OMPJ
10.5005/jp-journals-10037-1094
Mast Cells in Health and Oral Disease
REVIEW ARTICLE
Mast Cells in Health and Oral Disease
1
Meera Kunjumon Pynadath, 2Anthony George, 3Cheriyanthal Sisupalan Jayapalan, 4Ahammed Noufal
ABSTRACT
Introduction: Mast cells (MC) are multifunctional secretory
cells characterized by numerous large metachromatic staining protease-rich intracellular granules. They are derived from
hematopoietic progenitor cells in bone marrow and do not
mature into terminally differentiated cells until they reach the
tissue or organ in which they become resident. They play a
vital role in a number of defense and repair mechanisms due to
their strategic location in the connective tissue at the interface
with the microvasculature.
Objectives: This review attempts to help improve our understanding on the types of MC, their morphology, staining characteristics, distribution, biological function, and their pathogenesis
in inlammation, oral potentially malignant disorders, and oral
squamous cell carcinoma. We hope this review recognizes the
integral role of MC in oral pathological disorders and facilitates
the opening of novel approaches to better therapies for improving the quality of life.
Conclusion: Mast cells has shown to remodel extracellular
matrix during wound healing. The entire ambit of allergic and
hypersensitivity reactions are the adverse effects produced by
the degranulation of MC. They participate in many inlammatory
oral diseases as they possess diverse roles ranging from proinlammatory to immuno-modulatory. They accumulate at the
boundary between healthy tissues and malignancies and are
found in close association with blood vessels within the tumor
microenvironment as they play an early role in angiogenesis.
Keywords: Allergy, Biological, Function, Immunity, Inlammatory,
Intracellular granules, Leukoplakia, Lichen planus, Mast cell,
Morphology, Pathological, Response, Squamous cell carcinoma,
Submucous ibrosis.
How to cite this article: Pynadath MK, George A, Jayapalan CS,
Noufal A. Mast Cells in Health and Oral Disease. Oral Maxillofac
Pathol J 2017;8(1):23-27.
Source of support: Nil
Conlict of interest: None
INTRODUCTION
Mast cells (MC) have fascinated the medical community
over decades because of their metachromatic staining
protease-rich large cytoplasmic granules and due to the
general lack of true understanding of their biological
1,4
Reader, 2,3Professor
1-4
Department of Oral Pathology and Microbiology, MES Dental
College, Malappuram, Kerala, India
Corresponding Author: Anthony George, Professor, Department
of Oral Pathology and Microbiology, MES Dental College
Malappuram, Kerala, India, e-mail:
[email protected]
function.1 von Recklinghausen (1863), Kuhne (1864),
Friedlander (1867), and Flemming (1867) among others
together may be considered as the earliest researchers
who first identified and described MC. 2 Many later
researchers noted their perivascular habitat, but it was
the German biologist Paul Ehrlich (1877) who coined
the term “mastzellen,” which meant “sleek, fat, and well
fed.”2 He was of the opinion that they had a role in nutrition as the MC were found in tissues where nutrition was
enhanced and he believed that the intracellular granules
were phagocytosed nutrients.2 Some experts refer to MC
as “unicellular endocrine glands,” because of their ability
to release a wide variety of chemical mediators that have
potent biological actions, such as recruitment of inflammatory cells, phagocytosis, stimulation of fibroblasts, neoangiogenesis, and release of few vasoactive substances.3
They exhibit an array of surface molecules and immune
response receptors, which give them the capacity to react
against specific and nonspecific stimuli, hence playing
an important role in host defense mechanism, innate
immunity, homeostasis, remodeling, and fibrosis.4,5 Many
theories have been proposed toward the origin of these
cells, including from the pericytes located along the capillaries.5 They are now considered to be of hematopoietic
origin and are derived from the bone marrow cells.5 They
circulate as committed progenitors and on an inflammatory stimuli traverse from the vascular space and mature
in the peripheral tissues.2
In this review we provide an overview of the types
of MC, their morphology, staining characteristics, distribution, biological function, and their potential role
in pathological conditions of the oral cavity. Through
the understanding of MC, we hope to help researchers
in the development of novel interventions to alter MC
response in the pathological environment to help inhibit
the developing pathology.
