By
From the Departments of Pathology, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, Massachusetts 02215
Asthma affects millions of people worldwide, and its reported incidence is increasing dramatically in many
developed nations; the human and economic costs of this
disorder, in morbidity, health care expenses, lost productivity,
and, most tragically, even mortality, are staggering (1, 2).
It is now generally thought that asthma is a syndrome,
typically characterized by the three cardinal features of intermittent and reversible airway obstruction, airway hyperresponsiveness, and airway inflammation, that may arise
as a result of interactions between multiple genetic and environmental factors (1). Nevertheless, most cases of the
disorder (the so-called "atopic" or "allergic" asthma) occur
in subjects whom also exhibit immediate hypersensitivity responses to defined environmental allergens, and challenge
of the airways of these subjects with such allergens can produce reversible airway obstruction (1). It is also known
that the overall incidence of asthma in several different populations exhibits a strong positive correlation with serum
concentrations of IgE, which, in humans, is the main (if not
the only) Ig isotype that can mediate immediate hypersensitivity responses (1, 5). Moreover, it has been demonstrated that mast cells, derivatives of hematopoietic precursor
cells that undergo their terminal stages of differentiation/
maturation in the peripheral tissues in which they reside (6,
7), express cell surface receptors (Fc In light of these findings, it was once widely believed
that atopic or allergic asthma is a disease that primarily reflects the consequences of IgE- and allergen-dependent
mast cell activation. Yet several observations have called
into question the central role of mast cells in asthma. These
include the demonstration that additional cell types, including eosinophils (10) and Th2 lymphocytes (11), both
of which are well represented in the chronic inflammatory
infiltrates in the airways of patients with asthma (2, 12,
13), also can produce cytokines or other mediators that may
contribute to many of the features of the disease. Moreover, it has recently been shown that the Fc Given the large number of potential culprits, some of
which can express similar or overlapping functions, how
can one assess the relative importance of individual cell
types in the pathogenesis of asthma? Although this represents an exceedingly difficult challenge in the setting of human asthma, some aspects of this issue are accessible by taking advantage of animal models of the disease. However,
when considering the results of such animal studies, several
points should be kept in mind. (a) These are models of human asthma, not asthma itself, and the extent to which the
findings in these models actually elucidate the human condition(s) needs to be demonstrated by appropriate studies in
human subjects. (b) Experimental animal species and humans can differ in significant details of immunological and
inflammatory responses (e.g., in the mouse, antigen- and
mast cell-dependent airway obstruction can be mediated
by either IgE or IgG1 [16], whereas it seems likely that only
IgE is involved in the analogous human responses [1, 5]).
(c) The procedures of allergen sensitization and challenge that are used in animal models of asthma are typically "optimized" to give strong responses for endpoint analysis, and
this (as well as the increasing costs of animal experimentation, which discourages the use of large numbers of animals) may make it difficult to detect contributions of cell
types that function to amplify the intensity or kinetics of
such responses at relatively low levels of allergen challenge.
(d) Finally, the models used by different investigators may
differ in a number of factors, which can have potentially
significant effects on the results, including the species (or
strain) of experimental animal, the choice of antigen, the
protocols for antigen sensitization and challenge, and the means of assessing and quantifying the individual characteristics of the responses.
In other words, the demonstration that a particular cell
or mediator can produce a feature of asthma in an animal
model neither proves that this element can have the same
effect in human asthma nor excludes the possibility that
other cells or mediators can have similar, and perhaps even
more critical, functions, either in experimental animals or
humans.
