classically mast cells are considered critical effector cells in allergy by virtue of their potential to secrete a variety of allergic mediators .
the number of mast cells is increased at sites of allergic inflammation , and there is a correlation between mast cell density in the tissue and the severity of allergic symptoms . in allergy , plurivalent antigens bind and crosslink ige molecules bound to the high - affinity ige - receptor ( fcri ) expressed on mast cells , resulting in cell degranulation and release of proinflammatory mediators .
three major categories of mast cell mediators have been described : ( 1 ) preformed granule - associated mediators such as histamine and serotonin ; ( 2 ) newly generated lipid mediators such as leukotrienes and prostaglandins ; ( 3 ) de novo synthesized cytokines including chemokines .
ige - mediated activation of mast cells initiates the early phase of allergic responses , resulting in pathologies including greater epithelial permeability , mucus production , smooth muscle contraction , vasodilitation and neurogenic inflammation .
the immediate response is followed by recruitment of a variety of other immune cells that participate in the late phase of the reaction , further exacerbating allergic pathology .
mast cells are derived from hematopoietic progenitors in the bone marrow which migrate via blood to tissues all over the body where they further differentiate and mature into different phenotypes , depending on the local microenvironment
. stem cell factor ( scf ) , also known as steel factor , kit ligand , or mast cell growth factor , is found to be the primary growth and differentiation factor for mast cells .
the cellular receptor for scf is the product of the c - kit proto - oncogene .
in addition to scf , mast cell growth and differentiation can be facilitated by several other cytokines including il-3 .
immature mouse mast cells can be differentiated in vitro from bone marrow precursor cells in the presence of il-3 without scf .
mast cells are enriched in the skin , around blood vessels , and in mucosal membranes such as the respiratory and gastrointestinal tracts .
most notably , mast cells are highly enriched in the skin and mucosal barriers of the body , where they serve as a first line of defense .
it is noteworthy that mature mast cells are capable of differentiating both phenotypically and functionally as a consequence of tissue - specific stimulation under defined microenvironmental conditions .
for example , inflamed lungs are reported to have more tryptase / chymase - producing mast cells compared with non - inflamed lung tissue in which tryptase - producing mast cells are dominant .
two major subtypes of rodent mast cells have been characterized , i.e. connective tissue mast cells ( ctmc ) and mucosal mast cells ( mmc ) , based on their tissue localization .
for instance , skin mast cells and mast cells residing in the peritoneal cavity are ctmc , whereas mast cells located in the respiratory or gastrointestinal tracts are usually characterized as mmc .
in addition to tissue localization , other properties such as protease and cytokine profiles , membrane receptor distribution , and growth factor requirements also distinguish these two types of mast cells .
in addition to residing in connective and serosal tissues , ctmc in mice have been found in the submucosa of the stomach and nasal tissue .
in contrast , human mast cells are usually grouped based on the expression pattern of two mast cell - specific proteases , i.e. tryptase and chymase . according to this classification , two major human mast cell subgroups have been proposed .
mast cells that contain only tryptase are referred to as mct , whereas those that contain both tryptase and chymase are termed mctc . in terms of correlation to their murine counterparts , mct are found mainly in mucosal tissues , resembling mouse mmc , while mctc , which reside in such sites as the skin and small intestinal submucosa , are more closely related to mouse ctmc , although the tissue localization is less stringent for human  ctmc  and  mmc  .
similar to mouse mast cells , human mast cells also differ in the requirement for growth and differentiation factors .
specifically , scf is needed for the survival of both types , whereas il-4 is indispensable for mctc , but not for mct .
in addition to ige- and fcri - mediated cell activation , mast cells can be activated by a variety of other stimulators , such as igg immune complexes , cytokines , complement components , neuropeptides , chemical agents , and physical stimuli , as mast cells express broad - ranging surface receptors including fc receptors , complement receptors , and pathogen - associated molecular patterns ( pamp ) such as toll - like receptors ( tlr ) .
these observations , together with the description of a wide spectrum of mast cell mediators , provide a basis for proposals implicating mast cells in almost all aspects of immune responses . therefore , mast cells have been postulated to be modulators of numerous physiological and pathological responses beyond their classically defined role in allergies mediated mainly through fcri .
