• Mast cells are primary effector cells in
immunoglobulin E (lgE) mediated
• They are implicated in:– both acquired and innate immune responses,
– wound healing,
– fibrosis ,
– angiogenesis, and
– autoimmune diseases
• First described by Ehrlich in 1871 , who
distinguished them from other connective
tissues by their ability to stain
metachromatically with basic aniline dyes.
Structure and staining
• Mast cells are bone marrow-derived cells that
occur in the normal dermis in small numbers
as oval to spindle-shaped cells with a centrally
located round to oval nucleus.
• They contain in their cytoplasm numerous
granules that do not stain with routine stains
• The granules stain with methylene blue,
which is present in the Giemsa stain, with
toluidine blue, and with Alcian blue.
Mast cell with cytoplasmic granules and
villous projections from the cell surface.
• Mast cells are reservoirs of preformed inflammatory mediators
and rapidly synthesizes others on activation
• Mediators contributes to the changes in anaphylaxis and delayed
• Primes B-cell for antibody formation
• They play a role in the defense against parasites; stimulate
chemotaxis, activation and proliferation of eosinophils; promote
• stimulate connective tissue repair and angiogenesis
Mast cell distribution and identity
• Mast cells are widely distributed, long lived
cells found predominately in connective and
mucosal tissues and often in proximity to
blood vessels, nerves, and lymphatic tissues.
• Mast cells are abundant in the skin,
respiratory tract, gastrointestinal tract, and
• 7000 mast cells/cubic mm in normal skin.
• All human mast cells contain tryptase ,
histamine, and proteoglycans , including
heparin and chondroitin sulfate E.
• Mast cells are classically identified in tissue by
toluidine blue or giemsa dye that stains the
cytoplasmic granules, and more recently, by
immunohistochemistry using an antibody that
recognizes mast cell tryptase.
• Human mast cells are classically divided into
• Mast cells that contain tryptase and chymase
are referred to as TC mast cells .Such cells
tend to be located in sub mucosal tissues.
Increased numbers of these cells are found in
• Mast cells that contain tryptase but not
chymase are referred to as T mast cells (MCt)
and are increased in allergic and parasitic
Ultra-structure of mast cells
• Electron microscopic examination of mast cells
reveals numerous large and long villi at their
• The mast cell granules appear as round, oval,
or angular-shaped, membrane-bound
structures. Mature granules measure up to 0.8
Âµm in diameter.
• They contain two components: lamellae and
electron-dense, finely granular material .
Development & differentiation
• Mast cells arise from a CD34*, KIT+
pleuripotent progenitor stem cell.
• Cross linking KIT by stem cell factor (SCF) is
essential for these precursor cells to
differentiate into mast cell.
• Mature mast cells require SCF for survival.
• KIT (CD117) expressed on haematopoeitic
stem cell, is transmembrane tyrosine kinase
receptor for SCF.
• While KIT is down-regulated on other bone
marrow derived cells during their
differentiation , it remains highly expressed on
mast cells and is critical for many mast cell
functions such as survival, chemotaxis and
enhancement of signalling events .
Other cytokines that regulate SCF-dependent
mast cell differentiation and proliferation
include interleukin 13 (lL-13), IL-4,5, and
• IL-3 shares a number of signal transduction
pathways with SCF but has minimal direct
effects on human mast cell proliferation
except in early cultures.
• IL-4 enhances mast cell function when added
to mature culture.
• In contrast , when IL-4 is added during SCFdependent mast cell differentiation, it inhibits
cell division and decreases final mast cell
• In developing mast cells , IFN-y inhibits mast
cell proliferation and influences mast cell
phenotype and function.
• HISTAMINE causes local increase in permeability of capillaries and
Mast cell Activation
• Antigen-dependent aggregation of FceRl
bound IgE on the surface of mast cells is a
primary mechanism of activation of Mast cells
and subsequent release of preformed proinflammatory mediators, as well as of newly
• Non-IgE-driven signals that activate mast cells
include Toll-like receptor ligands such as
lipopolysaccharide and nucleic acids, the
anaphylatoxins C3a and C5a, and certain
chemokines and cytokines.
Mast cell degranulation
• Degranulation of mast cells occurs after crosslinking of IgE on the cell surface.
• Degranulation generally occurs within minutes
of exposure of the cell membrane to the
secretagogue, and usually consists of the
extrusion of entire granules, but some
granules may undergo intracellular
• Initial stages of degranulation consist of
granule swelling with loss of internal
substructure and electron density.
• Extrusion of granules takes place through
extensive membrane fusion between the
plasma membrane and peri granular
• This is associated with formation of
conduits resulting from fusion of the
membranes of multiple granules.
