1. Immunology Letters 138 (2011) 28–31
Contents lists available at ScienceDirect
Immunology Letters
journal homepage: www.elsevier.com/locate/immlet
Review
Basophils and mast cells: Underdog in immune regulation?
Edward F. Knol ∗ , Maciej Olszewski 1
Department of Dermatology/Allergology, University Medical Center Utrecht, Utrecht, The Netherlands
a r t i c l e i n f o a b s t r a c t
Article history: Mast cells and basophilic granulocytes have recently been recognized as potent immunomodulatory
Available online 17 February 2011 cells. Whereas these cells originally were described as potent cells that release their pro-inflammatory
contents (i.e. histamine) unconstrained after activation, nowadays this process is considered to be much
Keywords: more subtle. Especially, via the release of pro- and anti-inflammatory cytokines basophils and mast cells
Mast cells now can steer an immune response. Recently, it has become evident that at least in murine models
Basophilic granulocytes
basophils are crucial for the initial induction of a Th2 response in immunologically naive mouse.
Basophils
© 2011 Elsevier B.V. All rights reserved.
TNF
IgE
IL-4
1. Introduction are specialized organelles, found primarily in granulocytes, which
possess the unique capability of rapid release. Initial studies of
Mast cells and basophilic granulocytes are most recognized for human mast cell granule composition by enzyme-affinity labelling
their effector roles in the immune response towards parasites and and ultrastructural immunocytochemical techniques allowed for
allergens. Both cells are rather unique in the immune system by identification of proteases chymase and tryptase a proinflam-
sharing the expression of the high affinity Fc receptor for IgE (Fc␧RI). matory biogenic amine histamine and the proteoglycan heparin.
Upon cross linking of IgE on the Fc␧RI by allergen these cells are acti- Subsequently, new techniques allowed for establishing granu-
vated and release their inflammatory mediators via degranulation. lar localization of many more mediators, among them several
The most well-known granule product is histamine. Recently, it has cytokines such as bFGF, SCF, VEGF, IL-4 and TNF [1]. The presence of
been demonstrated that both cell types are potent immunomodu- cytokines in granules adds a new dimension to a role of mast cells
lating cells, not only via the release of stored and novel synthesized in cytokine biology. Perhaps the best example of novel mechanisms
cytokines and chemokines, but also via their antigen-presenting in cytokine biology is the role of mast cell granule-derived TNF. This
properties. In this review we will discuss in more detail the specific cytokine plays critical role in host defence against bacterial infec-
properties of these separate lineage cell types particularly in the tions [2] and its lack results in drastically reduced neutrophil influx
context of their immunomodulatory functions. and significantly increased mortality of experimental animals. Mast
cells are considered the only cells storing preformed TNF. Remark-
ably the selective granule targeting of TNF appears to be differently
2. Mast cells and their granules
regulated in mast cells from human and rat origin [3]. The unique
capability of the fast release of a considerable amount of preformed
Mast cells are tissue-dwelling cells that are predominantly
cytokines might enable mast cells to influence the course of the
located at the interfaces of the organism and the exterior, such as
immune processes being initiated, directing it towards inflamma-
skin, gut mucosal membranes and lung. They are evolutionarily old
tory or allergic response, depending on the profile of cytokines
cells that play multiple roles in many modes of immune response,
released.
including innate and antibody-dependent reactions. Mast cells
Until recently it was unclear how mast cells released cytokines
derive their name from the original name given by Paul Ehrlich,
can exert effects in draining lymph nodes. Kunder and cowork-
Mastzellen (well-fed cells) reflecting the fact that a mature mast
ers demonstrated that mast cell-released TNF is partly packed
cell contains large number of cytoplasmic granules. These granules
into submicrometer heparin-based particles [4]. Upon their release
these stable particles enter the lymphatic vessels and end up in
the draining lymph nodes. This is illustrating that in mast cells
∗ Corresponding author. a dedicated physiological drug delivery system facilitating com-
E-mail address: e.f.knol@umcutrecht.nl (E.F. Knol). munication between peripheral sites of inflammation and remote
1
Current address: Department of Cell Biology, NHLBI, National Institute of Health,
Bethesda, United States.
secondary lymphoid tissues is active.
0165-2478/$ – see front matter © 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.imlet.2011.02.012

2. E.F. Knol, M. Olszewski / Immunology Letters 138 (2011) 28–31 29
3. Basophilic granulocytes and their granules eral biologically and clinically important mechanisms of immune
response such as allergy, inflammation and, as shown recently, also
Basophilic granulocytes (basophils) reside, in contrast to mast immune tolerance [6]. Some of the more important mediators pre-
cells, in blood. It was again Paul Ehrlich that first described these stored and synthesized by mast cells and basophils and their major
cells in 1879 as cells in blood that contained granules and stained pathophysiological effects are summarized in Table 2.
metachromatically when exposed to basic dyes, naming this set of
granulocytes basophilic granulocytes. Basophilic granulocytes rep- 5.2. Innate immunity
resent only about 0.5% of the leukocyte population in human blood.