it has to be pointed out that the overwhelming research findings addressing the roles of mast cells have relied on the use of mast cell - deficient , kit mutant mice which have other phenotypic abnormalities in addition to mast cell deficiency .
these data await further experimental verification using the kit - independent mast cell - deficient models to eliminate the confounding elements as a result of kit mutation .
in addition to ige- and fcri - mediated cell activation , mast cells can be activated by a variety of other stimulators , such as igg immune complexes , cytokines , complement components , neuropeptides , chemical agents , and physical stimuli , as mast cells express broad - ranging surface receptors including fc receptors , complement receptors , and pathogen - associated molecular patterns ( pamp ) such as toll - like receptors ( tlr ) .
these observations , together with the description of a wide spectrum of mast cell mediators , provide a basis for proposals implicating mast cells in almost all aspects of immune responses .
therefore , mast cells have been postulated to be modulators of numerous physiological and pathological responses beyond their classically defined role in allergies mediated mainly through fcri .
it has to be pointed out that the overwhelming research findings addressing the roles of mast cells have relied on the use of mast cell - deficient , kit mutant mice which have other phenotypic abnormalities in addition to mast cell deficiency .
these data await further experimental verification using the kit - independent mast cell - deficient models to eliminate the confounding elements as a result of kit mutation .
the earliest observation of a beneficial role of mast cells is their potential in defense against parasitic infection .
both ige and mouse mast cell protease-6 ( mmcp-6 ) are required for chronic immune responses against trichinella spiralis infections . in a helminth infection model ,
mast cells contribute to pathogen clearance by migrating to the draining lymph nodes and producing il-6 and il-4 .
interestingly , mast cells have also been described to be critical for th1 response - mediated defence against oral infection with toxoplasma gondii .
in addition to defense against helminth infections , mast cells have also been described to be protective in bacterial infections .
one of the classic examples of mast cell - dependent anti - bacterial infection is demonstrated by the cecal ligation and puncture ( clp ) model of acute peritonitis which is dependent on tumour necrosis factor ( tnf ) and the ability of mast cells to lower neurotensin levels .
furthermore , -hexosaminidase , which is abundantly contained in mast cell granules , has recently been reported to have bactericidal activity .
the roles and relevance of mast cells in defense against viral and fungal infections have also been suggested .
mast cells can be activated , through the equipped tlr , by direct recognition of microbial components such as bacterial lipopolysaccharide ( lps ) and peptidoglycan resulting in distinct outcomes .
furthermore , mast cells can be stimulated by endogenous inflammatory factors such as cytokines and complement components secondary to infection .
indirect interaction of mast cells with pathogens can also be achieved through the recognition of pathogen - antibody complexes by fc receptors including fcri and fc receptors expressed on mast cells .
fc receptor - mediated mast cell activation may also be triggered in the presence of certain pathogen - derived proteins that can bind immunoglobulins in an antigen - independent manner .
a classic example of such a bacteria - derived superantigen is protein a from staphylococcus aureus which can activate human and mouse tissue mast cells , as the fcri molecules on these mast cells are most likely to have already been occupied with ige , resulting in crosslinking of fcri upon protein a binding . however , the pathophysiological roles of such superantigen - mediated mast cell activation in defence against infection await further clarification .
similar to mast cell activation in other circumstances , the activation by pathogens is also believed to include both degranulation of pre - formed granular contents and selective de novo mediator production , for example , cytokines and lipid mediators , the patterns of which differ greatly depending on the stimulus encountered .
these mast cell - associated products , such as tnf , il-4 , ox40 ligand and mmcp-6 , are important for the recruitment and stimulation of other innate immune participants , e.g. neutrophils , macrophages , natural killer ( nk ) cells and eosinophils , contributing to the clearance of pathogens .
mast cells not only interact with cells in the immediate vicinity where the infection first takes place but also influence distant targets , e.g. cells in lymph nodes through mediators that they release .
it is also reported that mast cells can kill bacteria by producing extracellular traps that contain antimicrobial mediators .
