast cells can be very long-lived and can retain their ability to
proliferate under certain conditions7'14. Mast cells are found particularly
around blood vessels, in close proximity to peripheral nerves, and
beneath epithelial surfaces that are exposed to the external environment,
such as those of the respiratory and gastrointestinal tract and skin14"16.
Studies in murine rodents, non-human primates, and humans indicate
that many aspects of mast cell development and survival are critically
regulated by stem cell factor (SCF), the ligand for the c-kit tyrosine
growth factor receptor, which is expressed on the mast cell surface7-16'17.
For example, local treatment of mice with SCF can induce marked local
increases in mast cell numbers, reflecting both enhanced recruitment/
retention and/or maturation of mast cell precursors and proliferation of
more mature mast cells18. By contrast, withdrawal of exogenous SCF
induces apoptosis in mast cells in vitro as well as in two16-19. Besides its
role in mast cell proliferation and differentiation, SCF can stimulate
and/or enhance mast cell function. Not only can SCF augment IgEdependent mast cell mediator release and directly induce secretion of
mast cell products1'3'7, but treatment with SCF in doses that do not
increase the number of mast cells can result in higher survival rates in a
mouse model of acute bacterial peritonitis20. Other cytokines and
growth factors which regulate mast cell development and differentiation
include IL-3, IL-4, IL-9, IL-10, and NGF7-14.
Mast cells begin to express the high affinity receptor for Immunoglobulin E (FceRI) early in their development, but apparently only after
they undergo lineage-commitment21. Crosslinking of IgE bound to the
FceRI, with resulting aggregation of FceRI, represents the best studied
and most important trigger of mast cell activation in acquired
immunological responses (see below).
Mast cell granules stain metachromatically with certain basic dyes,
probably primarily reflecting the granules' content of proteoglycans
such as chondroitin sulphates and heparin. Chondroitin sulphate and
heparin proteoglycans are thought to bind histamine, neutral proteases,
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Mast cells and basophils in acquired immunity
and carboxypeptidases primarily by ionic interactions and, therefore,
contribute to the packaging and storage of these molecules in the cells'
cytoplasmic granules. Mast cells are regarded as the only cells that store
true heparin in their granules, a feature which distinguishes them from
basophils7'14. Mice that lack the enzyme N-deacetylase/N-sulphotransferase-2 (NDST-2) are unable to produce fully sulphated {i.e. 'true')
heparin22'23. The phenotypic abnormalities of these 'heparin knock-out'
mice so far appear to be confined to mast cells, which exhibit severe
defects in their granules, with impaired storage of certain proteases and
reduced content of histamine22'23. When mast cells' cytoplasmic granule
matrices are exposed to physiological conditions of pH and ionic
strength during degranulation, the various mediators associated with the
proteoglycans dissociate at different rates - histamine very rapidly but
tryptase and chymase much more slowly14.
Studies in genetically mast cell-deficient and congenic normal mice
indicate that mast cells account for nearly all of the histamine stored in
normal tissues, with the exception of the glandular stomach and the
central nervous system (CNS)24. Histamine mediates its action via the
histamine receptors 1-3, which can transduce signals leading to a variety
of responses including vasodilation, bronchoconstriction, and markedly
enhanced permeability of post-capillary venules25. Accordingly,
histamine (in humans) or histamine and serotonin (in mice and rats) are
key mediators for some of the prominent signs and symptoms associated
with acute allergic reactions7-14.
Another important group of preformed, cytoplasmic granuleassociated mediators is the neutral proteases. The two most important
types of serine proteases found in mast cell granules are chymases and
tryptases. In the mouse, at least 5 different cytoplasmic granule-associated
chymases and 2 different granule-associated tryptases have been described
at the protein level4. There appear to be multiple forms of human tryptase
as well26. The specific protease content of individual mast cells can vary
depending on the mast cells' micro-environment and, therefore can
contribute significantly to the phenotypic (and therefore, functional)
heterogeneity of mast cells4'7'14. For example, populations of mast cells
found in mucosal tissue ('mucosal mast cells', MMCs) in mice express a
different pattern of proteases than do populations of mast cells in the
connective tissues or serosal cavities ('connective tissue mast cells',
CTMC, or 'serosal mast cells')4'7'14. Several biochemical functions have
been associated with the different proteases, e.g. cleavage of angiotensin I
and procollagenase and degradation of neuropeptides such as vasoactive
intestinal peptide (VIP) or calcitonin gene-related peptide (CGRP)4-14. A
useful approach to reveal further information about the diverse potential
biological roles of the many mouse mast cell proteases is to study genetargeted mice that lack specific mast cell proteases. So far, only findings
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from mice that have been 'knocked out' for mouse mast cell protease-1
(mMCP-1) have been reported27. However, C57BL/6 mice have been found
to lack mMCP-7 (a tryptase), mice with certain mutations at the mi locus
have significantly decreased expression of mMCP-4, mMCP-5 and
mMCP-62Si19, and NDST-2"^ 'heparin knock-out' mice exhibit markedly
reduced storage of mMCP-4, mMCP-5 and mMC carboxypeptidase A22*23.
