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Allergy

REVIEW

Mast cells and basophils in cutaneous immune responses


A. Otsuka1 & K. Kabashima1,2
1
Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto; 2PRESTO, Japan Science and Technology Agency,
Kawaguchi, Saitama, Japan

To cite this article: Otsuka A, Kabashima K. Mast cells and basophils in cutaneous immune responses. Allergy 2015; 70: 131–140.

Keywords Abstract
allergic contact dermatitis; atopic dermatitis;
basophil; mast cell.
Mast cells and basophils share some functions in common and are generally asso-
ciated with T helper 2 (Th2) immune responses, but taking basophils as surrogate
Correspondence cells for mast cell research or vice versa for several decades is problematic. Thus
Kenji Kabashima, MD, PhD, Department of far, their in vitro functions have been well studied, but their in vivo functions
Dermatology, Kyoto University Graduate remained poorly understood. New research tools for their functional analysis
School of Medicine, 54 Shogoin Kawara, in vivo have revealed previously unrecognized roles for mast cells and basophils in
Sakyo-ku, Kyoto 606-8507, Japan. several skin disorders. Newly developed mast cell-deficient mice provided evidence
Tel.: +81-75-751-3310 that mast cells initiate contact hypersensitivity via activating dendritic cells. In
Fax: +81-75-761-3002 addition, studies using basophil-deficient mice have revealed that basophils were
E-mail: kaba@kuhp.kyoto-u.ac.jp
responsible for cutaneous Th2 skewing to haptens and peptide antigens but not
to protein antigens. Moreover, human basophils infiltrate different skin lesions
Accepted for publication 17 September
2014
and have been implicated in the pathogenesis of skin diseases ranging from atopic
dermatitis to autoimmune diseases. In this review, we will discuss the recent
DOI:10.1111/all.12526 advances related to mast cells and basophils in human and murine cutaneous
immune responses.
Edited by: Hans-Uwe Simon

Mast cells and basophils are in some respects similar and are might function as modulators of immune responses by
generally associated with T helper 2 (Th2) immune responses, enhancing, suppressing, or polarizing the adaptive immunity
which are mainly characterized by the presence of Th2 cells (2, 3, 6, 7).
and high levels of immunoglobulin E (IgE). Th2 immunity Taking basophils as surrogate cells for mast cell research
develops in response to allergens and parasites. Mast cells and or vice versa is problematic for many reasons. Their develop-
basophils express several effector molecules in common, ment, distribution, and proliferation are different as summa-
including mast cell-associated proteases, vasodilating sub- rized in Table 1. Mast cells are widely distributed throughout
stances such as histamine, various cytokines, pro-inflammatory tissues, especially near surfaces exposed to the environment,
chemokines, and lipid mediators. Many of these effector mole- such as the skin, airways, and gastrointestinal and genitouri-
cules are rapidly released in response to the activation of the nary tracts, where pathogens, allergens, and other environ-
high-affinity receptor for IgE (FceRI) or other surface recep- mental agents are encountered (8). On the other hand,
tors that are expressed on mast cells and basophils (1, 2). basophils are primarily found in the blood circulation under
Previous studies have reported the involvement of mast cells steady-state conditions and are mobilized to the blood,
in other processes such as protection of the host against a spleen, lungs, and liver in response to inflammatory signals
range of parasitic and bacterial infections, degradation of tox- that rapidly induce basophil expansion in the bone marrow.
ins, induction of tolerance to skin transplants, and tumor In addition, the lifespan of basophils is short, but mast cells
rejection. Conversely, they cause detrimental inflammatory can survive for a long time, and some tissue mast cells prolif-
responses to allergens and might also exacerbate autoimmuni- erate in situ in response to certain form of stimulation (9).
ty (3). Basophils can contribute to protection against helm- Although a number of functions of mast cells or basophils
inths and ticks (4), but they can also play a pivotal role during have been reported, the physiologic in vivo functions of both
IgE-mediated chronic allergic inflammation of the skin and are cell types are still largely unknown due to the fact that these
implicated in the late-phase response of allergic asthma (5). cells are rare and are difficult to isolate as pure populations
In addition to their effector functions, basophils and mast without interfering with their activation. Furthermore, there
cells can rapidly respond to the environmental signals and have been no ideal tools to evaluate their in vivo role, such as