in addition to contributing to innate immune responses by virtue of their large spectrum of granular products , mast cells also form a link between innate and adaptive immunity .
mast cells modulate the phenotype and function of key players in adaptive immunity , such as dendritic cells ( dc ) , b cells , and t cells .
mast cells have been shown to functionally interact with professional antigen presenting cells ( apc ) such as dc and regulate their function mainly through mast cell - derived granular products .
for example , histamine is capable of regulating the chemotaxis of immature dc and cross - presentation of extracellular antigens .
tlr7 ligand - mediated mast cell activation is effective for the migration and maturation of langerhans cells .
maturation and activation of immature dc by mast cell - dc direct contact results in the activation of t cells that release ifn- and il-17 promoting th1 and th17 responses , respectively .
mast cells provide essential signals such as il-6 and cd40l to enhance proliferation of b cells and drive their differentiation toward iga - secreting plasma cells .
mast cells can enhance the activation of t cells by providing costimulatory signals and secreting tnf .
mast cells also contribute to the recruitment of t cells to sites of viral infection by secreting chemotactic molecules .
one of the key processes in achieving successful adaptive immunity is the presentation of microbial antigens to t lymphocytes .
whether or not mast cells are capable of acting as antigen - presenting cells is still controversial .
this is largely because of the argument that mast cells under steady state do not seem to constitutively express major histocompatibility complex class ii ( mhc - ii ) or co - stimulatory molecules such as cd86 .
in contrast , mast cells upregulate expression of mhc - ii and costimulatory molecules following stimulation by inflammatory factors such as ifn- and lps . therefore , mast cells may have the potential to directly present antigens to t cells at least under certain circumstances , for example , in inflamed tissues , to initiate adaptive immune responses .
mast cells have also been demonstrated to present antigen to and activate cd8 t cells through mhc - i molecules .
alternatively , mast cells are reported as participating in antigen cross - presentation to t cells .
cross - presentation refers to a process , most typically following intracellular microbial infection , during which professional apc ingest infected cells and display the antigens of the microbes originally engulfed by the infected cells for recognition by t lymphocytes .
this is an efficient mechanism for presenting the antigens of those microbes that have infected host cells that may not produce all the signals , e.g. mhc - ii recognition and costimulation needed to initiate t cell activation .
the professional apc that have ingested infected cells may present the microbial antigens to both cd4 and cd8 t lymphocytes depending on the processing and presentation routes .
morphological changes of the host cells as a result of , e.g. microbial infections , apoptosis , and tumourigenesis , will facilitate ingestion by apc . in principle , any type of cells that have internalized antigens can participate in cross - presentation upon ingestion by apc .
importantly , mast cells have been implicated in the phagocytosis of various types of antigens .
indeed , mast cells can serve as an antigen - reservoir and participate in antigen cross - presentation . in vitro cultured bone marrow - derived cultured mast cells ( bmmc )
can internalize ige - bound chicken ovalbumin ( ova ) protein , followed by engulfment by dc which process and present the ova peptide to t cells that have specific receptors for the ova peptide .
induction of bmmc apoptosis is documented to be critical for efficient presentation by dc to t cells of the antigen originally phagocytosed by mast cells .
owing to the fact that mast cells are capable of participating in both innate and adaptive immunity , and that they are enriched at the mucosal and skin barriers between the body and the external environment , mast cells , similar to skin langerhans cells , tissue - resident dc and epithelial cells , are believed to be sentinel cells that are probably the first responders to a threat within seconds .
equipped with their immunologic armory of mediators , mast cells may possibly exert a pivotal role in the surveillance and elimination of pathogens by diversified mechanisms .
while people have been endowing mast cells with a more positive image in health , new findings also implicate mast cells or their released products negatively in infection .
although mast cell - associated tnf has been reported to be critical for a clp model of acute peritonitis , it has to be pointed out that mast cell - derived tnf is not always protective in acute peritonitis , especially in models of severe clp .
the detrimental effects of mast cells in severe peritonitis have also been ascribed to the release of il-4 that inhibits the phagocytic potential of macrophages .
even the potential of mast cells to recruit other immune effector cells during an infection is not always protective as this has been found to promote chlamydia pneumoniae infection .