The most important mast cell-derived lipid mediators are certain
cyclooxygenase and lipoxygenase metabolites of arachidonic acid, which
can have potent inflammatory activities and which may also play a role in
modulating the release process itself1'7-14. The major cyclooxygenase
product of mast cells is prostaglandin D2 (PGD2), and the major lipoxygenase products derived from mast cells are the sulphiodopeptide
leukotrienes (LTs): LTC4 and its peptidolytic derivates LTD4 and LTE47'14.
Human mast cells can also produce LTB4, although in much smaller
quantities than PGD 2 or LTC4, and some mast cell populations represent
a potential source of PAF.
Studies with mouse and/or human mast cells indicate that mast cells
represent a potential source of a vast array of cytokines and growth
factors including IL-1, IL-2, H - 3 , IL-4, IL-5, IL-6, IL-8, IL-13, IL-16,
GM-CSF, TNF-a, TGF-p, bFGF, FGF-2, PDGF, NGF, VPF/VEGF and
several C-C chemokines1'3'7'14. It appears that one of the more important
cytokines produced and released by mast cells is TNF-a. In contrast to
findings in other potential sources of TNF-a such as macrophages, Tcells and B-cells, several lines of evidence indicate that certain mature
resting mouse or human mast cells contain pools of stored TNF-a that
are available for immediate release7-14'30'31. Certain mast cell populations
may also have preformed stores of VPF/VEGF716'32. Many other
cytokines have been identified in various mast cell populations by
immunohistochemical or immunocytochemical methods; these may
represent additional cytokines which can be released in part from stored
pools. Thus, in IgE-dependent reactions, mast cells are likely to
represent an important initial source of TNF-a and perhaps other
cytokines, while other cytokines whose production is induced from new
mRNA transcripts as a result of FceRI-dependent mast cell activation
may contribute to late phase responses or even to certain aspects of
chronic allergic inflammation.
Mast cell knock-in mice
A particularly useful approach to study mast cell function in vivo is to
employ genetically mast cell-deficient WBB6T1-Kitw/Kitw-" mice (W/W
mice), which lack expression of a functional c-kit receptor due to spontaneous mutations in both copies of c-kit33'*4. This marked reduction in c-kit940
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Mast cells and basophils in acquired immunity
dependent signalling produces a complex group of phenotypic abnormalities, including a moderate anaemia and a virtual absence of tissue mast
cells, germ cells, melanocytes and interstitial cells of Cajal7'33'34. However
the mast cell activity in W/W" mice can be selectively reconstituted by the
adoptive transfer of immature mast cells cultured from the bone marrow
cells of the congenic wild type mice (bone marrow-derived cultured mast
cells; BMCMCs). These BMCMCs can be administered systemically, by i.v.
injection, or locally, by i.p or i.d. injection or by direct injection into the
anterior wall of the stomach, thus producing 'mast cell knock-in mice'7.
This approach enables investigators to assess whether the expression of
acquired immune responses (and many other biological processes) differs
in the presence or absence of mast cells. The selective local reconstitution
of mast cells in the skin or stomach of W/W" mice has the advantage of
permitting the analysis of mast cell-deficient and mast cell-containing
tissues simultaneously in the same animals.