Basophils are spheric cells with a diameter of about 10 ␮m and a Looking from a broader perspective of host defence especially
multilobe nucleus. The most evident characteristics of basophils mast cells play several roles in innate and acquired immunity.
are the round cytoplasmic granules with diameters up to 1.2 ␮m. Although there is some evidence of mast cells exhibiting directly
Within the granules histamine is stored, at about 1–2 pg per cell. germicidal activity by phagocytosis or bactericidal peptide release,
The characteristic metachromatic staining of basophils is due to several lines of evidence suggest that the most important way by
the presence of proteoglycans in the granule. Basophils release a which mast cells contribute to innate immune response is initia-
variety of pre-stored and newly sensitized pro-inflammatory medi- tion and regulation of the magnitude of leukocyte infiltration into
ators (e.g. Histamine and LTC4 ) and cytokines (e.g. IL-3, IL-4, IL-13 the site of inflammation. It has been demonstrated using mast-cell
and VEGF) which are involved in the pathogenesis of allergies. deficient mice that at least TNF and leukotrienes are important fac-
The basophil population in blood represent a population that can tors in neutrophil recruitment towards sites of bacterial infection
rapidly migrate in tissues. At tissue sites of allergic inflammation a and mast cells deficiency correlates with much worse prognosis
marked influx of basophils can be found. The influx of basophils is in experimentally infected mice. Experiments in other model sys-
often accompanied by a simultaneous influx of eosinophilic gran- tems have shown that secretion of TNF and leukotrienes in the acute
ulocytes and Th2 lymphocytes. Basophils enter tissue sites within phase of inflammatory processes may also promote influx of leuko-
several hours after exposure to allergens. However, it is conceivable cytes other than neutrophils, such as T cells or macrophages which
that by the time basophils enter these tissues the allergens may well are typical for chronic inflammatory state. Such leukocytes can then
have been cleared. This evidently leads to the question as to what initiate and maintain features characteristic of the chronic inflam-
else, other than allergen-mediated stimulation, can drive basophil matory state. Another function mast cell play in innate responses
activation following extravasation into tissue sites affected by aller- is limiting the toxicity of certain substances generated by the host
gic inflammation. Recently, it was demonstrated that basophils can which have adverse effects when present in high concentrations.
be activated by IL-18 and IL-33 to release large amounts of cytokines An example of such activity is degradation of endothelin-1, a pep-
such as IL-4, IL-13, IL-6, IL-9, RANTES, GM-CSF, MIP-1a, MIP1b and tide that is involved in sepsis, by the proteases released from mast
MCP-1, but not IL-17, IL-5 and IFN-␥ [5]. cell granules. Mast cells are also capable of releasing mediators
influencing (positively or negatively) the transition from innate to
acquired immunity. It has been reported that mast-cell derived TNF
4. Relation between mast cells and basophils
plays a role in draining lymph node hypertrophy and T cell recruit-
ment to these nodes in a model of E. coli infection in mouse. This
There is much confusion on the relation between basophils and
indicates that while there is a mast cell-dependent component in
mast cells. It is not uncommon that basophils are mistakenly con-
the development of adaptive immune response, the mechanisms
sidered to be the blood-derived progenitor of tissue mast cells,
are likely to be more redundant as compared to innate response.
such as the link between monocytes and macrophages. Although
mast cells and basophils share several unique properties, they are
5.3. IgE-associated adaptive responses
derived from distinct progenitors. Basophils differentiate in bone
marrow and are released in the blood as mature basophils, whereas
Another aspect of mast cells and basophils contribution to
mast cells progenitors are found in bone marrow and blood, but
immune response is their involvement in adaptive immunity. Orig-
differentiation of these cells does not occur before entering the
inally, these activities were connected to antigen-specific IgE that,
tissue. For the development of basophils IL-3 is crucial, whereas
when bound to Fc␧RI and crosslinked by an antigen, activate mul-
stem cell factor (c-kit ligand) is important for the differentiation
tiple pathways in these cells. Recent findings demonstrate, that,
of mast cells. The mast cell development in tissue is fine-tuned
in mast cells, IgE at high concentrations has more than just a pas-
by additional cytokines, such as TGF-␤, IL-4, IL-9 and matrix pro-
sively sensitizing activity. Some antibodies are able to elicit full
teins, resulting in different phenotypes of mucosal tissue mast cells
responses in the absence of antigen while other only upregulate
compared to connective tissue mast cells. In general it seems that
Fc␧RI and enhance mast cells survival. This survival enhancement
basophils are much more related to eosinophils and mast cells are
is mediated by autocrine IL-3 stimulation and activation of Bcl-
much related to monocytes/macrophages. In Table 1, we provide a
xL/Bcl-2. The extent of mast cell activation in absence of antigen
comprehensive list of differences between mast cells and basophils.
depends on a particular antibody, although the molecular determi-
nants of this anti-apoptotic activities are not defined. Additionally,
5. Mast cells and basophils in immune responses the increased survival after Fc␧RI stimulation differs between mast
cell subpopulations [7].