interestingly , mmcp-4 , the mouse counterpart of human mast cell chymase , can degrade tnf , thus dampening the severity of inflammation associated with sepsis and limiting the damage caused by tnf , suggesting antagonism between mast cell mediators , thus favouring protection .
therefore , the implication and relevance of mast cells in host defense is a complex issue and the net outcome may depend on many antagonistic factors .
a vaccine is a biological preparation that stimulates an immune response against specific antigens that either are derived from the pathogen itself or resemble the structure of the pathogen .
ever since the first documented vaccination attempt by edward jenner for the prevention of small pox in 1796 , vaccines have played a crucial role in protecting people against many infectious diseases .
the eradication of smallpox and the effective control of polio represent two classic success stories of how vaccines can play a major role in improving global health .
nevertheless , the demand for better and more effective vaccines against many infectious diseases is still growing , especially when infections such as tuberculosis , hiv , dengue fever and malaria still present enormous global problems . from a societal point of view
, vaccination remains the most effective intervention in the control of infectious diseases and for the improvement of global health .
there are two principal forms of vaccines : those that are live attenuated vaccines and those that are killed whole pathogens or subcomponent vaccines .
an advantage of live attenuated vaccines is that they usually stimulate long - term immune responses similar to natural infection .
however , live attenuated vaccines always come with a risk of reversion into more virulent organisms that could cause adverse reactions or more severe infections .
in contrast , killed vaccines or subcomponent vaccines are more predictable and , therefore , safer .
furthermore , another concern that makes live attenuated vaccines less practical is the demand for a cold - chain for storing or transporting these vaccines . therefore
, killed vaccines are still much in use , even though they are weaker and usually do not promote as strong long - term memory responses . to make killed vaccines more effective , we need adjuvants which are substances that enhance immune responses and stimulate long - lasting , robust protective immunity .
an adjuvant that is included in the vaccine contributes greatly to the efficacy of the vaccination by affecting the immune responses both quantitatively and qualitatively .
importantly , protective immunity following vaccination may be generated with lower amounts of antigen and a reduced dosing frequency after addition of an adjuvant .
of all currently available adjuvants , aluminium salts ( alum ) have the longest history in practical vaccination .
alum - based vaccines have a good safety record and are capable of inducing early , high - titer , long - lasting protective immunity . at present , alum is still the most widely used adjuvant in both veterinary and human vaccines .
the mechanism of action has been proposed to depend on a depot effect , enabling physical adsorption of antigen onto the alum depots .
interestingly , mast cells are found to respond to alum stimulation by releasing histamine and a panel of cytokines including il-5 and il-1. although by using the mast cell - deficient kit mice it is demonstrated that mast cells are not required for the priming of endogenous cd4 and cd8 t cells , this does not formally exclude the contribution of mast cells to the adjuvant activity of alum in the wild - type mice as redundant pathways may exist .
however , alum does not seem to be effective for mucosal immunisation , a route that has appreciable advantages compared with routes that require needle injections , i.e. intramuscular or subcutaneous delivery of vaccines .
needle - free mucosal vaccination can be achieved via oral , intranasal , sublingual , or intravaginal routes .
the obvious benefits of mucosal immunisation include avoidance of blood - borne contamination through re - use of syringes and needles as well as the fact that no trained professional personnel are required for vaccine delivery .
strikingly , mucosal immunisation can generate effective secretory iga even at mucosal sites distant from where the vaccine is delivered .
for example , nasal immunisation can generate protective mucosal antibodies in the genital tract mucosa , which signifies the advantage of nasal vaccination .
as most pathogens enter the body through mucosal surfaces , local mucosal immune responses are critically important in defense against invading pathogens .
therefore , how to achieve strong local protection has become one of the major goals of vaccine development . as the mucosal route of vaccination ,
as opposed to the parenteral route , often results in immune tolerance development , potent adjuvants are much warranted .
therefore , the selection of a strong mucosal adjuvant for effective vaccination is vital and possibly as important as the vaccine antigens themselves .