In addition to using BMCMCs of congenic wild type origin to repair
selectively the mast cell deficiency of W/W mice, one can substitute mast
cells generated in vitro from various transgenic or knock out mice. An
additional new approach, that uses embryonic stem cell derived mast cells
(ESMCs) to reconstitute mast cell-deficient mice35, has the great advantage
of permitting the in vivo analysis of the effects of even 'embryonic lethal'
mutations of genes that can be expressed in mast cells35. Unfortunately,
there is no 'basophil knock-in' system available at this time. Even mice
that are null for the major basophil growth factor IL-3 have normal
baseline levels of bone marrow and circulating basophils and therefore
can not be regarded as strictly 'basophil-deficient' mice9.
Activation via FceRI and other mechanisms
Mast cells and basophils share the ability to bind IgE antibodies to FceRI,
the high affinity receptor for IgE36-37. Indeed high 'constitutive' levels of
FceRI expression are restricted to mast cells and basophils, while low levels
of expression can be detected in human peripheral blood dendritic cells and
monocytes, Langerhans' cells, and eosinophils37*38. By contrast, in the
absence of genetic manipulation, mice express FceRI solely on mast cells
and basophils37-38. In mast cells and basophils, FceRI has a tetrameric
structure composed of a single IgE binding a-chain, a single [J-chain (which
functions as a signal amplifier) and two identical disulphide-linked ychains36-37. All three subunits must be present for efficient cell surface
expression in rodents, while human cells can express FceRI function in
the absence of the (3-chain37-38. In humans, FceRI* cells other than mast
cells and basophils (e.g. monocytes) express primarily the ay2 form of
the receptor37'38.
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Allergy and allergic diseases: with a view to the future
Parasite
Pollen
Sensitization Phase
of IgE-Associated Acquired Immune Response*
Antigen
presenting
cell
(Dendritic cell)
Basophll
B-cell
Mast Cell
Circulating In blood
Resident hi tissue
A
IgE receptor upregulatlon
w
f
Specific tgE production
(wttti In
4. levels of total IgE)
Y
Y
Yi
Y
IgE receptor upregulation
Fig. 1 Cellular interactions in the sensitization phase of IgE-associated immune responses.
Antigen presenting cells (APC) (e.g. dendritic cells) acquire allergens at or close to epithelial
surfaces (skin, airways, intestines); these cells then migrate to regional lymphoid tissue,
where they can present peptide-MHC complexes t o naive T-cells and induce T-cell activation
and Th-2 development, with production of IL-4 and IL-13. This subsequently leads to B-cell
activation and induces specific IgE production. IgE is bound to mast cells and basophils
expressing FceRI on their cell surface. IgE bound to FCERI up-regulates FceRI expression on
both cell types. Mast cells and basophils are thereby primed to respond vigorously to a
second exposure to specific allergen.
In mast cells and basophils, the aggregation of FceRI that are occupied
by IgE (e.g. by binding of IgE to multivalent antigens) is sufficient for
initiating down-stream signal transduction events that activate the cells
to degranulate and also induce the de novo synthesis and secretion of
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Mast cells and basophils in acquired immunity
lipid mediators and cytokines36"38. It is of considerable interest, given
that the FCERI (3-chain functions as an amplifier of signalling which can
markedly up-regulate the magnitude of the mediator release response to
FceRI aggregation38, that certain mutations that result in amino acid
substitutions in the human (3-chain may be linked to atopic diseases38-39.
In vitro and in vivo studies in both mice and humans have revealed
that levels of FceRI surface expression on mast cells and basophils are
regulated by levels of IgE (Fig. I)7'40.41. For example, genetically IgEdeficient mice exhibit a greater than 80% reduction in mast cell and
basophil FceRI expression compared to the corresponding wild type
mice, and this abnormality can be corrected by administration of
exogenous monomeric IgE7'40. Up-regulation of FceRI expression can
permit mouse or human mast cells to secrete increased amounts of
mediators after anti-IgE or antigen challenge and to exhibit IgEdependent mediator release at lower concentrations of specific
antigen7'40'41. Furthermore, mast cells that have undergone IgEdependent up-regulation of surface FceRI expression, upon subsequent
FceRI-dependent activation, may secrete cytokines and growth factors
that are released in very low levels, or perhaps not at all, by mast cells with
low levels of FceRI expression7'32'40. Thus, basophils and mast cells in
subjects with high levels of IgE (as typically characterizes patients with
allergic disorders or parasite infections) can be significantly enhanced in
their ability to express IgE-dependent effector functions or, via production
of cytokines that can influence Th-2 polarization and IgE production,
such as IL-4, IL-13, and MlP-lct, may also express potential immunoregulatory functions. While the mechanism(s) by which monomeric IgE
regulates FceRI expression are not yet fully understood (at least in part,
the phenomenon reflects the ability of IgE binding to stabilize the
expression of FceRI on the cell surface), research in this area may suggest
novel therapeutic approaches for the management of allergic disease.