Allergy 70 (2015) 131–140 © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd 131
Mast cells and basophils Otsuka and Kabashima

Table 1 Characterization of mast cells and basophils deficiency model using Cpa3-Cre transgenic mice, which exhi-
bit reductions in mast cells and basophils. Considering the
Mast cells Basophils
phenotype of these mast cell depletion models, Cpa3 might
Development Bone marrow Bone marrow play some roles in the development of both mast cell and ba-
Distribution Peripheral tissues Blood sophils. We also reported Mas-TRECK Tg mice using DTR
Survival time Long (weeks) Short (2–5 days) transgene under the control of 50 enhancer, promoter, and in-
Surface marker FceRIa+, CD117 (c-kit)+ FceRIa+, DX5+, CD34+ tronic enhancer of IL-4 (6). After DT treatment of the mice,
both mast cells and basophils are depleted, but basophils are
restored earlier than mast cells.

conditional depletion systems. Recently, new types of geneti-


Basophil-specific depletion model
cally modified mouse strains have been developed, and previ-
ously proposed functions of mast cells and basophils have Due to the lack of any natural mouse mutants with basophil
been revisited extensively. In this review, we summarize these deficiencies, antibodies have often been used to study the con-
recent studies of mast cells and basophils and focus on their tribution of basophils in different experimental settings. These
role in cutaneous immune response. antibodies recognize either FceRI (clone MAR-1) or the
orphan-activating receptor CD200 receptor 3 (CD200R3)
(clone Ba103), which are both mainly expressed by basophils
Mast cell-specific depletion model
and mast cells. Although both antibody clones can efficiently
The selective depletion of mast cells or basophils in vivo is a deplete basophils, they can also activate mast cells (21, 22).
useful approach through which the role of these cell types Furthermore, the depletion of basophils by Ba103 is FcR
during immune responses is addressed. Classical models used dependent and might therefore activate myeloid cells and natu-
to study the mast cell functions are based on Kit-mutant ral killer (NK) cells (23). MAR-1 also depletes a subset of
mouse strains. In addition to their mast cell defect, KitW/Wv FceRI-expressing dendritic cells (DCs) (24). Several new
mice have multiple hematopoietic abnormalities that include mouse strains with a constitutive or inducible depletion of ba-
compromised fitness of the hematopoietic stem and progeni- sophils have recently been generated (Table 2). Mcpt8 is a
tor cells (10), severe macrocytic anemia (11), impaired T basophil-specific gene in the conserved chymase locus (25).
development in the thymus (11), and a shift in intraepithelial Three groups generated the basophil depletion models by tak-
T cells in the gut in favor of T-cell receptor (TCR) ab+ cells ing advantage of this gene regulation (21, 26, 27). In these
and against TCR cd+ cells (12). Importantly, this Kit mutant mice, basophils, but not mast cells or other cell types, were
is neutropenic, which may be a major factor affecting depleted in blood and spleen. Mukai et al. (28) reported a dif-
immune responses in this strain (13). ferent basophil depletion model, in which the N-terminal
New mouse models have recently been developed to avoid sequences for P1-Runx were replaced with neor gene, resulting
these problems. Several groups have reported the generation in the absence of both P1-Runx1 transcriptions and protein.
of mice expressing Cre recombinase under the control of These mice showed a severe reduction in basophils, but not eo-
mast cell protease genes (14–16) (Table 2). In 2011, four lab- sinophils, neutrophils, or mast cells. Sawaguchi et al. (29)
oratories used their mice or additionally generated lines to reported Bas-TRECK Tg mice using DTR transgene under
obtain Kit-independent mast cell-deficient mouse strains (6, the control of 50 enhancer, promoter, and intronic enhancer of
17–19). These strains differ in the selected gene loci as well as IL-4. Whereas new mast cell depletion models exhibited mar-
in the methods to drive ectopic gene expression in mast cells ginal effects on basophil depletion, new basophil depletion
(targeted knock-in or transgenic overexpression) and in models seem to have no effect on other immune cell depletion.
depletion mechanisms. Dudeck et al. generated a mast cell
depletion model, which is based on mast cell protease (Mcpt)
Mast cell and/or basophil involvement in several skin
5-Cre transgenic mice crossed with i diphtheria toxin receptor
diseases
(iDTR) line (17). In the Mcpt5-Cre+iDTR+ mice, a single
injection of DT results in a complete loss of peritoneal mast Various models of severe inflammatory autoimmune diseases
cells but not skin mast cells. For the depletion of mast cells reveal that neutrophil infiltration into the sites of local
in ear skin, Mcpt5-Cre+iDTR+ mice need additional local inflammation and tissue destruction critically depends on
injection of DT (17). The constitutive mast cell depletion mast cells. Involvements of mast cells have been suggested in
model was generated with Mcpt5-Cre mice crossed with the several animal disease models, such as psoriasis, rheumatoid
R-DTA line (20). Both models exhibited no depletion in other arthritis (RA) (30–32), and bacterial infection (33, 34). These
cell types. Lilla et al. (19) crossed mice carrying the Cpa3-Cre observations seem to be highly relevant in terms of our
transgene with mice in which the first exon of myeloid cell understanding of human diseases, as large numbers of acti-
leukemia sequence 1 (Mcl-1) is flanked by LoxP sites and vated mast cells infiltrate the tissues in the corresponding
generated constitutive mast cell deficiency. These mice exhibit human diseases, such as allergic contact dermatitis, psoriasis,
reductions in mast cell number in all tissues but also marked and RA (35–37). In addition to these diseases, mast cells are
reduction in basophils, splenic neutrophilia, and macrocytic involved in multiple inflammatory and malignant diseases
anemia. Feyerabend et al. (18) also generated a mast cell (Table 3).