CLASSIFICATION
• BasedonageofMC
– Young MC (type I): Stains metachromatically blue
and homogeneously with toluidine blue (TB)
and stains negative for periodic acid Schiff (PAS)
reaction6
– Mature MC (type II): Stains metachromatically
violetandwithgranularityonTBandstainspositive for PAS6
Oral and Maxillofacial Pathology Journal, January-June 2017;8(1):23-27
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Meera Kunjumon Pynadath et al
• Basedondifferencesinneutralproteasecomposition,
ultrastructure, and dependency on T-lymphocyte
function
– MCT cell: Containing tryptase7
– MCTC cell: Containing tryptase and chymase7
– Immature forms have been described which have
indistinct ultrastructural features but have the
same protease compositions as of their mature
counterparts.7
• Basedontissuedistribution,stainingcharacteristics,
and presence of proteases
– Mucosal MC: Positive for chymase8,9
– Connective tissue MC: Positive for both tryptase
and chymase8,9
• MCinhumangingiva
– Typical MC (TMC): Having distinct metachromatic
cytoplasmic granules with definite cytoplasmic
boundaries.8
– Atypical MC (AMC): Having indistinct or faint
metachromatic material of granular, linear, vacuolated, or homogeneous appearance partially or
totally surrounding the nucleus, and with indefinite cytoplasmic boundaries.8
Morphology
Light microscopic study of MC revealed four basic cell
morphologies: round, ovoid, spindle or elongated, and
pseudopodia.10 Tissue MC have small nucleus with a mean
diameter of 4 µ and have a round-oval shape, which may
sometimes be longitudinally stretched, indented, kidney,
or fusiform shaped.2 The cells have polymorphous cytoplasmic contour and appear as oval, pyriform, spindle, or
star shaped due to the aggregation of the intracytoplasmic
granules.2 The granules are often so numerous that they
may obliterate the view of the cell nucleus. Oval and
oblong MC vary in diameter from 3.5 to 14 µ and in some
instances may attain 28 µ.8 The intracytoplasmic granules
are spherical-oval membrane-bounded organelles with
a mean diameter of 0.2 to 0.4 µ.8 Often empty vacuoles
representing discharged granules are present.8 Changes
in the morphology may occur due to the intrinsic (genetic
origin, ameboid movement, physiological conditions)
and/or extrinsic factors (environmental factors, such as
the medium of fixation, embedding, staining).2 Under the
electron microscope, the nucleus appeared to lie more or
less centrally with clumped chromatin.10 The cells had an
irregular outline with numerous characteristic cytoplasmic
processes in the form of pseudopodia and microvilli.10
The cytoplasm contained numerous mitochondria, fibrillar structures, sparse smooth endoplasmic reticulum,
diffusely distributed ribosomes, well-developed golgi
complex, and scattered secretory granules.10
24
Staining Characteristics
Under hematoxylin and eosin (H&E), MC are not
prominent and can be easily overlooked.4Basicaniline
dyes, such as ethylene blue or crystal violet are classically used to demonstrate their presence.4 MC granules
have a strong affinity for basic dyes and they stain the
granules metachromatically, with the blue dyes giving
a red stain and the red dyes giving a yellow stain.2 The
metachromasia is due to the presence of large amount
of sulfated glycosaminoglycan heparin in the granules.4
The other basic dyes that stain MC are thionine, TB,
methylene blue, methylene violet, cresyl violet, brilliant
cresyl blue, amethyst, acridine red, neutral red, pyronine,
safranine, azure, and acridine orange.2,11 Positivity for
PAS, alcian blue, astral blue, and colloidal iron suggests
the presence of acid mucopolysaccharides.4 The different
staining characteristics of MC within the same tissue and
between tissues suggests the heterogeneity of their chemical constituents or the difference in cell maturation.2 MC
have shown immunopositivity toward bcl-x(L), CD68R,
CD45, CD117 (c-kit), and HLA-DR.29 CD2 may be a novel
useful marker in mastocytosis, since in other pathologic
conditions MC are CD2 negative.12
Distribution
MC are granular secretory cells seen in the underlying
connective tissue of the oral mucosa.13 MC are abundant in the bone marrow, serous membranes, around
superficial small vessels or capillaries of all organs,
microvascular endothelium of the oral mucosa, and in
the extremities including face, hands, and feet.2,5 They
are seen in close proximity to the basement membranes
of blood vascular channels and nerves as a result of their
interaction with the laminin-specific receptor CD49f
(a6/pi) integrin.14 Large numbers of MC are found around
the blood vessels in the gingiva and in the middle layers
of lamina propria of the buccal mucosa.15 MC have been
identified within the bilaminar tissues and vasculature of
temperomandibular joints.16 MCT are almost exclusively
found in the alveolar walls of the lungs and intestinal
mucosa, while MC TC were seen more predominant
around the blood vessels and the skin appendagial