While we most commonly think of mast cells and basophils as
effectors of IgE-associated acquired immunity, several recent studies
have suggested that the roles of these cells in host defence may be
considerably broader than previously supposed. The HIV glycoprotein
120, as well as protein Fv (pFv), which is released into the intestinal
tract in patients with viral hepatitis, can interact with the VH3 domain
of IgE and thereby induce histamine, IL-4 and IL-13 release from human
basophils and/or mast cells42'43. Human basophils also have been shown
to respond to stimulation with immobilized secretory IgA (slgA) by
releasing both histamine and LTC4, but only if the cells had first been
primed by pretreatment with IL-3, IL-5, or GM-CSF44. Since IgA is the
most abundant immunoglobulin isotype in mucosal secretions, this
finding suggests that slgA may contribute to basophil activation during
immune responses at mucosal sites44.
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Allergy and allergic diseases: with a view to the future
A growing body of evidence also indicates that mast cells can
contribute significantly to several aspects of host defence during innate
immune response to bacterial infection16. Mast cell knock-in mice were
used to show that mast cells can represent a central component of host
defence against bacterial infection, that the recruitment of circulating
leukocytes with bactericidal properties is dependent on mast cells, and
that TNF-a is one important element of this response45-46. While certain
bacterial products - including lipopolysaccharide and at least one
fimbrial adhesin47 - can directly induce the release of some mast cell
products, pathogens may also activate mast cells indirectly during innate
immune responses via activation of the complement system16'48.
IgE-associated allergic inflammation and related diseases
Allergen challenge of sensitized individuals can elicit three types of IgEassociated responses which occur in distinct temporal patterns: (i) acute
allergic reactions, which develop within seconds or minutes of allergen
exposure; (ii) late-phase reactions, which develop within hours of
allergen exposure, often after at least some of the effects of the acute
reaction have partially diminished; and (iii) chronic allergic inflammation, which can persist for days to years. While allergic disorders like
anaphylaxis, hayfever or asthma can be thought of as exhibiting various
proportions of these three reaction patterns, specific signs and
symptoms may reflect composite responses that incorporate overlapping
components of the three classical reaction patterns (Fig. 2).
Acute allergic reactions
The major features of acute allergic reactions primarily reflect the
actions of preformed mediators released from mast cells, and in some
responses such as anaphylaxis, perhaps also from basophils3>7>14. Passive
cutaneous anaphylaxis represents one of the simplest experimental
models used to study such acute IgE-associated allergic reactions. In this
model, IgE antibodies of defined allergenic specificity are injected into
the skin and, at 24 h thereafter, the specific allergen is administered
intravenously. The ensuing FceRI aggregation in dermal mast cells
results in the secretion of all classes of mast cell-derived mediators at the
site where the IgE was injected. These products in turn produce multiple
local effects, including enhanced local vascular permeability (leading to
leakage of plasma proteins, including fibrinogen, resulting in local
deposition of crosslinked fibrin and tissue swelling), increased cutaneous
blood flow, with intravascular trapping of red cells due to arteriolar
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Mast cells and basophils in acquired immunity
Effector Phase
of IgE-Associated Acquired
Immune Response
Effects
ell
proliferati^n/functlor
ExtrKdlular matrix
Adhesion, migration and
actlvatlon/prlmlng of
circulating leukocytes,
Including basophils and
eoslnophlls
Llpld metllat0r8
Chemokines
CytoWnes
Hlstamlne
Proteases
CytoWnes
Chemokines
PAF
Proteases
VPF/VEG
and other
CytoWnes
(MMP9?)