132 Allergy 70 (2015) 131–140 © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Otsuka and Kabashima Mast cells and basophils

Table 2 Summary of mast cell- and basophil depletion models

Mouse strain Description Model of depletion Deleted population Remarks Refs

Mast cells
Mcpt5-Cre BAC transgene (129 kb, Cross with Cre-iDTR CTMCs (>90%) MMCs and basophils (16, 17)
Cre inserted after the mice or R-DTA mice. are not deleted
Mcpt5 start codon)
Cpa3-Cre Promoter transgene Mcl-1fl/fl mice causes CTMCs and MMCs (>90%), Mice develop splenic (19)
impaired survival basophils (60–80%) neutrophilia and
macrocytic anemia
Cpa3Cre Knock-in of Cre before Constitutive depletion CTMCs and MMCs (100%), NA (18)
the first exon of Cpa3 basophils (60% in the
spleen)
Mas-TRECK DTR transgene (under DT injection CTMCs, MMCs, and Basophils are restored (6, 29)
the control of 50 basophils (90–100%) two weeks after DT
enhancer, promoter, treatment
and intronic enhancer
of IL4)
Basophils
Basoph8 Knock-in of IRES-YFP-Cre Cross with R-DTA mice Basophils (>90%) NA (26)
cassette before the
Mcpt8 start codon
Mcpt8-Cre BAC transgene (228 kb, Constitutive depletion Basophils (>90%) NA (21)
Cre inserted after the
Mcpt8 start codon)
Mcpt8DTR Knock-in of IRES-DTR-EGFP DT injection Basophils (>90%) NA (27)
cassette in 30 UTR
of Mcpt8
P1-Runx1 Knockout P1-Runx1 seems to be Basophils (>90%) NA (28)
important for the basophil
lineage
Bas-TRECK DTR transgene (under DT injection Basophils (>90%) NA (29)
the control of 50
enhancer, promoter,
and intronic enhancer
of IL4)

BAC, bacterial artificial chromosome; BMMCs, bone marrow-derived mast cells; CTMCs, connective tissue mast cells; DTR, diphtheria toxin
receptor; EGFP, enhanced green fluorescent protein; iDTR, inducible DTR; IL4, interleukin-4; IRES, internal ribosome entry site; P1-RUNX1,
distal promoter-derived runt-related transcription factor 1; Mcpt, mast cell protease; MMCs, mucosal mast cells; NA, not applicable; NR, not
reported; R-DTA, ROSA-diphtheria toxin-a; UTR, untranslated region; YFP, yellow fluorescent protein.