These reservations notwithstanding, how have the results
of studies in experimental animals influenced our thinking
about the pathogenesis of asthma, and in particular, the potential role of the mast cell in the expression of the three
cardinal features of the disorder? The most definitive approach for characterizing the importance of a single potential effector cell or molecule in a biological response is to
attempt to elicit the response in animals that differ solely in
having or lacking the element of interest. With respect to
mast cells, the best current approximation of this ideal is to
investigate genetically mast cell-deficient (WB-W/+ × C57BL/6-W v/+)F1-W/Wv (WBB6F1-W/Wv) mice (now
more properly designated WBB6F1-KitW/KitW-v mice [17])
and the congenic normal (WBB6F1-+/+) mice (6, 18, 19). Because of the effects of their mutations at c-kit, which encodes the receptor for a pleiotropic growth factor that
represents a major mast cell survival/developmental factor,
stem cell factor (also known as kit ligand or mast cell
growth factor; 18), adult KitW/KitW-v mice virtually lack
tissue mast cells (<1.0% the +/+ number in the skin, essentially none in the airways and other sites), but they are
also mildly anemic, lack melanocytes in the skin and interstitial cells of Cahal in the gastrointestinal tract, and are
sterile due to a virtual absence of germ cells (18). However, these mice appear to have little or no abnormalities of
B or T cell function, levels of granulocytes (including basophils) or platelets, or hemostasis, nor do they exhibit Ig deficiencies or impairments in their ability to generate IgE or
IgG1 antibody responses (18, 19). Finally, the mast cell deficiency of KitW/KitW-v mice can be selectively repaired by
the adoptive transfer of lineage-committed immature mast
cells (BMCMCs, or bone marrow-derived cultured mast
cells) which have been generated in vitro from the bone
marrow cells of the congenic +/+ mice (6, 19, 21). Such
"mast cell knock-in mice" can be used to test whether abnormalities in the expression of biological responses in
KitW/KitW-v mice, which theoretically could be due to any
direct or indirect consequence of their c-kit mutations,
specifically reflect the animals' mast cell deficiency (6, 18,
19, 21).
Studies in KitW/KitW-v and congenic normal mice have
clearly established that, in the mouse: (a) IgE-dependent
acute reversible airway obstruction can occur by mechanisms that appear to be entirely mast cell dependent (16,
22, 23). (b) Although many manifestations of active anaphylactic reactions in the mouse, including changes in airway function and death, can occur by IgE- and mast cell- independent, but IgG1-dependent, mechanisms, IgE and
mast cells probably contribute importantly to the initial
rapid and partially reversible phases of airway obstruction,
and diminished pulmonary compliance, that are observed
during certain models of active anaphylaxis (16). (c) The
acute airway hyperresponsiveness to intravenous methacholine challenge that can be detected in immunologically naive mice 20 min after intravenous challenge with anti-
mouse IgE antibodies is largely (if not entirely) mast cell
dependent, and is expressed before the development of any
histologically apparent leukocyte infiltration in the airways at
sites of mast cell degranulation (23). Although the specific
mediator(s) responsible for this example of mast cell-dependent airway hyperreactivity remain to be defined, the candidates include representatives of all three classes of mast
cell-derived mediators (see reviews in references 4, 8, 9,
and 23).
These findings show that, in WBB6F1 mice, IgE-dependent mast cell degranulation can result in both reversible
airway obstruction and airway hyperresponsiveness to cholinergic stimulation, in the absence of detectable infiltration
of the airways with circulating leukocytes. On the other
hand, it is now clear that eosinophil recruitment to the airways of mice can occur in response to aerosol challenge
with antigen even in the virtual absence of mast cells, at
least with some protocols of antigen sensitization and challenge. For example, in this issue, Takeda et al. (24) report
that when KitW/KitW-v and congenic +/+ mice were sensitized with OVA and then assessed 48 h after the last of 3 consecutive daily aerosol challenges with OVA, both the
mast cell-deficient and the wild type mice exhibited similar
numbers of eosinophils in bronchoalveolar lavage fluid and
lung digests, as well as similar levels of airway hyperreactivity to methacholine challenge.
At least four previous studies (each using a different protocol of antigen sensitization and challenge, and, in some
cases, a different antigen) also reported that mast cells are
not essential for the development of antigen-induced infiltration of the airways with eosinophils (25). However,
Kung et al. (27), 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 KitW/
KitW-v mice was Taken together, these five studies suggest that the relative contribution of mast cells to eosinophil infiltration of
the airways may vary; mast cells may have no detectable
role in experiments that use strong procedures of immunization and challenge, but may contribute significantly when
protocols for sensitization and, especially, challenge have
been selected to yield relatively attenuated responses. Moreover, in a model of peritoneal inflammation, the mast cell
significantly enhanced the kinetics of leukocyte recruitment, even though it had no effect on the final magnitude of the response (29). The data of Kung et al. (27) indicate that mast cells can also enhance the kinetics of eosinophil
responses to aerosol allergen challenge.
