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Review Article
Mast Cell and Autoimmune Diseases
Yunzhi Xu and Guangjie Chen
Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine,
Shanghai Institute of Immunology, Shanghai 200025, China
Correspondence should be addressed to Guangjie Chen; guangjie chen@.com
Received December ; Revised March ; Accepted March
Academic Editor: Teresa Zelante
Copyright © Y. Xu and G. Chen. is is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Mast cells are important in innate immune system. ey have been appreciated as potent contributors to allergic reaction. However,
increasing evidence implicates the important role of mast cells in autoimmune disease like rheumatoid arthritis and multiple
sclerosis. Here we review the current stage of knowledge about mast cells in autoimmune diseases.
1. Introduction
If the immune system fails to recognize self- from non-
self-molecules, self-reactive lymphocytes can be activated by
innate immune cells and lead to an autoimmune response
[]. Genetics, hormonal inuences, and environment play
important roles in autoimmune diseases. Some of the factors
have been identied [–]. However, the specic determi-
nants that initiate an autoimmune response and allow it
to be sustained and cause pathology are still unknown.
Autoimmune diseases and allergic diseases share important
features. Both of them are the result of “hypersensitive”
immune responses directed toward inherently harmless anti-
gens []. Besides, many diseases models that we now know
are regarded as autoimmune diseases, such as “experimental
allergic” neuritis, encephalomyelitis, orchitis, uveitis, and
glomerulonephritis []. It is accepted that the cells of the
adaptive immune system are the directors of autoimmune
responses [].Inaddition,innateimmunecellsarecriticalfor
sustaining the response that leads to pathology [–].
Mast cells (MCs) are rst described by Paul Ehrlich in
[].eyhavebeenviewedaseectorsinIgE-mediated
allergic or antiparasitic responses; however, researches in the
last two decades have found that MCs are also involved
in innate immunity and inammation by releasing a large
array of inammatory mediators [,]. ese mediators
include compounds such as histamine and MC specic
proteasesprestoredincytoplasmicsecretorygranules(SGs)
and newly synthesized lipid mediators such as leukotrienes
or prostaglandins or a variety of cytokines, chemokines, and
growth factors [].
e idea that MCs are involved in the initiation and
sustaining events of autoimmunity is based on abundant data
from studies of both human disease and animal models [–
].
2. Mast Cells
MCswerediscoveredbyFriedrichvonRecklinghausenin
and named by Paul Ehrlich in []. Connective
tissue is derived from undierentiated mesenchymal cells.
Duringtherstyearsaerthediscovery,itwasbelieved
that MCs were a component of connective tissue, functioned,
anddiedwithinconnectivetissue[]. Furthermore, MCs
complete dierentiation in connective tissue []. Until the
s, in vivo and in vitro evidence showed that MCs originate
from hematopoietic stem cells, but the mast cell-committed
precursors (MCPs) have not been identied [,]. In the
work of Chen et al., MCPs in the bone marrow of adult
mice were identied. ey are identied by the phenotype
Lin−c-Kit+Sca-−Lyc−Fc𝜀RI𝛼−CD−𝛽+T/ST+[].
In addition, the experiment strongly suggests that MCPs are
the progeny of multipotential progenitors (MPPs) other than
common myeloid progenitors or granulocyte/macrophage
progenitors [].
Development of MCs from MPPs does not need cell
division [].ItisknownthatMCsleavethebonemarrow
as immature cells and they mature via abundant cytokines
Hindawi Publishing Corporation
Mediators of Inflammation
Volume 2015, Article ID 246126, 8 pages
http://dx.doi.org/10.1155/2015/246126
Mediators of Inammation
Mast
cell
OX40L
Tre g
OX40
Inhibits MC degranulation,
suppresses Treg and,
promotes 17
17
Tre g
IL-6
Dierentiation
17
T cell
Mast
cell
CD4+
TGF𝛽, IL-21, and IL-23
F : Direct cell interaction between mast cells and T cells.
inthelocaltissuemicroenvironment[,]. For example,
nervegrowthfactor(NGF)iswellknownasanimportant
MCs growth factor []. However, MCs show plasticity [].
Moreover, mature MCs show extensive proliferation potential
[].
e granules of MCs can be stained metachromatically
purple with Toluidine Blue and it is routine staining for
the demonstration of MCs [,]. MCs are dened as
connective tissue mast cells (CTMCs) and mucosal mast
cells (MMCs) by the histamine, cytokines, and proteolytic
enzyme which MCs store []. In addition to innate and
acquired immunity, MCs play important role in bacterial
infection and autoimmunity [,,]. MCs can secrete the
contents of preformed cytoplasmic secretory granules (SGs)
while encountering certain stimulants. For MCs, this process
is fundamental to their role in innate and acquired immunity
[].VariousmoleculesareabletoactivateMCs.