tlr agonists have been tested and these include tlr4 ligand monophosphoryl lipid a , tlr9 ligand cpg oligodeoxynucleotides ( odn ) and the tlr5 ligand flagellin .
bacterial enterotoxins which include cholera toxin ( ct ) and escherichia coli heatlabile toxin ( lt ) constitute another major group of experimental mucosal adjuvants . both ct and lt
are composed of five b - subunits ( ctb and ltb ) and a single copy of the a subunit ( cta or lta ) .
the cta subunit is produced as a single polypeptide chain that is post - translationally modified through the action of a vibrio cholerae protease to form two chains , cta1 and cta2 , which remain linked by a disulphide bond .
cta1 is enzymatically active by adp - ribosylating the cell membrane bound gs-protein , whereas ctb binds to gm1-gangliosides present on virtually all nucleated cells .
dc are believed to play a central role in the presentation of antigens to nave t cells , which is a critical process for the development of adaptive immunity following natural infection .
as adjuvants are expected to mediate the same consequences as natural infections , quite a number of adjuvant studies are focused on the interaction of adjuvant with dc .
for example , b cells , macrophages , nk cells and nkt cells have also been implicated as targets for vaccine adjuvants .
given the accumulating evidence suggesting a functional interplay between mast cells and other immune cells such as dc , t cells and b cells in adaptive immune responses , also mast cells have been implicated in adjuvant functions .
indeed , mast cell activators such as c48/80 have been reported as exerting a mucosal adjuvant function .
more specifically , c48/80 is demonstrated to be an efficient adjuvant by mobilizing dc to the draining lymph nodes through production of tnf .
successful vaccinations of several animal infection models using c48/80 as adjuvant have now been reported .
retention of c48/80 and antigen on mucosal surfaces by chitosan - based nanoparticles can further promote mucosal immunisation .
the il-1 family cytokines such as il-1 , il-18 and il-33 have been shown to exert adjuvant function capable of augmenting protection against influenza virus infection .
interestingly , the effect of il-18 and il-33 is suggested to be mast cell - dependent , which is not surprising as both cytokines can activate mast cells resulting in proinflammatory cytokine production . il-18 together with il-2 is potent in expanding the mucosal mast cell pool and the production of mmcp-1 , which is critical for parasite expulsion .
il-33 is described as a danger signal that can alert mast cells and keratinocytederived il-33 can stimulate mast cells to produce tnf and il-6 , cytokines critical for defence against herpes simplex virus infection . polymyxins which are clinically approved antibiotics can activate mast cells and boost immunisation . in a quila - adjuvanted cattle vaccination model for protection against nematode infection ,
mast cells are most likely to be involved in the mechanism of adjuvanticity through the production of granzyme b and granulysin .
synthetic particles harboring tnf , mimicking mast cell granules , have been reported to be powerful adjuvant in a mouse model of influenza .
furthermore , it is suggested that the gold standard mucosal adjuvant ct may stimulate the release of il-6 from mast cells boosting humoral immune responses .
although the bacterial enterotoxins have been demonstrated to be powerful mucosal adjuvants experimentally , these substances are precluded from clinical use because of their toxicity and , hence , they have very limited applicability in human vaccines .
extensive studies have , however , focused on the detoxification of these molecules using various approaches .
for example , site - directed mutagenesis has generated detoxified mutants , such as ct112k , ltg192 , ltr72 , or ltk63 , with little or no enzymatic activity , but with retained adjuvant function in experimental models .
however , a drastically different approach was applied by lycke and co - workers who developed an adjuvant based on the intact cta1 molecule without the b - subunit .
the cta1 is linked genetically to a dimer of the d - fragment of staphylococcus aureus protein a forming the cta1-dd adjuvant .
thus , cta1-dd has retained the adjuvant function while the molecule can not bind to gm1-ganglioside , rendering the molecule nontoxic .
in contrast to ct , intranasal administration of cta1-dd results in neither inflammation nor accumulation in nervous tissues as is found with ct or lt .
the adjuvanticity of cta1-dd has been well documented in various infectious disease models , which include chlamydia trachomatis , influenza , hiv , mycobacterium tuberculosis , and helicobacter pylori .