Takeda et al. (24) are the first to show that mast cell-
deficient KitW/KitW-v mice can express allergen-induced
airway hyperresponsiveness to cholinergic stimulation. This
important observation provides yet more support for the
now widespread view that there may be multiple routes to
this defining characteristic of asthma. Indeed, it is thought
that airway hyperresponsiveness, i.e., the development of
bronchoconstriction in response to an immunologically
nonspecific stimulus that would have no discernable effect
in a normal individual, may reflect a consequence of any of
a number of acute and/or chronic processes, including
damage to the bronchial epithelium, submucosal edema, alterations of smooth muscle function (e.g., in response to
mast cell mediators or other products present at sites of inflammation), and alterations in the production or degradation of neuroactive mediators (4, 8, 30). And although airway hyperresponsiveness and infiltration of the airways
with eosinophils are often linked, both in animal models
and in human asthma, airway hyperresponsiveness has been
reported to occur in the absence of significant eosinophilia in certain settings such as in aerosol-challenged BALB/c
mice that had been treated with an anti-IL-5 neutralizing
antibody (31).
Depending on the model system, airway hyperresponsiveness also can occur either by IgE-dependent mechanisms (23, 32) or independently of IgE (33, 34) and/or
IgG1 (34). IL-5 derived from CD4+ T cells has been implicated in the development of IL-4- and IgE/IgG1-independent airway inflammation (34), adding to a large body of
evidence that indicates that CD4+ T cells can mediate airway hyperreactivity (35) as well as infiltration of the
airways with eosinophils (25, 35). And although it has
often been proposed that CD4+ T cells promote the development of airway hyperreactivity indirectly through the recruitment of eosinophils and/or other leukocytes, the possibility that products derived from the T cells themselves can importantly contribute to airway hyperresponsiveness
must also be considered (35).
Perhaps the simplest conclusions to draw from the various studies of mouse models of allergic asthma are that, in
mice: (a) Airway hyperreactivity to cholinergic stimulation
can occur by either mast cell-dependent mechanisms (which
can be expressed even in the absence of leukocyte recruitment) or by CD4+ T cell-dependent mechanisms (which
typically occur in a setting that also includes eosinophil infiltration of the airways). (b) Mast cells are not necessary for
the recruitment of Th2 cells or eosinophils to the airways after aerosol challenge with antigen, but can influence the
kinetics or magnitude of the responses, especially at "suboptimal" levels of antigen exposure. (c) The extent to which
eosinophils are necessary for the expression of T cell-
dependent changes in airway hyperreactivity in different models remains to be fully defined. (d) In many experimental
settings, particularly in various strains of normal mice, the
expression of airway hyperresponsiveness (and other "asthma-like" features of these models) probably reflects the combined contributions of both mast cell- and T cell-dependent pathways.
But what about the role of the mast cell in "real" allergic
asthma, in humans? It seems very likely that IgE-dependent
mast cell activation importantly contributes to acute allergen-induced bronchoconstriction in human atopic asthma,
and that mast cells can contribute to the airway inflammation associated with this disorder as well (2, 6, 8, 9).
However, in humans, unlike in mice, the Fc In addition, two newly recognized aspects of Fc These findings thus identify two Fc The clinical significance 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 diseases, which proposes that both T cells and
mast cells (and other FcRI) that permit them
to bind the Fc portion of IgE with high affinity, and also
that such IgE-sensitized mast cells, upon encounter with specific antigen that is recognized by their Fc
RI-bound
IgE, secrete a broad panel of bioactive mediators, including: (a) preformed mediators that are stored in the cell's cytoplasmic granules (e.g., histamine, heparin, and neutral
proteases), (b) newly synthesized lipid products (e.g., prostaglandin D2 and leukotriene C4), and (c) diverse cytokines
(4, 6, 8, 9). Finally, several lines of evidence indicate that
many of these potentially mast cell-derived mediators can
promote reversible airway obstruction, bronchial hyperreactivity, and/or airway inflammation (see reviews in references 2, 8, and 9).
RI, which was once thought to be restricted to tissue mast cells and basophils (circulating granulocytes that can produce a panel of
mediators that is similar, but not identical, to that of mast
cells [6, 9]) can also be expressed on the surface of monocytes, circulating dendritic cells, Langerhans' cells, and eosinophils (see reviewes in references 14 and 15), thus identifying these cells as additional potential sources of mediators
in various IgE-dependent inflammatory responses.