On the other hand, it is still largely unclear in which skin two major hypotheses have come to the fore as possible
diseases basophils are involved. Recent studies have shown explanation for the pathogenesis of this heterogeneous dis-
infiltration of basophils in several skin diseases, such as ato- ease: (I) One assumes that the primary defect is an immune
pic dermatitis (AD), prurigo, and urticaria (38). It is notable dysregulation that causes Th2-predominant inflammation and
that the skin lesions of bullous pemphigoid, classical eosino- IgE-mediated sensitization(42). In the other hypothesis (II),
philic pustular folliculitis (Ofuji’s disease), and Henoch– an intrinsic defect in skin barrier function such as a filaggrin
Sch€ onlein purpura also frequently show tissue basophilia mutation is underscored as a primary cause of the disease(43,
(38–41) (Table 4). 44). In the latter scenario, even the uninvolved phase of the
disease presents cutaneous hypersensitivity of nonlesional
skin, which results from a defective skin barrier that allows
The role of mast cells during AD pathogenesis
the penetration of allergens and microbial pathogens(44).
Atopic dermatitis is characterized by skin inflammation, As most studies have shown increased numbers of mast
impaired skin barrier function, and IgE-mediated sensitiza- cells in skin lesions in human AD and mouse AD models, it
tion to food and environmental allergens. The etiology of this is generally assumed that the mast cells contribute to skin
disease is not yet understood completely, but it is multifacto- inflammation. However, few studies have directly addressed
rial; the disease, moreover, is characterized by complex inter- whether, to what extent, or by what mechanism, mast cells
actions between genetic and environmental factors. Recently, play a role in the development of AD pathogenesis. IL-31, a

Allergy 70 (2015) 131–140 © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd 133
Mast cells and basophils Otsuka and Kabashima