5.1. General remarks It has been widely accepted that mast cells contribute sig-
nificantly to acute inflammatory reactions to antigens/allergens
Mast cells and basophils are important elements of both innate against which the host bears antibodies of the IgE class. Mast
and acquired immunity. They express numerous receptors that, cells are responsible for virtually all of the increased vascular per-
when stimulated, may induce production of a plethora of medi- meability and tissue swelling early in the IgE-dependent passive
ators. These receptors include IgE and IgG, complement, IL-1, TNF cutaneous anaphylactic response. If the stimulation is of more
and several Toll-like receptors, to name just a few most impor- persistent or more severe nature, acute response may undergo tran-
tant. Upon stimulation they can degranulate, release and synthesize sition into late-phase reaction (LPR) which, except for the time scale
highly bioactive, proinflammatory, vasodilative, chemotactic, and ranging from few to several hours from initial antigen challenge, is
cytotoxic substances. These cells are crucial for the function of sev- characterized by recruitment of leukocytes to the site of inflamma-

3. 30 E.F. Knol, M. Olszewski / Immunology Letters 138 (2011) 28–31
Table 1
Distinct properties of basophils and mast cells.
Properties Basophils Mast cellsa
Size 7–10 ␮m 14–20 ␮m
Nucleus Multi-lobed Single-lobed
Granules Fewer and larger than those of mast cells Smaller, more numerous than those of basophils
Location Blood, can migrate into tissue Tissue
Life span Days Weeks to months
Development
Maturation site Bone marrow Tissue, progenitors move from bone marrow via blood in tissue
Differentiation factors IL-3 Stem cell factor (fine tuning with other local cytokines and tissue matrix
Contents
Histamine 1–2 pg/cell 1–15 pg/cell
Major proteases – Tryptase
Arachidonic acid metabolites LTC4 LTC4 , PGD2 , thromboxanes
Granule contents Major basic protein, Charcot Leyden crystals No major basic protein or Charcot Leyden crystals
Activation
fMLP Activation No effect
PMA/A23187 Activation by each separate agent Only activation when added together
Compound 48/80 No effect Activation
Substance P No effect Activation
Morphine No effect Activation
Pharmacological inhibition
H2 agonists Inhibition No effect (also no H2 receptor)
Steroids Inhibition No effects
Indomethacin Enhances No effects
a
Within the mast cell population different cell types have been demonstrated. Therefore some of the characteristics given in this table do not account for all mast cell
types.
tion. In this chronic response basophils can play an important role 5.4. IgE-independent responses
in the sustained nature of inflammation upon entering the affected
tissue, not only due to the release of stored and newly synthesized Apart from IgE-dependent responses, mast cells and basophils
mediators, such as histamine and LTC4 , but also via the release of have been implicated in pathogenesis of several autoimmune dis-
high amounts of the cytokines IL-4 and IL-13 [8]. eases, including multiple sclerosis and rheumatoid arthritis in
In this view, a wide range of innate and IgE-associated immune humans and experimental autoimmune encephalomyelitis (EAE)
responses appear to represent a situation in which mast cell activ- and IgG1 antibody-dependent autoimmune arthritis in mice.
ity, depending on particular circumstances, may be either beneficial Moreover, under some experimental conditions mast cells are nec-
or detrimental to the host. essary for complete elicitation of inflammation associated with
Table 2
Mast cell and basophil mediators.