50% of that in the +/+ mice (P <0.05)
and was largely normalized after the selective repair of the
animals' mast cell deficiency. Brusselle et al. (26), who performed daily OVA challenge for 7 d, also found that eosinophil influx into bronchoalveolar lavage fluid was reduced
by ~50% in KitW/KitW-v versus +/+ mice (P = 0.06).
RI can be expressed on several potential effector cells in addition to mast
cells and basophils (14, 15). Also, the form of the Fc
RI
expressed on monocytes and dendritic cells (which lacks the
chain) can function to enhance the processing/presentation of antigens attached to proteins that are recognized by
the cells' surface-bound IgE (14). Thus, in humans, IgE may
not only serve to arm mast cells and other effectors of the
efferent limb of acquired immune responses, but may also contribute, by promoting antigen processing/presentation,
to the evolution of such responses.
RI
function or expression provide strong support for the hypothesis that mast cells (and perhaps other Fc
RI+ effector
cells) may have a particularly important role in initiating and/or amplifying IgE-dependent inflammatory reactions,
especially in response to low dose antigen challenge. First,
Lin et al. (39) have identified the Fc
RI
chain as an "amplifier" of signaling through this receptor, which can markedly upregulate the magnitude of the mediator release response to Fc
RI aggregation; notably, it has been reported
that certain mutations that result in amino acid substitutions
in the human
chain may be linked to atopic disease (see
reviews in reference 39). Second, studies in both mice (40,
41) and humans (42, 43) indicate that the level of expression of Fc
RI on the surface of mast cells and basophils can
be regulated by ambient concentrations of IgE and that this IgE-dependent upregulation of Fc
RI expression both permits the cells to exhibit mediator release at lower concentrations of specific antigen (40, 42, 43), and also primes
such cells to produce strikingly higher levels of certain mediators, including IL-4 and other cytokines (40, 43), under
optimal conditions of antigen challenge.
RI-dependent
mechanisms (
chain "amplifier" function, IgE-dependent
upregulation of Fc
RI surface expression) for enhancing the
sensitivity and intensity of the effector phase of IgE-dependent
reactions. They also suggest a potential positive feedback
mechanism (
IgE
Fc
RI
antigen-, IgE-, and Fc
RI-dependent release of IL-4 [40] and/or IL-13 [44]
IgE)
by which mast cells (and possibly basophils) may enhance the further evolution, and persistence, of Th2-biased, IgE-associated immune responses. And studies in mice have
identified yet another IgE-dependent, but apparently mast
cell- and Fc
RI-independent, mechanism to augment Th2
responses and associated eosinophil infiltration in the airways: IgE- and CD23-facilitated antigen presentation to T
cells (28). Finally, mast cells and basophils may enhance IgE
production via expression of the CD40 ligand (44, 45).
RI+ cells) can have both effector
cell and immunoregulatory roles in these disorders. This hypothesis has a number of interesting implications with respect to existing, and proposed, therapeutic approaches for
asthma and other allergic diseases. For example, anti-IgE-based strategies, which are already in clinical testing (42),
not only may reduce CD23-dependent antigen presentation (28) and Fc
RI+ cell effector function (40), but
also may diminish Fc
RI+ cell immunoregulatory function by
reducing both mast cell (or basophil) IL-4/IL-13 production (40, 44) and Fc
RI+-dependent antigen presentation
(14). Conversely, the findings that corticosteroids and other
"immunosuppressive" drugs can diminish mast cell cytokine production, as well as reduce IgE- and mast cell-dependent inflammation and leukocyte recruitment in mice in vivo (see reviews in references 9, and 46), raise the possibility that the clinical benefits of such agents in asthma may
reflect, at least in part, actions on mast cells as well as on the
T cells, eosinophils, and other effector and target cells that
participate in these complex disorders.
Address correspondence to Stephen J. Galli, Division of Experimental Pathology, Beth Israel Deaconess Medical Center-East Campus, 330 Brookline Ave., Boston, MA 02215. Phone: 617-667-5970; FAX: 617-667-3616; E-mail: sgalli{at}bidmc.harvard.edu
Received for publication 29 May 1997 and in revised form 11 June 1997.
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