Table 3 Dermatological diseases with evidence for mast cell activator of transcription 6 (Stat6) and IgE but dependent on
involvement CRTH2 (chemo-attractant receptor homologous molecule
Urticaria (92) expressed on Th2 cells), a PGD2 receptor. However, mast-
Localized mastocytoma (93) cell-reconstitution experiments have not been performed in
Systemic mastocytosis (93) either study. Interestingly, a recent study showed that FcɛRI
Contact dermatitis (6) and FccR are involved in a cutaneous OVA patch model(53).
Psoriasis and psoriasis arthritis (94, 95) However, the involved cell type was not investigated in this
Atopic dermatitis (96) study. Analysis using new cell-specific depletion models may
Bullous autoimmune diseases: bullous pemphigoid (97) answer this question.
Autoimmune vasculitis (98)
Systemic lupus erythematodes (99)
Systemic sclerosis and morphea (100)
The role of basophils during allergic skin response
Chronic graft-vs-host disease (101) The development of allergic reactions of the skin seems to be
Morbus Morbihan and rosacea (102) associated with basophil recruitment and activation (38).
Skin infections: bacteria, fungi, parasites (Leishmania major) While the effector functions of basophils in allergic airway
(103, 104) inflammation have been well studied (54), the roles of
Skin tumors: basal cell carcinoma, spinocellular carcinoma,
basophils in the allergic skin reactions remain largely unclear.
angiosarcoma (105)
Recent findings using basophil-specific depletion models have
revealed the essential roles of basophils in allergic skin
response.
The development of Th2 responses is one of the most piv-
Table 4 Dermatological diseases with evidence for basophil infiltra-
otal steps during allergic skin reaction. Basophils have been
tion
proposed to play a crucial role for Th2 cell differentiation in
Atopic dermatitis (38) mice (55–57). It has been reported that CD49b+ FceRI+
Prurigo (38) c-Kit basophils migrate into draining LNs from the skin site
Urticaria (38) of papain injection and thus act as antigen-presenting cells
Pemphigus vulgaris (38) (APCs) by taking up and processing antigens (56). In addi-
Drug eruption (38) tion, basophils express MHC class II and costimulatory mol-
Henoch–Scho €nlein purpura (38)
ecules and secrete IL-4 and thymic stromal lymphopoietin
Insect bite: tick bite (41)
(TSLP), which are critical for Th2 development. Therefore,
Scabies (38)
basophils alone are considered to induce Th2 polarization
Dermatomyositis (38)
from na€ıve T cells without requiring DCs under certain con-
Eosinophilic pustular folliculitis (40)
ditions. In contrast, another group has found that IL-4-pro-
Leprosy: LL type (39)
Bullous pemphigoid (106)
ducing basophils were recruited to the mediastinal LNs upon
Eosinophilic folliculitis (106) primary exposure to house dust mites. In this case, they con-
Wells’ syndrome (106) tributed to the strength of the Th2 response in the lungs, but,
in this model, basophils could not present antigens or express
the chaperones involved in antigen presentation (24). There-
fore, the authors claimed that DCs were necessary and suffi-
4-helix-bundle cytokine, is a new candidate of itch mediator, cient for inducing Th2 immunity to house dust mites in the
preferentially produced by T cells skewed toward Th2 (45). lungs without the requirement of basophils. It has consis-
Leukocytes in patients with AD expressed significantly higher tently been reported that Th2 responses are severely impaired
IL-31 levels compared with those of control subjects, and either after Schistosoma mansoni egg injection or during
serum IL-31 levels correlate with disease activity in AD (46– active Schistosoma mansoni infection by the depletion of
48). It was reported that the number of IL-31-positive mast CD11c+ cells but not by the depletion of basophils
cells was increased in the lesional skin with AD patients, and using anti-FceRIa antibody (58). Therefore, the role of
human mast cell lines upregulated IL-31 in the presence of basophils in the development of the Th2 response has been
antimicrobial peptides that were highly detected in the AD controversial.
skin lesion (49, 50). These results provide evidence that mast We have demonstrated that basophils are responsible for
cells may be involved in the pathogenesis of AD. cutaneous Th2 skewing to haptens and peptide antigens but
In mice, epicutaneous application of ovalbumin (OVA) not protein antigens using Bas-TRECK Tg mice, a new baso-
protein is widely used for the induction of AD-like dermati- phil-deficient model (7). Interestingly, basophils expressed
tis. Although skin inflammation induced by epicutaneous MHC class II, CD40, CD80, CD86, and IL-4 in the hapten-
application of OVA is comparable in wild-type and KitW/Wv induced cutaneous Th2 model. In vitro experiment, we
mice (51), skin inflammation induced by cutaneous sensitiza- showed that basophils could not take up or process OVA
tion with cedar pollen antigens was abolished in KitW/Wv protein sufficiently using the DQ-OVA system. We assume
and KitSl/Sld mice (52). This cedar pollen dermatitis model that the discrepancy stems not from the different routes of
was found to be independent of signal transducer and antigen administrations but from the different types of

134 Allergy 70 (2015) 131–140 © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Otsuka and Kabashima Mast cells and basophils