structures in the superficial dermis.7 MCT and MCTC
demonstrated almost equal distribution in the connective tissue.7 Scars, cartilage, and bone are devoid of MC.2
Biological Function
MC arise from multipotent CD34+ precursors in the
bone marrow and circulate in the peripheral blood as a
granular monocytes.3 The progenitors differentiate from
primitive cells under the influence of interleukin (IL)-3
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Mast Cells in Health and Oral Disease
and migrate to other parts of the body.12 On migrating
into the connective tissues, these immature cells assume
their typical granular morphology.5 MC has surface
adhesion molecules integrins and c-kit that mediate
binding to other cells and extracellular matrix (ECM)
glycoproteins.17 MC activation results in the expression
of adhesion molecules and their ligands, which help in
their localization and migration. Extracellular matrix
proteins, such as laminin of vascular and neural basement
membrane, are important in the localization of MC.17
Two principal cytokines IL-3 and stem cell factor (SCF)
promotes MC proliferation and differentiation.1 IL-3 is
important for its early proliferation, whereas SCF acts to
maintain cell viability by suppressing apoptosis and by
promoting maturation.1 MC along with the neutrophils,
macrophages, and platelets play an important role in
immunity. It contains chemical mediators, such as histamine, tryptase, tumor necrosis factor (TNF), and IL that
can increase fibroblast proliferation and act as chemotactic
factor for neutrophils.1 Heparin, fibroblast growth factor
(FGF), and vascular endothelial growth factor (VEGF)
induce endothelial cell migration and angiogenesis.1
MC induce and enhance angiogenesis via multiple
interacting pathways including: (i) Release of potent
proangiogenic factors, such as VEGF, bFGF, TGF-α, -β,
and IL-8; (ii) proteinases and heparin that release heparinbinding proangiogenic factors; (iii) histamine, VEGF, and
certain lipid-derived mediators that induce microvascular hyperpermeability; (iv) chemotactic recruitment of
monocytes/macrophages and lymphocytes; (v) activation of platelets; (vi) activation of neighboring non-MC,
which release ECM degrading proteinases and SCF; (vii)
auto- and paracrine stimulation of MC by SCF.17 As a
result of ECM degradation and changes in the microenvironment, the MC populations may change in number,
phenotype, and function. Chemical mediators in MC can
be grouped into: (1) Preformed secretory granule mediators: Histamine, proteoglycans, serine proteases, carboxypeptidases; (2) lipid-derived mediators: Leukotriene – C4,
D4, E4 (SRS-A), prostaglandin, platelet activating factor;
(3) MC-derived cytokines: (a) Proinflammatory cytokines
– TNFα, IL-1α, -1β, (b) mitogenic cytokines/growth
factors: IL-3, -4, -5, -10, GM-csf, (c) immunomodulator
cytokines: IL-1α, -1β, IL-4, -10, IFNγ.18
Mast Cells in Disease
Adverse effects of anaphylaxis and drug allergy are
produced by the activation of MC and basophils.5 MC
are activated to release inflammatory mediators during
expressions of cell-mediated delayed hypersensitivity.5 Their proliferation in cellular immune response
is regulated by the products of T lymphocytes.5 When
immunoglobulin (Ig)-E antibodies are raised against a
certain allergen, they bind to MC surface Fc-receptors
and cause the MC to undergo characteristic biochemical
and morphological changes and release their contents by
degranulation.3,5 They release histamines, leukotriens,
and prostaglandin in response to the antigen challenge.5
Subsequent exposure leads to immediate degranulation
and release of the chemical mediators.3 MC and their
proteases increase in inflammatory conditions and bring
about alterations in the basement membrane that allows
cytotoxic lymphocytes to enter the epithelium.2
MC in periodontitis: The exact role of MC in inflammation
is not yet known but their presence has been interpreted
as a sign of healing. MC count is decreased in acute gingivitis but increased in chronic gingivitis, chronic generalized periodontitis, and in proliferative fibrotic lesions
like phenytoin enlargement.19 The increase in MC count
suggests the possible participation of these cells in the
defensive and the destructive events of chronic inflammation. MC express matrix metalloproteinase (MMP)
which are enzymes that degrade the gingival ECM, and
they are known to release preformed cytokines which
initiate immune response.20
MC in periapical lesion: MC are now recognized for its
immunoregulatory properties, but little is known about
the complex interactions between the cells, cytokines, and
other inflammatory elements in periapical lesions. They
tend to be more in the peripheral regions of periapical
lesions and are found in close proximity to lymphocytes
in both periapical granulomas and cysts.21 A functional
relationship exists between these two cell populations and
may facilitate elicitation of an immune response i.e., contributory to the pathogenesis of the periapical lesions.21