• This results in extensive labyrinthine channels
in the cell through which swollen, less electrondense granules, all of which have lost their
individual surrounding membranes, are
released into the extracellular space.
• Concomitant with their release into the
extracellular space, the granules release their
preformed and stored mediators histamine,
heparin, serine proteinases, and certain
Immunological and non –immunological stimuli lead to
activation of intracellular kinases and increase in intracellular
Degranulation of mast cells
Release of preformed mediators hiatamine, tryptase, chymase
All these lead to rapid onset of local increase in permeability of
submucosal or subcutaneous capillaries and post capillary
Local plasma extravasation
PRE-F0RMED SECRET0RY MEDIAT0RS
• Pre –formed secretory granular mediators are
released In response to aggregation Of the
high-affinity IgE receptor activation through
complement receptors , or activation by
• Mast cell tryptase is released upon activation
of mast cells, along with
histamine, heparin, chymase ,and
• Most abundant human mast cell protein and
exists in two forms that show 90 percent
homology, alpha and Beta tryptases.
• The biologic function of tryptase has not been
completely defined, but it appears to activate
protein cascade systems, enhance
vasopermeability , and alter airway smooth
• Tryptase has the capability to Cleave
fibronectin , vasoactive intestinal peptide, and
• Also a growth factor for epithelial cells and
• The total tryptase level in Blood is used as an
indirect parameter of mast cell burden and
mast cell activation.
• Baseline tryptase levels are generally elevated
in patients with systemic mastocytosis (SM).
• Increased serum tryptase levels are also
observed within 15minutes of onset of
anaphylaxis with a peak level seen at 1 to 2
hours, although this is not consistent.
• The mast cell protease chymase converts
angiotensin I to angiotensin II.
• The vasoactive properties produced by
angiotensin II may contribute to transient
hypertension in some individuals during mast
cell activation reactions .
• Carboxypeptidase A similarly converts
Angiotensin I to angiotensin II.
• Histamine is stored in all mast cells, as well as
basophils and released with cell activation.
• The biological effects of histamine are
mediated through activation of H1,H2, H3,
and H4 receptors.
• H1 receptors are located on epithelial cells as well
as vascular and perivascular cells and mediate
vascular permeability and instability.
• H2 receptors are present on epithelial Cells in the
gastrointestinal tract and are associated with
• H3 receptors are found in the brain and
gastrointestinal tract and may be associated with
certain neurologic effects such as headache.
• H4 receptors are present on eosinophils and mast
cells but their significance Is still unknown.
• Heparin stabilizes and regulate secretory
• In addition, it binds to antithrombin III,
inhibiting activation of the clotting cascade.
• Heparin binding also regulates and stabilizes
cytokines and growth factor.
• Heparin mediated effects include bleeding
diathesis , osteopenia and osteoporosis.
Newly formed ,membrane-derived Lipid
mediators ,produced by mast cell
activation, include prostaglandinD (PGD2)
,cysteinyl Leukotrienes and platlet-activating
These mediators have profound effects in both
the immediate and late allergic reactions.
• Receptors for PGD2, are present on vascular
and perivascular cells and mediate effects
including bronchospasm ,vasodilation
vasopermeability and inhibition of platelet
• flushing in response to niacin is mediated by
• Cysteinyl Leukotrienes increase vascular
Permeability and cause bronchoconstriction.
• These mediators also are Responsible for the
long-lasting wheal and flare in responseto
injection of antigen in human skin.
• Leukotrienes are believed to contribute to
abdominal Symptoms in patients with SM.
• PAF is a potent inducer of bronchoconstriction
mediated through microvascular leakage in
the airways and the subsequent development
of submucosal edema.
• Various cells synthesize PAF including
endothelial cells, neutrophils and
• Functions as a chemotactic agents for
eosinophils , neutrophils and mast cells.
• Mast cells similarly produce and release a
number of cytokines viz.
• Tumor necrosis factor causes cachexia and
• Transforming growth factor-Beta contributes
to tissue fibrosis, abnormal bone remodeling
,osteopenia and eosinophilia.
• IL -4 is implicated in IgE synthesis and the
development of a T helper2 phenotype.
• IL-5 is instrumental in the recruitment and
survival of eosinophils that contribute to
• IL -6 has been linked to the Pathogenesis of
osteoporosis and is elevated in the plasma of
patients with SM.
• Mast cell products may both induce an
immediate reaction with in minutes of Fc
epsilon receptor I cross linking and its
consequence are referred to as immediate
• Whereas late phase reaction peaks 6-12 hours
following antigen challenge and are associated
with cytokine and chemokine from
eosinophils, neutrophils and basophils that
have been secondarily recruited.