antigens used such as proteins, peptides, and haptens. Hapten An essential step in the sensitization phase for CHS is the
antigens may bind to MHC class II on the surface of migration of hapten-bearing cutaneous DCs, such as
basophils directly, and peptides can be acquired and pre- epidermal Langerhans cells (LCs) and dermal DCs, into the
sented by basophils, while protein antigens are not presented skin-draining lymph nodes (LNs). After completing their
efficiently by basophils because the protein is hardly digested maturation, matured DCs present antigens to naive T cells in
by basophils. In fact, previous reports have demonstrated the LNs, thus establishing the sensitization phase. In the sub-
that basophils promote Th2 induction using OVA peptide sequent challenge phase, re-exposure to the cognate hapten
but not OVA protein in vitro (56, 57). The protease allergen results in the recruitment of antigen-specific T cells and other
papain reaches the LNs after cutaneous immunization and non-antigen-specific leukocytes.
induces MHC class II expression on basophils in accord with The functions of cutaneous DCs are modulated by kerati-
the preparation of OVA peptide antigens from OVA protein nocyte-derived pro-inflammatory cytokines (64). The role of
in vivo (56). Another group has reported that basophils the different skin DC subsets in CHS (inducers, regulators,
pulsed with anti-2, 4-dinitrophenyl (DNP-IgE) exhibit or functional redundancy) is a matter of active debate (65).
enhanced Th2 skewing upon exposure to DNP-conjugated In addition, dermal DCs, including Langerin (CD207)+, may
OVA by taking up DNP-OVA–IgE anti-DNP immune com- also play an important role in CHS (66).
plexes (57). Although house dust mites also contain cysteine Mast cells are a candidate DC modulator as they express
protease activity, they are not sufficient for Th2 induction as and release a wide variety of intermediaries, such as hista-
they do not upregulate MHC class II on basophils in this mine, TNF-a, and lipid mediators. It has been reported that
model even though cysteine protease may work to prepare activated human cord blood-derived mast cells induce DC
peptide antigens from protein antigens in vivo (24). maturation in vitro (67), that IgE-stimulated mast cell-derived
Additionally, our group reported that basophils increase histamine induces murine LC migration in vivo (68), and that
the frequency of IL-4-positive CD4+ T cells by the aid of MC-derived TNF-a promotes cutaneous murine DC migra-
DCs (7). As basophils cannot take up or process protein tion in vivo in an IgE-independent manner (69), and coculture
antigens efficiently, DCs may prepare peptides to be pre- of mast cells and DCs results in upregulation of DC matura-
sented by basophils or may promote basophils to produce tion markers, such as CD40, CD80, and CD86 (70). More-
IL-4 to skew Th2. In line with this, our study has demon- over, mast cells were a requisite for the migration of
strated that Langerhans cells, an epidermal DC subset, medi- plasmacytoid and CD8+ subsets of DCs into the draining
ate epicutaneous sensitization with OVA protein antigens to LNs (71). On the other hand, prostaglandin (PG) D2 is abun-
induce Th2-type immune responses (59). In addition, Th2 dantly produced by mast cells in response to allergens (72)
reaction was reduced upon sensitization with protein antigens and inhibits LC migration (73). Therefore, MCs might have
or schistosome infections in a CD11c-depletion model (24, bi-directional effects on DC activity in a context-dependent
58); therefore, DCs seem to be necessary for Th2 induction manner, and the question of the mechanisms by which DCs
both in vivo and in vitro upon protein antigen exposure. are modulated by mast cells is an important issue to pursue.
Given that basophils were found in the vicinity of T-cells in While basophils operate irrespective of the stage of CHS
the T-cell zone of the draining LNs, it is possible that ba- development (7), the role of mast cells in CHS remains con-
sophils, T-cells, and DCs promote Th2 induction in a coordi- troversial. In some studies, mast cell-deficient mice have
nated way. It would be intriguing to further evaluate whether exhibited a reduced inflammation in TNCB-induced CHS
DCs present peptides to basophils directly or by trogocytosis (74, 75). Other studies reported undiminished CHS induced
for the transfer of plasma membrane fragments from APCs with TNCB or DNFB (76, 77). Furthermore, a recent publi-
to lymphocytes. cation reported that mast cells have regulatory roles through
Although murine basophils have been reported to function their production of IL-10, as mast cell-deficient mice exhib-
as APCs, subsequent studies investigating the role of basoph- ited enhanced urushiol and DNFB-induced CHS (78). In
ils as APCs in human subjects have been less clear. It has these studies, however, mice carrying mutations in the stem
recently been demonstrated that human basophils also cell factor or its receptor c-Kit were used as mast cell-defi-
express MHC class II (60, 61) and that MHC class II cient mice (C57BL/6-KitWsh/Wsh or WBB6F1-Kitw/wv).
expressing basophils were incapable of inducing antigen-spe- Although these mice lack mast cells, they also have various
cific T-cell activation or proliferation upon house dust mite other immunological alterations, making it difficult to form a
allergen as antigens (61). Therefore, future studies are needed conclusion regarding the role of mast cells in CHS based
to determine the clinical significance of human basophils as solely on studies using these mice.
APCs. In new mast cell depletion models (7, 17), it has been
reported that mice depleted of mast cells exhibited reduced
CHS induced with FITC, oxazolone, or DNFB (7, 17). In
The role of mast cells during contact hypersensitivity
addition, mast cell-specific depletion of IL-10 did not result in
Contact hypersensitivity (CHS) has been widely used as a exacerbated CHS. Using Mas-TRECK Tg mice, we demon-
model to study cutaneous immune responses, as it is a strated that skin DC migration and/or maturation and T-cell
prototype of delayed-type hypersensitivity mediated by anti- priming in the sensitization phase were impaired (6). Mast cells
gen-specific T cells (62, 63). Contact hypersensitivity is stimulated DCs via ICAM-1 or lymphocyte function-associ-
classified into a sensitization phase and an elicitation phase. ated antigen 1 interaction and by membrane-bound tumor