Llpld mediators
Chemokines
Cytoklnes
PAF
FceRI
upregulatlon
Pollen
Parasite
FCERI
upregulatlon
Hlstamlne
Upld
Mediators
Cytoklnes
IgE production
Hlstamlne
Proteases
Llpld mediators
Cytoklnes
Chemokines
Hlstamlne
Llpld mediators
Proteases
Cytoklnes
Hlstamlne
Llpld mediators
Allergic diseases t
Parasite infections +
Inflammation, bronchoconstrlctlon, mucus secretion, |
cough, airway remodeling
Inflammation, Impairment
of tick feeding, Itching
Hlstamlne
Upld mediators
other mediators
Fig. 2 Cellular interactions in the effector phase of IgE-associated immune responses. Binding of multivalent allergen
to IgE bound to FceRI on the mast cell surface initiates downstream signal transduction, events that activate the cells
to degranulate and also induce the de novo synthesis and secretion of lipid mediators and cytokines. Besides a wide
array of other effects on various target cells and tissues, this mast cell mediator/cytokine production can have effects
that induce the recruitment of basophils and other leukocytes from the circulating blood into the tissues.
Subsequently, binding of IgE to multivalent antigens can induce basophil activation and degranulation.
•Activated mast cells and basophils represent potential sources of IL-4 and IL-13, but both cytokines can also be
secreted by other cells as well (e.g. T-cells).
tWhile only one example of an IgE-associated disease (asthma) or protective immune responses (to the feeding of
larval ticks) is illustrated, similar mechanisms may also contribute to the expression of other IgE-associated allergic
disorders or acquired immune responses to parasites.
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Allergy and allergic diseases: with a view to the future
dilation and increased loss of intravascular fluid from postcapillary
venules producing erythema, and other effects such as itching, due to
stimulation of cutaneous sensory nerves by histamine.
We have shown that mast cell-deficient W/W" mice are not able to express
detectable IgE-dependent PCA reactions49. By contrast, IgE-dependent PCA
reactions can readily be expressed in W/W" mice that have been selectively
repaired of their mast cell deficiency49. Similar approaches have been used
to show that essentially all of the assessed features of acute IgE-dependent
reactions elicited in the respiratory tract or stomach of mice are also mast
cell-dependent7. While humans contain cells distinct from mast cells and
basophils that express FceRI (e.g. Langerhans' cells) and these cells might,
therefore, also represent effector cells in acute allergic reactions, there is
little actual evidence for this. Moreover, many of the signs and symptoms
associated with acute allergic disorders can be explained by mast cell
degranulation; these include the swelling, itching and redness detected in
positive allergen prick tests, as well as the rhinitis and itching associated
with hayfever and allergic conjunctivitis. In contrast to the local elicitation
of allergic reactions in diseases like hayfever and asthma, systemic
anaphylaxis represents an acute hypersensitivity response to allergen that
typically involves multiple organ systems and which, if untreated, can lead
to death. Again, studies with mast cell-deficient W/W" mice indicate that the
expression of most models of IgE-dependent anaphylaxis requires mast
cells7. By contrast, active anaphylaxis to penicillin V, which is thought to be
mediated primarily by IgE, can be elicited in W/W" mice, perhaps reflecting
an important role of basophils in this response50. W/W" mice can also
express multiple pathophysiological features of IgG,-dependent
anaphylaxis, since the major receptor for IgG, (FceRIII) occurs on mouse
hematopoietic cells in addition to mast cells7.
Late phase reactions (LPRs) and chronic allergic inflammation
In addition to their roles in classic acute IgE-associated immediate hypersensitivity responses, such as anaphylaxis, several Lines of evidence indicate
that mast cells and basophils can also contribute to late-phase reactions.
Late-phase reactions occur when antigen challenge is followed, hours after
initial IgE-dependent mast cell activation, by the recurrence of signs (e.g.
cutaneous oedema) and symptoms (e.g. bronchoconstriction)2'7. Unlike
acute allergic reactions, for which suitable animal models have been
available for many years, models for LPRs in non-human subjects have
been slower to develop and to gain widespread acceptance. Several
points about human LPRs appear to be well-established: (i) the response
can be elicited by appropriate allergen challenge in the skin and upper
airways as well as in the lungs; (ii) the symptoms are usually (but not
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Mast cells and basophils in acquired immunity
always) preceded by an acute allergic reaction, and at least some of the key
pathological features of these acute responses usually resolve before the
onset of the LPR; (iii) the signs and symptoms characteristic of LPRs are
associated with the recruitment of circulating leukocytes to the sites of the
reactions; and (iv) a variety of treatments which are associated with a
reduction in the leukocyte recruitment that is elicited at sites of LPRs can
also reduce the signs and symptoms that are characteristic of these
responses. In humans, basophils are recruited to LPRs in the skin, nose and
lower airways51"53.