3. Interactions between Mast Cells and
Other Cells
MCs can work with other cells like T and B lymphocytes
to enhance activation and migration by cell-cell interactions
or secreted products [,]. Recently, the role of the inter-
actions between mast cells and other cells in autoimmune
diseases is becoming apparent [].
3.1. Interaction among Mast Cells, T Regulatory Cell (Treg),
and 17 Cells. Treg cells are dened as CD+CD+FoxP+
and are known to suppress T eector cell response. us
Treg cells can induce tolerance and control autoimmunity.
MCs and Treg cells constitutively express OXL and OX,
respectively. erefore, mast cell-Treg cell interactions are
in an OX-dependent way. Gri et al. found that Treg
cells directly inhibited Fc𝜀RI-dependent MC degranulation
through cell-cell contact requiring OX-OXL interaction
[](Figure ). Kashyap’s group showed that coculture
with Treg enhanced cytokines production by MCs [].
In addition, MCs can also suppress Treg activity in an
OXL-independent way []. However, the relationship
between MCs and Treg cells needs to be further explored in
autoimmunity.
cells are CD+T cells. At the meantime, they are
dened by the expression of the transcription factor ROR𝛾t
and cytokines IL-. As cells, cells are involved in
the mouse models of MS and RA. e combination of TGF𝛽,
IL-,IL-,IL-,andIL-𝛽contributes to the dierentiation
of from a na¨
ıve CD+Tcell.TGF𝛽is essential for
the development of Treg cells, but it is inhibited by IL-.
MCs can express TGF𝛽, IL-, IL-, and IL- under some
condition and promote Treg and cell dierentiation and
plasticity []. It is interesting that MCs counteract Treg cells
suppression through IL- and OX-OXL axis towards
cell dierentiation [](Figure ).
3.2.InteractionbetweenMastCellsandBCell. MCs express a
variety of B cell-modulating molecules and immunoglobulin
(Ig) receptors []. MC FcRs include IgE and IgG receptors
[]. Depending upon the type of MCs, IgG-antigen com-
plexes may activate MCs []. Conversely, the coengagement
of IgG and IgE receptors inhibits cells activation []. Increas-
ing data has been established indicating that MCs play critical
roles in IgG-dependent tissue-specic autoimmune diseases
[]. Low amounts of MCs are eective in inuencing B cell
survival and proliferation in vitro through cell-cell contact
and MC-derived IL- expression whatever state the MC
activation is in []. Furthermore, MCs can promote B cells
to dierentiate into CD+plasma cells secreting IgA and it
is dependent on CD-CDL expressed on B cells and MCs,
respectively [](Figure ).
4. MCs and Autoimmune Diseases
It is well known that T cells are important in directing and
initiating the immune response in the target tissues []. In
addition, other cells also play an important role in aggravat-
ing the inammatory damage []. Furthermore, there are
several examples of MCs association with autoimmune dis-
eases including multiple sclerosis (MS), rheumatoid arthritis
(RA), insulin-dependent diabetes mellitus (IDDM), bullous
Mediators of Inammation
CD40LCD40
B cell
Mast
cell
FcRs
IgG IgE
Dierentiation
CD138+
plasma
cells
IgE binds without
antigens and MCs
are activated
F : Direct cell interaction between mast cells and B cells.
pemphigoid, chronic idiopathic urticaria, and experimental
vasculitis [–]. Here we take MS, RA, IDDM, and chronic
urticaria (CU) for example and summarize the role of MCs
in the autoimmune diseases.
4.1. MCs and MS. Mostly, the interest in the role of MCs in
the initiation and propagation of autoimmune disease comes
from studies on MS [].
MS is a progressive demyelinating disease. Widespread
inammatory lesions present in the brain and spinal cord
of patients with MS []. e symptoms of MS contain
visual disturbances, bowel and bladder incontinence, and
sensory and motor dysfunction []. Furthermore, patients
with MS are found to lose memory, impair attention, and slow
information processing [,]. Experimental autoimmune
encephalomyelitis (EAE) is a murine model of MS. Similar
to MS, the symptoms of EAE resulted from breach of the
blood-brain barrier (BBB) which allows inammatory cells to
inltrate into the central nervous system (CNS) and destruct
myelin and oligodendrocytes []. CD+Tcells,including
IFN-𝛾-secreting T helper cells (), IL--producing T
helper cells (), and IL--producing T helper cells
(), contribute to the pathogenic autoimmune response in
EAE []. However, the roles of these cells in MS are still
unclear [].
ere are MCs in the leptomeninges, the choroid plexus,
thalamus, hypothalamus, and median eminence []. Similar
to CTMCs and MMCs, brain mast cells (BMCs) can be
identied morphologically by Toluidine Blue staining mostly.