Allergy 70 (2015) 131–140 © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd 135
Mast cells and basophils Otsuka and Kabashima

necrosis factor a on mast cells (6) (Fig. 1). Interestingly, acti- humans or cutaneous basophil hypersensitivity (CBH) in gui-
vated DCs in turn increased Ca2+ influx in mast cells (6), sug- nea pigs (83). CBH is distinct from the classical delayed-type
gesting that mast cells and DCs interact to activate each other. hypersensitivity in several aspects (83). In general, CBH is
In the elicitation phase, mast cell deficiency resulted in an elicited by the immunization of proteins in incomplete Fre-
impaired CHS response, probably as a result of reduced vascu- und’s adjuvant (without mycobacterial components), whereas
lar permeability caused by a loss of histamine release from immunization using complete Freund’s adjuvant (with myco-
mast cells (17). bacterial components) is usually needed to elicit the classical
To date, it remains unknown why there is such a discrep- hypersensitivity. CBH is characterized by erythema and a
ancy between the reports using stem cell factor-deficient or slight thickening; it peaks at 18–24 h after the antigen chal-
c-Kit-deficient models and those using conditional mast cell lenge and fades by 48 h. Classical delayed-type hypersensitiv-
ablation models. One of the differences between these two ity, on the other hand, is characterized by erythema and
models is the existence of melanocytes and hematopoietic induration; it reaches its maximal intensity within 24–30 h
stem cells. Recently, melanocytes were shown to express and remains indurated as long as 48–72 h (84).
TLRs to modulate immune responses and to produce IL-1a In 2005, it was reported that basophils contributed to a
and IL-1b (79, 80). In addition, because of the congenital novel type of chronic IgE-mediated allergic inflammation in
absence of mast cells in KitW/Wv and KitWsh/Wsh mice, a mice (85). Although basophils are not essential for the imme-
compensatory mechanism may exist such as the repopulation diate- and late-phase responses that occur after multivalent
of the skin with basophils (81). Therefore, KitW/Wv and antigens are administered via a single subcutaneous injection
KitWsh/Wsh mice may not necessarily be appropriate to into the ear, they are required for the IgE-mediated chronic
evaluate the exclusive roles of mast cells. Consistent with the allergic inflammation that follows. IgE-mediated chronic
results using Mas-TRCK Tg mice, the CHS response was allergic inflammation (IgE-CAI) was found to be independent
reduced in DT-treated Mcpt5-Cre+iDTR+ mice (17), which of mast cells and T cells but was dependent on an FceRIa+,
showed the attenuation of CHS response using DNFB and CD49b+ cell population identified as basophils (85). Interest-
FITC as hapten. Thus, newly generated mast cell depletion ingly, although basophils accounted for only 1–2% of the
mouse models provided evidence that mast cells promote the cellular infiltrate at the site of the skin lesion, their depletion
development of CHS irrespective of the type of haptens. led to a dramatic reduction in inflammation associated with
a decrease in the number of eosinophils and neutrophils and
a marked reduction in ear thickness (85). Recent studies have
Basophil-dependent delayed-type hypersensitivity
shown that inflammatory monocytes recruited to IgE-CAI
A cutaneous delayed-type hypersensitivity reaction containing lesions acquire an anti-inflammatory M2 phenotype via baso-
large basophil infiltrates was extensively studied in the 1970s phil-derived IL-4 (86). Collectively, these results illustrate the
(82). It was termed Jones-Mote hypersensitivity (JMH) in potent inflammatory effects of small numbers of basophils