in addition , mechanistic studies have identified several mechanisms of action that may explain the adjuvanticity of cta1-dd in vivo .
as the dd domain binds to all immunoglobulins , cta1-dd can target b cells through the b cell receptor , i.e. surface bound immunoglobulins , and promote b cell activation and germinal center development .
importantly , cta1-dd stimulates germinal center formation effectively generating long - lived plasma cells and long - lived b memory cells .
furthermore , also follicular dc and complement activation have been found to be essential elements for the function of this adjuvant .
in contrast to intact staphylococcus aureus protein a , which can activate mast cells , cta1-dd fails to activate mast cells .
however , as the double d domains derived from protein a have binding sites for immunoglobulins , cta1-dd can bind to all immunoglobulins including igg .
we demonstrated that cta1-dd and igg may form complexes that are able to activate mast cells through fc receptors , resulting in degranulation and the production of tnf and il-6 .
intranasal immunisation in the presence of cta1-dd and igg as an adjuvant can enhance antigen - specific immune responses compared with cta1-dd alone .
furthermore , we demonstrated that only ctmc , but not mmc , can be activated by immune complexes composed of cta1-dd and igg .
this effect is mediated by fcriiia , an activating receptor that is confirmed to be only expressed on ctmc .
indeed , ctmc are found in the nasal submucosa and these cells are demonstrated to express fcriiia . as mmc are not activated in response to stimulation by igg immune complexes because of the lack of fcriiia , it was intriguing to investigate whether or not mmc could contribute to adaptive immune responses somehow , perhaps using another mechanism .
we have recently reported that igg immune complex - primed mmc can mediate enhanced antigen - specific activation of t cells , possibly providing a cross - presentation mechanism to boost mucosal vaccination . in practical immunisation
the development of adjuvants that enhance the potency of subunit vaccines formulated for administration through the mucosal routes is much desired . dissecting and revealing the molecular mechanisms , through which mast cells precisely control adaptive immune responses to combat microbial infections , may have implications for rationally designing mucosal vaccine formulations .
we propose that igg immune complex - induced mast cell activation may be considered as one of the components for mucosal vaccine adjuvants .
1 summarizes the current knowledge regarding the strategies for the selection of vaccine formulations that target mast cells for enhancing immune responses .
mast cells can be activated by various factors including compound 48/80 ( c48/80 ) , il-33 , il-18 , cholera toxin ( ct ) , quila , alum and igg immune complexes ( igg ic ) . upon activation ,
mast cells release tnf- , il-6 , il-5 , il-1 , histamine , mouse mast cell protease ( mmcp ) , granzyme and granulysin that are critical in mobilizing immune responses .
however , these are just examples of functional consequences of mast cell activation specific to the findings of those studies addressing roles of mast cells in vaccination cited in this review ; the actual spectrum of mediators released by mast cells can be much more dynamic and complex .
one of the challenges associated with mast cell - mediated immune enhancement , of course , lies in overcoming the complexity of safety issues for the clinical development of the vaccines .
the constant threats posed by infectious diseases over millions of years may have driven evolutionary pressure to keep mast cells , despite their adverse properties , e.g. in causing allergy , in humans to exploit these cells beneficial functions in host defense .
our immune system has evolved mechanisms to balance the positive and negative contributions of mast cells to health .
it is worth exploring strategies to make use of the adjuvant properties of mast cells to provide high - quality vaccination while minimizing any health - compromising factors .
 abstractin addition to their well - established role in allergy mast cells have been described as contributing to functional regulation of both innate and adaptive immune responses in host defense . 
 mast cells are of hematopoietic origin but typically complete their differentiation in tissues where they express immune regulatory functions by releasing diverse mediators and cytokines . 
 mast cells are abundant at mucosal tissues which are portals of entry for common infectious agents in addition to allergens . here , we review the current understanding of the participation of mast cells in defense against infection . we also discuss possibilities of exploiting mast cell activation to provide adequate adjuvant activity that is needed in high - quality vaccination against infectious diseases . 
Introduction
Mast cell subtypes
Multitalented cells beyond allergy
The roles of mast cells in host defense
The implication of mast cells in vaccination