Moreover, histamine uorescence with o-phthaldialdehyde
is able to show BMCs in the leptomeninges, thalamus, and
hypothalamus. And histamine immunohistochemistry can
showBMCsinthemedianeminence[–]. However,
many BMCs are stained with Sudan Black which is distinct
from CTMCs or MMCs []. Additionally, the ultrastructural
appearance of activated BMCs is dierent from that of
CTMCs because it is primarily characterized by intragranular
changes without typical compound exocytosis [,]. ey
may regulate vascular permeability and inammatory cell
entry in the brain parenchyma []. Moreover, there is
interaction between functional MCs and neuron in the brain
and it can mediate neuroinammation.
Kruger et al. have observed MCs within the demyelinated
plaques in the brains of patients with MS []. Moreover,
MCswerefoundmostlylocatedincloseconnectionwith
small vessels []. e data suggest that MCs playing a role
in MS have continued to accumulate []. It is reported that
mast cell decient mice fail to develop EAE []. As in MS,
an increase of MCs is also found at sites of inammatory
demyelination in the brain and spinal uid of EAE []. MCs
are associated with Fc𝜀R, the histamine- (H) receptor, and
tryptase []. Elevated levels of tryptase are present in the
cerebrospinal uid of MS patients and gene array analyses of
MS reveal overexpression of genes encoding Fc𝜀R, H recep-
tor, and tryptase [,]. BMCs do not express their surface
growth factor (c-kit) receptor normally but do so during EAE
[]. Several studies reveal that mast cell-derived mediators
can increase BBB permeability [,]. Products produced
by MCs can enter neurons and this indicates a new brain-
immune system []. Rat BMCs can produce tumor necrosis
factor (TNF) and TNF take part in both brain inammation
and increased vascular permeability [,]. An increased
mast cell tryptase in the cerebrospinal uid (CSF) of MS
patients can activate peripheral mononuclear cells to secrete
TNF, IL-, and IL- and stimulate protease-activated receptor
(PAR) which leads to microvascular leakage and widespread
inammation [,,]. Besides, human MCs will secrete
matrix metalloproteinase- (MMP-) and IL- while contact-
ing activated T cells []. So we proposed that MCs may be
an underestimated contributor to the demyelinating process
of MS.
All in all, MCs participate in the pathogenesis of MS
in many dierent ways []. Firstly, they release cytokines/
chemokines to recruit and activate T cell/macrophage aer
stimulation. Secondly, MCs present myelin antigen to T
cell. Furthermore, MCs disrupt the BBB to allow activated
T cells to inltrate to brain and target in myelin basic
protein(MBP).Whatismore,MCsdamagemyelinand
then release fragments resulting in stimulating secretion of
tryptase. In turn, it enhances demyelination and induces
further inammation through stimulation of PAR possibly.
As a result, MCs can be a possible therapeutic target for MS.
In vitro, on one hand, mast cell proteases degrade myelin
protein, while on the other hand, myelin stimulates mast
Mediators of Inammation
cell degranulation directly [,]. erefore, treatment with
inhibitors of mast cell degranulation may be a good way to
inhibit MS. Dimitriadou et al. found that hydroxyzine was
able to inhibit EAE [].
4.2. MCs and RA. RAisasystemicandchronicinammatory
disease that aects about % of the population worldwide
[,]. Aer decades of research, we have found that T and B
lymphocytes, neutrophils, monocytes, and vascular endothe-
lium play the roles in RA []. However, the pathogenesis and
mechanism of RA are still unclear []. Rodent models of
autoimmunediseasesareofgreatusetostudythepathogenic
process of diseases. ere are a number of models of RA
including K/BxN, adjuvant-induced and pristane models, but
the streptococcal cell wall (SCW) arthritis in rat and the
collagen-induced arthritis (CIA) in mice are the most widely
used [].