It is possible that the cellular infiltrates at sites of chronic allergic inflammation represent, at least in part, the result of multiple, overlapping LPRs
elicited by persistent or repeated exposure to allergen. Indeed, the inflammatory infiltrates present at sites of human experimental LPRs and naturally
occurring chronic allergic inflammation are similar in composition
(prominent eosinophils and T-cells, with smaller numbers of monocytes,
macrophages and basophils). Nevertheless, controversy persists regarding
the mechanisms involved in the initiation of late phase responses or the
development of chronic allergic inflammation. Several groups have shown
that various features of late phase reactions or chronic allergic inflammation
can be expressed in mice that lack IgE, B-cells or mast cells7*54. As a result,
interest has focused increasingly on eosinophils and Th-2 lymphocytes as key
effector cells of late phase reactions55. However, we feel that the key question
is not whether IgE and mast cells, as opposed to eosinophils or T-cells, are
mainly responsible for the pathology associated with chronic allergic
diseases, since each cell type is likely to contribute, but to identify the extent
to which particular clinically-significant characteristics of these disorders
reflect the specific contributions of distinct potential effector cell types3.
Our group has formulated the hypothesis that a mast cell-leukocyte
cytokine cascade can critically contribute to the initiation, amplification,
and perpetuation of IgE-associated allergic inflammation in the airways
and other sites7. Specifically, we propose that the activation of mast cells
through the FceRI can initiate both the acute and late-phase components
of the response, the latter orchestrated in part through the release of
TNF-a and other cytokines that can influence the recruitment and function
of additional effector cells. These recruited cells then promote the further
progression of the inflammatory responses by providing additional sources
of certain cytokines that may also be produced by mast cells stimulated by
ongoing exposure to allergen, as well as new sources of cytokines and
other mediators that may not be produced by mast cells. Certain mast cell
cytokines, such as TNF-a, VPF/VEGF, and TGF-P, may also contribute to
chronic allergic inflammation through effects on fibroblasts, vascular
endothelial cells, and other cells resident at the sites of these reactions.
Certain aspects of this hypothetical model of allergic inflammation
have already been confirmed by studies in mast cell knock-in mice and
British Medical Bulletin 2OO0;56 (No. 4)
947
Allergy and allergic diseases: with a view to the future
are also supported by more indirect lines of evidence, including data
derived from studies in human subjects. Our studies in mast cell knockin mice showed that mast cells were required for essentially all of the
leukocyte infiltration observed in the skin after challenge with IgE and
specific antigen and that ~50% of such IgE- and mast cell-dependent
leukocyte recruitment was inhibitable with a neutralizing antibody to
recombinant mouse TNF-oc56. Furthermore, we showed that either
dexamethasone or cyclosporine A (CsA) can substantially suppress: (i)
the IgE-dependent secretion of TNF-oc by mouse mast cells in vitro; (ii)
the leukocyte recruitment induced by the injection of recombinant
mouse TNF-oc into mouse skin in vivo; and (iii) the mast cell-, IgE- and
TNF-a-dependent leukocyte infiltration observed at cutaneous reaction
sites in mice in vivo57.
Are mast cells important in orchestrating eosinophil infiltration into the
airways, a hallmark of human asthma? Many studies of asthma models in
mice have suggested that the answer to this question is no. For example,
at least four studies using mast cell-deficient W/W" mice reported that
mast cells were not essential for the development of antigen-induced
infiltration of the airways with eosinophils58"61. However, in each of these
studies, the investigators used strong procedures of sensitization and
challenge, often in conjunction with an adjuvant such as alum;
approaches that favour the production of strong non-specific antibody
responses. In contrast, human subjects often express dramatic pathophysiological responses after sensitization and challenge with very low
doses of specific antigen. Notably, Kung et al., using a protocol in which
aerosol challenge with OVA was performed only twice on a single day,
found that eosinophil infiltration of the airways in W/Wv mice was < 50%
of that in the wild-type mice62. Subsequently, using mast cell knock-in
mice, we showed that mast cells can importantly contribute to the
recruitment of eosinophils to the airways, especially in a model of asthma
that does not employ alum as an adjuvant during sensitization54. Based on
these findings, we hypothesize that mast cells can indeed be critical in
regulating eosinophil infiltration during allergic inflammation in mice.