Mediator Major pathophysiologic effect
Prestored
Biogenic amines
Histamine Vasodilation, angiogenesis, mitogenesis, suppressor T-cell activation
5-HT Leukocyte regulation, vasoconstriction, pain
Chemokines (IL-8, MCP-1, MCP-3, MCP-4, RANTES) Chemoattraction and tissue infiltration of leukocytes
Enzymes
Chymase Tissue damage, pain, angiotensin II synthesis
Tryptase Activation of PAR, inflammation, pain, tissue damage, degradation of antigens and peptides
Kinogenases Synthesis of kinins, pain
Nitric oxide synthase NO production
Carboxypeptidase A Degrades enzymes
Polypeptides
CRH Inflammation, vasodilation, mast cell VEGF release
Endothelin Sepsis
Kinins Inflammation, pain, vasodilation, mast cell trigger
Somatostatin (SRIF) Anti-inflammatory (?), mast cell trigger
VEGF Neovascularization, vasodilation
Proteoglycans
Chondroitin sulfate Connective tissue component, anti-inflammatory, mast cell inhibitor
Heparin Angiogenesis, NGF stabilization, mast cell inhibitor
De novo synthesized
Cytokines
IL-1, -3, -4, -5, -6, -9, -10, -13, -16, IFN-␥, MIF, TNF Multiple roles
Growth factors
SCF, GM-CSF, GnRH-I ␤-FGF, NGF, VEGF Growth of a variety of cells, mast cell proliferation
Phospholipid metabolites
LTB4 Leukocyte chemotaxis
LTC4 Vasoconstriction, pain
PAF Platelet activation, vasodilation, inflammation
PGD2 Bronchoconstriction, pain
NO Vasodilation, neuromodulation

4. E.F. Knol, M. Olszewski / Immunology Letters 138 (2011) 28–31 31
hapten-induced contact hypersensitivity (CHS) or asthma and were crucial for the Th2-response because depletion of peripheral
inflammatory bowel disease. blood basophils with Mar-1 antibodies blocked the development
of Th2 cells. Finally, further evidence for the important role of
basophil-derived IL-4 in the induction of Th2-responses was pro-
6. Mast cells do also limit inflammation
vided by research from the group of Yoshimoto. This group studied
the role of basophils in the induction of Th2 responses by infec-
Although there is a solid body of evidence that mast cells exert
tion with the nematode Strongyloides venezuelensis. In addition, this
predominantly proinflammatory activities, there are a few reports
group demonstrated that activation of basophils did not depend on
stating otherwise. Examination of biological activity of mast cell
the presence of IgE antibodies on their membrane. This can be con-
mediators, indicates that some of them, including TGF-␤, IL-4, IL-10
sidered an important finding because it indicates that basophils
and histamine have potentially anti-inflammatory activity. The first
might be responsible for the initial induction of IgE.
report of such activity of mast cells in knockin mouse concerned
Since the time that IL-4 has been demonstrated as mast cell and
UV-induced suppression of contact hypersensitivity to DNFB that
basophil products, now almost 20 years ago, it has been hypothe-
was, at least partly, mediated by IL-10. It has also been demon-
sized that these cells are important in the early induction of Th2
strated, that mice that were bitten by a mosquito display lowered
cells and the development of allergy. However, convincing stud-
antigen-specific T cell responses in the model of delayed hypersen-
ies were not yet published. In the three papers described above
sitivity to OVA and that this phenomenon requires mast cells at the
clear indications are provided that basophilic granulocytes induce
site of the bite. The mechanism of this regulatory activity remains
TH2 responses via the peptide presentation on MHC-II and simul-
unknown. The results of yet another study show that mast cells
taneous release of IL-4. Extrapolation of these results obtained in
are necessary for peripheral tolerance to skin allografts. In toler-
mouse models towards human is not clear yet. Expression of MHC-II
ant mice considerable increase of mast cell-specific transcripts and
on human basophils has not been convincingly demonstrated and
number of mast cells was observed. This increase correlates with
the mouse basophils appear to be morphologically distinct from
the influx to the graft of IL-9-producing CD4+ Foxp3+ T cells. Mast
the human basophils. It will probably be shortly before follow-up
cell-deficient mice cannot be tolerized and experience rapid graft
papers will address the potency of human basophils.
rejection, which can be prevented by local skin reconstitution with
mast cells. IL-9 released by Tregs is the major mediator of mast cells
8. Final conclusion
recruitment and activation in the dermis of these tolerant grafts.
Mast cells may then act by limiting the influx of inflammatory T
Mast cells and basophils have long been considered to be small
cells or cooperating with dermal Tregs. Unexpected as it sounds,
bags filled with potent inflammatory mediators that were released
mast cells do contain TGF-␤ that is a major Tregs inducing factor.
after a specific stimulation. Especially in the context of allergic
Even in the response to cobra venom and bee venom it was found
inflammation these cells are thought to be crucial in the initi-
in mice that the presence of mast cells was an important factor in
ation and maintenance of the inflammatory reactions. Recently,
limiting the pathologic effects. Most likely this limitation was due
much more subtle roles of these cells have been demonstrated, not
to release of carboxypeptidase A and possibly other proteases by
only via the large numbers of cytokines and chemokines that these
the mast cells.
cells can produce, but also via their pro- and anti-inflammatory
In conclusion, mast cell activators may yield pro- or
functions. In addition, most pronounced for the basophils, there is
anti-inflammatory responses [9]; most probably are the pro-
a potent antigen-presenting cell activity described that together
inflammatory effect most pronounced in the earlier phase of the
with the release of IL-4 might be important for the very early
response and is the anti-inflammatory effects more pronounced at
Th2 skewing of the immune response towards allergens and para-
the later phase of the response to limit ongoing inflammation.
sites.
7. Basophils are important cells in the induction of an References
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