Lee et al. found that W/Wv and Sl/Sld, which are decient
in MCs, were resistant to development of joint inammation.
eyproposedthatMCsmayserveasacellularlinkamong
numerous components in inammatory arthritis []. What
is interesting is that MCs are normally expressed in the
synovial compartments of healthy people but increased in
RA patients []. e number of MCs increases - to -
fold in aected joints in human RA when compared to the
number of those in normal joints []. It is also found that
MCsnumberexpandmorethan-foldinmultipleanimal
models of RA [–]. Besides, the cytokines and proteases
which are produced by MCs are involved in the pathogenic
process of RA, particularly TNF, IL-𝛽,IL-,andtryptase
[,]. Tryptase is a preformed mast cell-specic protease
and is thought to lead to the inammatory response by
working with heparin to induce the neutrophils and synovial
broblasts to release cytokines []. Tryptase can also directly
activate synovial broblasts by interacting with the protease-
activated receptor (PAR) to express more proteases that
degrade cartilage and bone [,].
Matsumoto and Staub’s group found that RA may be asso-
ciatedwiththeenzymeglucose--phosphateisomerase(GPI)
[]. K/BxN mice produce autoantibodies that can recognize
GPI. e antibodies aggregate with GPI, and then immune
complex is deposed on the surface of the articular cavity to
initiate a signaling cascade including MCs. Cytokines such
as IL- and IL-A are also involved [,]. e serum from
K/BxN mouse causes similar inammatory arthritis in a wide
range of mouse strains, but KitW/W-v mouse decient in MCs
resistant to autoimmune inammatory arthritis was induced
by injection of sera from K/BxN mouse. If the MCs are recon-
stituted, the sensitivity would be restored []. KitW-sh mice
decient in MCs are sensitive to autoimmune inammatory
arthritis induced by injection of sera from K/BxN mouse and
mast cell-reconstituted KitW-sh mice are still susceptible to
arthritis induced by sera from K/BxN mouse [].
MCs accumulate in the synovial tissues and uids of
patients with rheumatoid arthritis and produce inamma-
tory mediators []. In addition to the degranulation in the
articulate cavity aer antibody administration, the activation
of MCs through the IgG immune complex receptor Fc𝛾RIII
can precipitate the initiation of inammation within the
joint through the production and release of IL- [,].
Stem cell factor (SCF) is essential for mast cell survival and
development in vitro []. Furthermore, TNF-𝛼derived from
MCs can induce broblasts to produce SCF, the ligand for the
CD/c-Kit receptor [,]. SCF increases the recruitment
of MCs and creates an amplication loop [,].
4.3. MCs and IDDM. Insulin-dependent diabetes mellitus
(IDDM) is also called type I diabetes. IDDM is a chronic
metabolic disorder that develops in two discrete phases and
is mediated in part by CD+Tcells[,]. In the process
of IDDM, various leukocytes invade the pancreatic islets
and lead to insulitis. en the insulin-producing 𝛽cells of
the pancreas are destructed and lead to hyperglycemia [].
Furthermore, IDDM is commonly associated with immune-
mediated damage []. ere are several rodent models of
IDDM. In susceptible rodents, small dose of streptozotocin
induces insulinopenic diabetes in which immune destruction
playstherole,asinhumantypeIdiabetes[]. In addition,
the nonobese diabetic (NOD) mouse and biobreeding (BB)
rat are the two most commonly used animals that sponta-
neously develop diseases with similarities to human type I
diabetes [].
Normally, MCs locate within the pancreatic ducts and are
close to the pancreatic islets []. A lot of studies have found
a striking increase in the frequency of MCs in the acinar
parenchyma in inammatory disease of pancreas [–].
Besides, MCs produce various mediators which are able to
aect the development of IDDM. For example, leukotriene B
(LTB), which is released by MCs and may be important for
recruitment or retention of autoreactive T cells in the target
organ,isfoundincreasedintypeIdiabetes[]. What is the
most important is that Georey et al. discovered more MCs
in the pancreatic lymph nodes of lymphopenic diabetic BB
rats before disease onset []. As a result, there is suspicion
that MCs are involved in IDDM.
4.4. MCs and CU. Chronic urticaria (CU) is a distressing
disorder that adversely impacts the quality of life, but its
pathogenesis is not delineated well []. An autoimmune
subset of chronic spontaneous urticaria is increasingly being
recognized internationally based on laboratory and clinical
evidence that has accrued over the last years []. In ,
Lezno et al. suggested that urticaria should be considered
autoimmune []. Gruber et al. detected functional anti-
IgE antibodies and proposed that these could be the cause
of urticarial wheals []. And now it is well recognized
that about –% CU patients have circulating functional
autoantibodies against the high-anity IgE receptor or
against IgE []. Besides, CU is associated with various
autoimmune diseases [].