The specific mechanisms by which mast cells might regulate eosinophil
recruitment and/or activation remain to be determined, but it seems
reasonable to suggest that chemokines, and particularly eotaxin, may be
involved. Persistent chronic allergic inflammation can result in remodelling
of the affected tissues and these structural changes are often associated
with functional alterations. For instance, some patients with asthma
develop irreversible changes in lung function, despite apparently
appropriate and aggressive anti-inflammatory therapy63, and many
subjects with asthma exhibit a decline in lung function over time64'65.
Moreover, airway tissues from patients with asthma can exhibit structural
abnormalities such as epithelial thickening, smooth muscle hypertrophy,
948
British Medical Bulletin 2OOO;56 (No. 4)
Mast cells and basophils in acquired immunity
mucus gland hyperplasia, blood vessel proliferation and collagen
deposition beneath the epithelial basement membrane 66 .
We feel that it is too soon to conclude whether and to what extent mast
cells contribute to the tissue remodelling associated with chronic allergic
inflammation. However, several lines of evidence suggest that mast cells
may indeed participate in this process. Mast cell-derived proteases,
cytokines, growth factors and other mediators have been shown to have a
number of in vitro or in vivo effects that are consistent with the hypothesis
that mast cells can promote tissue remodelling. For example, Kanbe et al.
recently showed that human skin, lung and synovial mast cells are strongly
positive for matrix metalloproteinase-9 (MMP-9) by immunohistochemistry67. Because they can promote the degradation of extracellular
matrix, matrix metalloproteinases are believed to play a role in the
pathogenesis of certain disorders associated with tissue remodelling.
Various populations of mast cells also have been identified as sources of
several growth-promoting peptide mediators, including TNF-a, VPF/VEGF,
FGF-2, PDGF, TGF-p and NGF79'14'32; in aggregate, these products might
contribute to the neovascularization, connective tissue remodelling and/or
epithelial repair associated with chronic tissue remodelling, in the context
of allergic disease and in other settings, such as IgE-associated responses to
parasites and perhaps even carcinogenesis.
Mast cells and basophils in host defence and parasite immunity
It does not seem very likely that Th-2 and IgE-associated acquired
immune responses evolved so that we can experience allergic disorders.
What then is the adaptive advantage of these immune responses? Several
lines of evidence now indicate that mast cells and basophils may
represent important components of acquired immunity to at least some
parasites. Infections with many parasites, particularly helminths, induce
strong primary and secondary IgE responses, with some of the IgE being
specific for parasite-derived antigens. Such responses also can be
associated with increased levels of circulating basophils and eosinophils,
increased numbers of mast cells at sites of parasite infection and
infiltration of the affected tissues with basophils and, especially,
eosinophils.
Nevertheless, it has been difficult to prove that individual components of
IgE-associated responses to helminths, such as IgE, mast cells, eosinophils
or basophils, are truly essential for the expression of protective host
immunity. For example, IgE-deficient mice exhibit relatively modest
abnormalities in their immune responses to Schistosoma mansonf^. Several
studies demonstrated that W/W" mice develop little or no mast cells at sites
of parasite entry and, depending on the parasite, W/W" mice may also
British Medical Bulletin 2000;56 (No. 4)
949
Allergy and allergic diseases: with a view to the future
exhibit a delay in parasite clearance; however, W/W mice, unlike T-celldeficient nude mice, ultimately are able to clear these infections7.
Moreover, perhaps because of difficulties in achieving selective
reconstitution of intestinal mucosal mast cells populations in WfW" mice,
in many cases it is not clear to what extent the defects in parasite
resistance in W/W" mice reflect the mast cell deficiency of the mice, as
opposed to c-kit related abnormalities in other hematopoietic cells and/or
the lack of interstitial cells of Cajal. Notably, W/W" mast cell-deficient
mice which are also genetically devoid of IL-3 exhibit a striking
impairment in their ability to expel a primary infection with the nematode
Strongyloides venezuelensis9; this impairment is much greater than that
exhibited by WfWv mice that can produce IL-3 or by EL-3^~ mice with
normal c-kit9. W/W", IL-3^~ mice also fail to develop increases in bone
marrow and blood basophils in response to the infection, and they exhibit
virtually no hyperplasia of mucosal mast cells in the intestines at sites of
infection.