MC in oral lichen planus (OLP): A specific pattern of MC
distribution in mucous membrane diseases like OLP,
pemphigoid, and desquamative gingivitis has been
described by various researchers.10 They are increased
significantly in OLP.10,22 They contain proinflammatory
TNF-α in their granules, the release of which promotes
leukocyte infiltration through the induction of endothelial leukocyte adhesion molecules. TNF induces lesional
T-cells to secrete chemokine RANTES, which stimulates
MC degranulation.22 The expression of RANTES and its
receptors on MC and T-cells prolong the survival of these
cells and thus induce inflammation.22 The association
of MC with laminin was an important determinant of
MC density in the immediate perivascular region, thus
providing an ideal situation for MC-derived mediators
to influence the circular endothelium and cause the progression of OLP.22
MC in oral submucous fibrosis (OSMF): MC was observed
in all the grades of OSMF. In grade I and II, they were
Oral and Maxillofacial Pathology Journal, January-June 2017;8(1):23-27
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Meera Kunjumon Pynadath et al
identified predominantly near the blood vessels where
the reaction of the tissues to the irritants were strong.23
MC were low in advanced stages where the connective
tissue was hyalinized.23 The MC and vascular response
in OSMF was similar to those identified in autoimmune
diseases.24 Researchers claim that MC histamine chain
causes changes in the submucosa and basement membrane that lead to cancerous change in OSMF. The MC
response in OSMF is consistent with the overall sequential tissue response in the disease. The smooth muscle
hypertrophy in OSMF could be due to the degranulating
MC products.24
MC in leukoplakia: Researchers found an increase in MC
in epithelial dysplasia, suggesting a probable role in
its pathogenesis.25 The biological and pharmacological
active agents in MC may contribute to the inflammatory reaction seen in leukoplakia. The stimulated MC
release IL-1 causes increased keratinocyte proliferation.26
Histamine increases mucosal permeability that facilitate
increased access for the antigen to the connective tissue.
MC mediators IL-1, TNF, histamine, and heparin could
lead to the various histopathological and clinical features
identified in leukoplakia.25 MC response was significantly
greater in precancerous epithelial dysplasia than in overt
carcinoma.27
MC in Oral Squamous Cell Carcinoma (OSCC): MC are said
to play a defensive role in tumor growth. Studies suggest
that MC exert an inhibitory effect on tumor growth and
that the inhibitory factor could be serotonin.27 Tissue MC
are usually absent or extremely sparse in deeper regions
of carcinoma but tend to accumulate in the adjoining
normal tissue and in the regional lymph nodes.2 The
density of MC consistently decreased with increasing
dedifferentiation and with increasing numbers of mitotic
figures. In high MC group the overall survival rate was
double that for the group with few MC. 28 In tumor
models MC have shown to play a decisive role in inducing the angiogenic switch which precedes malignant
transformation.17 The number of MC and microvasculature were found to be higher in OSCC, suggesting that
MC may upregulate tumor angiogenesis by expressing
tryptase. MCTC were significantly increased at tumor
invasion zone where both ECM degradation and angiogenesis are required. MCT were found at the intratumoral
stroma where angiogenesis was required.7,29
CONCLUSION
MC serve as the gate keepers of microvasculature due
to their unique distribution and properties in health and
disease. They exhibit an array of adhesion molecules,
immune response receptors, and other surface molecules that give them the capability to react to multiple
26
nonspecific and specific stimuli. There is no disease, biological condition, or animal model till date that exhibits
an absolute lack of MC from which or in which their
exact biological role could be studied in detail. MC and
its mediators have a definite role to play in the pathogenesis of many pathological conditions. They have been
regarded as being important in the initiation and amplification of acute inflammatory responses. In tumor models,
MC have been shown to play a decisive role in inducing
angiogenesis which precedes malignant transformation.
We hope that this review recognizes the integral role of
MC in oral pathological disorders and help researchers in
the development of novel interventions to help improve
the quality of life in these patients.
AUTHOR CONTRIBUTION
All the authors contributed actively in the conception,
design, drafting, and critical revision of the manuscript.
All the authors read and approved the final version of
the manuscript.
ACKNOWLEDGMENTS
The authors acknowledge the supporting and auxiliary staff of the Department of Oral Pathology and
Microbiology.
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