Urticaria is triggered by inappropriate activation and
degranulation of dermal mast cells. And the cellular contents
released by MCs prime the immediate phase of inamma-
tion, resulting in a lymphocyte and granulocyte mediated
hypersensitivity reaction []. In turn, the inltrating inam-
matory cells produce more proinammatory mediators to
Mediators of Inammation
recruit and activate other cells and extend the host response
[]. It lowers the reactive threshold of MCs to induce stimuli
and promotes the maintenance of susceptibility to urticaria
[]. It provides an explanation for Smith’s discovery that
MCs numbers remain unaltered [].Bossietal.evaluated
permeabilizing activity of sera from CU patients and healthy
people by measuring serum-induced degranulation of two
MC lines (LDA and HMC-) []. ey discovered that
almost all the CU patients sera promoted degranulation of
MCsand/mastcellsupernatantfromHMC-andSNs
from LAD incubated with CU sera increased endothelia
permeability []. It is said that histamine released from
MCs is the major eector on pathogenesis []. Bossi et al.
also found that endothelial cell leakage was prevented by
antihistamine [].
5. Conclusion
It is clear that MCs play an important role in autoimmune
diseases. In conclusion, MCs can worsen disease by a number
of mediators and counteracting Treg cells function. In the
mouse models of RA and MS, MCs promote inammation
inthesamewaylikeTNF.
MCs can be a new treatment target in the autoimmune
diseases because of their pivotal position in the inammation
process. e therapeutic strategies focus on three aspects as
follows: () at the level of the molecules produced by MCs,
() at the level of MCs activation, and () at the level of
MC proliferation []. e study of Saso demonstrated that
MCs can be inhibited through the action of an Fc𝜀–Fc𝛾
fusion protein engineered to engage human Fc𝛾RIIb with
high anity. is study suggests that analogous fully human
Fc𝜀–Fc𝛾tandem Fc biologic has potential as a potent and
selective inhibitor of cellular activation and degranulation
and thus represents a promising approach in treating mast
cell and basophil-mediated pathogenesis []. Masitinib, a
selective oral tyrosine kinase inhibitor, eectively inhibits the
survival, migration, and activity of MCs. Vermersch’s group
assessed the masitinib treatment in patient with progressive
MS and the data suggested that masitinib is of therapeutic
benet to MS patients [].
Cpa3Cre/+ mice are a strain decient in MCs. In spite
of a great deal of evidence of the involvement of MCs in
the autoimmune disease models, using Cpa3Cre/+ mice in
study did not nd an active role of MCs in both the K/BxN
serum transfer model of RA and the EAE model of MS [].
Besides, Gutierrez et al. found that IDDM in NOD mice
was unaected by mast cell deciency []. erefore, the
research about the roles of MCs in autoimmune diseases
remains a matter of great debate and ought to be further
studied, which is important for creating new MC targeted
therapies [].
Abbreviations
BB: Biobreeding rat
BBB: Blood-brain barrier
BMCs: Brain mast cells
CIA: Collagen-induced arthritis
CNS: Central nervous system
CSF: Cerebrospinal uid
CTMCs: Connective tissue mast cells
CU: Chronic urticaria
EAE: Experimental autoimmune
encephalomyelitis
GPI: Glucose--phosphate isomerase
H: Histamine-
IDDM: Insulin-dependent diabetes mellitus
Ig: Immunoglobulin
LTB: Leukotriene B
MBP: Myelin basic protein
MCPs: Mast cell-committed precursors
MCs: Mast cells
MMCs: Mucosal mast cells
MMP: Matrix metalloproteinase
MPPs: Multipotential progenitors
MS: Multiple sclerosis
NGF: Nerve growth factor
NOD: Nonobese diabetic mouse
PAR: Prot ease- a c t ivated receptor
PAR: Protease-activated receptor
RA: Rheumatoid arthritis
SGs: Secretory granules
SCW: Streptococcal cell wall
: T helper cells
: T helper cells
: T helper cells
TNF: Tumor necrosis factor
Treg: T regulatory cell.
Conflict of Interests
e authors declare that there is no conict of interests
regarding the publication of this paper.
Acknowledgments
is work was supported by grants from National Nature
Science Foundation of China (), Shanghai Com-
mission of Science and Technology (JC), Shanghai
Municipal Education Commission (ZZ), and Shanghai
Board of Health Foundation ().
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