Taken together, these findings are consistent with the hypothesis that
mast cells and basophils provide overlapping or complementary function
during IgE-associated acquired immune responses to certain parasites.
Indeed, in other settings, basophils may have a more important role in
acquired immunity to parasites than do mast cells. For example, in the
guinea pig, basophils (and eosinophils) appear to be required for the full
expression of immune resistance to infestation of the skin by larval ixodid
ticks of the species Amblyomma americanum69, whereas expression of
IgE-dependent immune resistance to the cutaneous infestation of larval
Haetnaphysalis longicornis ticks in mice is dependent on mast cells70. By
contrast, W/W" mice can express immune resistance to the feeding of
larval ticks of the species Dermacentor varibilis, and the tick feeding sites
exhibit prominent infiltration of basophils by electron microscopy71. Such
studies support the notion that, in most cases, the maintenance of effective
acquired immune resistance to helminths or ectoparasites may simply be
too critical to permit the response to be ablated by the loss of a single
effector component, such as IgE, mast cells, basophils or eosinophils. As
noted previously, studies in mast cell knock-in mice have shown that mast
cells can also contribute significantly to innate immunity in host defence
against some bacterial infections20-45'46.
Finally, mast cells and/or basophils represent potential sources of
mediators and cytokines that can have potential down-regulating effects
in inflammation; some of these cells also express cell surface receptors that
can mediate down-regulation of FceRI-dependent signalling7*37-38-72. Thus
mast cells and basophils represent potential participants in the downregulation or attenuation, as well as in the initiation and/or perpetuation,
of acquired immune responses.
950
British Medical Bulletin 2000;56 (No. 4)
Mast cells and basophils in acquired immunity
Conclusions
It seems very likely that mast cells and basophils express complex, and
partially overlapping, roles in acquired immunity, and that these roles
include both effector cell and immunoregulatory activities. Clearly, IgEdependent mast cell activation importantly contributes to the expression of
many acute allergic reactions, including acute allergen-induced
bronchoconstriction in human atopic asthma, and both mast cells and
basophils are activated during IgE-associated anaphylaxis. Studies in mice,
and correlative analysis in humans, indicate that mast cells can contribute
to the leukocyte infiltration associated with allergic inflammation as well.
Moreover, in humans, basophils are prominent in the leukocytic infiltrates
elicited at sites of late phase reactions in the skin, nose, and airways. Based
on the known function of the wide spectrum of cytokines and growth
factors that can be produced by mast cells, these cells may represent
important contributors to many of the structural and functional changes
observed in tissues at sites of chronic inflammation.
Notably, two newly recognized aspects of FceRI function or expression
(fj-chain amplifier function, IgE-dependent up-regulation of FceRI surface
expression) provide strong support for the hypothesis that mast cells and
basophils may have particularly important roles as effector cells in initiating
and or amplifying IgE-dependent inflammatory reactions, especially in
response to low dose antigen challenge. Mast cells and basophils may also
express immunoregulatory functions in these settings, through the
production of certain cytokines. For example, both mouse and human mast
cells and basophils can produce IL-4 and/or IL-13, and other cytokines
which can enhance IgE production. This fact, taken together with the
findings about IgE-dependent regulation of FceRI surface expression
suggest a potential positive feedback mechanism (TlgE —> TFceRI surface
expression —> Tantigen-, IgE-, and FceRI-dependent release of IL-4 and/or
IL-13 —> TlgE) by which mast cells and possibly basophils may enhance the
further evolution, and persistence, of Th-2 biased, IgE-associated immune
responses. Finally, mast cells and basophils may enhance IgE production via
expression of the CD40 ligand. The clinical significance of many of these
new findings largely remains to be established. However, this work clearly
supports a complex, but more unified, view of the pathogenesis of allergic
disease and host defence mechanisms, which proposes that mast cells and
basophils can have both effector cell and immunoregulatory roles in these
contexts.
Acknowledgements
Some of the work reviewed in this chapter was supported by United
States Public Health Service grants CA 72074, AI 23990, AI 31982, AI
British Medical Bulletin 2000;56 (No. 4)
951
Allergy and allergic diseases: with a view to the future
41995 (project 1), by Deutsche Forschungsgemeinschaft grant WE 2300/1
and/or by AMGEN Inc.; Dr Galli consults for AMGEN Inc. under terms
that accord with Stanford University conflict-of-interest guidelines.
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