Figure 1 Schema of contact dermatitis. Upon exposure to anti- and membrane-bound TNF-a expressed by mast cells. DCs, in turn,
gens, keratinocytes produce pro-inflammatory cytokines, such as induce calcium flux into MC by unknown mechanism. In the drain-
TNF-a and IL-1a. These cytokines promote DC maturation and ing LNs, matured DCs present antigens to na€ıve T cells for the
migration into draining LNs. In addition, mast cells interact with induction of memory/effector T cells and their expansion.
DCs in the dermis and stimulate DCs via ICAM-1-LFA-1 interaction

136 Allergy 70 (2015) 131–140 © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Otsuka and Kabashima Mast cells and basophils

and suggest a novel, nonredundant role for basophils in the beyond our understandings a decade ago. At the same time,
initiation and maintenance of chronic IgE-mediated inflam- however, some key questions remain unanswered, such as
matory responses in mice. what role basophils play in pathogenic processes, where they
Human basophils have some different roles when com- are detected in the lesional skin, and how DCs present pep-
pared with mouse basophils. For instance, mouse basophils tides to basophils during Th2 skewing. In addition, there still
produce platelet-activating factor upon activation, which sig- remains a compelling need to determine whether these find-
nificantly contributes to the development of anaphylaxis in ings in mouse models are relevant to humans, especially
response to penicillin–IgG antibody complexes; however, about basophils, most of the current knowledge in vivo is
human basophils do not respond to IgG immune complexes based on the murine model. Further studies are needed to
(87, 88). On the other hand, some findings from mouse investigate the counterpart in human skin diseases in the
basophils might shed light on the pathogenesis of human future. However, the newly developed mast cell-deficient or
cutaneous diseases. Approximately 40% of patients with basophil-deficient models can provide us with valuable infor-
chronic idiopathic urticaria (CIU) have antibodies to FceRIa. mation on the mechanisms of cutaneous diseases. Future
Some patients with CIU exhibited urticaria in response to studies focusing on this topic will enable us to develop novel
IgG anti-IgE and/or FceRIa antibodies that might activate therapeutic approaches to controlling cutaneous inflamma-
mast cells or basophils (89). In addition, incubation of donor tory diseases.
basophils with sera from patients with CIU and positive autol-
ogous serum skin test demonstrated a significant upregulation
Acknowledgments
of CD203c (90). Furthermore, basophils in urticarial lesions of
CIU are known to increase in number (38, 91). Consistently, This work was supported in part by Grants-in-Aid for Scien-
basopenia in CIU appears to be due to the migration of ba- tific Research from the Ministry of Education, Culture,
sophils from the peripheral blood to urticarial lesions (38, 91). Sports, Science and Technology and the Ministry of Health,
Therefore, the phenomenon seen in a mouse IgE-CAI model Labor and Welfare of Japan. Dr Kabashima is the winner of
might explain the pathogenesis of human CIU. PhARF (Phadia Allergy Research Forum) Award 2013.
http://www.phadia.com/en/Allergy-Blood-Testing/Learn-more/
PhARF/Award-2013/.
Conclusion
Through studies with newly developed mast cell-deficient or
Conflicts of interest
basophil-deficient mice, our understanding of the mechanisms
of cutaneous immune reaction has advanced significantly The authors declare that they have no conflicts of interest.

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