Mast cells in health and disease

MAST CELLS : IN HEALTH AND
DISEASE
PRESENTER- DR. PANNAGA P KUMAR
MODERATOR- DR. ANISHA T S

INTRODUCTION
Although MCs (mast cells) were discovered over 100 years ago, for the majority of this time their
function was linked almost exclusively to allergy and allergic diseases with few other roles in health
and disease.
It is now known that MCs have very broad and varied roles in both physiology and disease which will
be reviewed here.

OVERVIEW
● ORIGIN AND DEVELOPMENT
● PHENOTYPE AND LOCATION
● ACTIVATION AND DEGRANULATION
● ROLE IN PHYSIOLOGY
● ROLE IN DISEASE PATHOLOGY
● MAST CELL DISORDERS

1878
PAUL EHRLICH
MASTZELLEN (MAST
CELLS)
1966
ENERBÂCK
MAST CELL
HETEROGENEITY
1977
KITAMURA
HEMATOPOIETIC
ORIGIN OF MAST CELLS
1989
CHABOT/ BESMER/
BERNSTEIN
cKIT AS MAST CELL GROWTH
FACTOR RECEPTOR
2000
KINET/ JARDETSKY
IgE/ FcεR1 CRYSTAL
STRUCTURE

ORIGIN
MCs are derived from the bone marrow.
Mast cells develop from progenitor cells that in turn arise from uncommitted hematopoietic stem
cells in the bone marrow. MCps are CD34 + , c-kit + , and CD13 -
MCs are from the bone marrow into the peripheral blood as committed MCps and undergo
maturation under the control of local cytokines, once they are recruited into specific tissues.

DEVELOPMENT
The interactions between SCF and c-kit and the subsequent signaling that follows are crucial for
the growth and development of mast cells.
Interleukin 6 (IL-6), eotaxin, and nerve growth factor (NGF) also enhance mast cell development
from hematopoietic stem cells
Adventitial cells, including fibroblasts, contribute to further differentiation and maturation of
mast cells in tissue by elaboration of SCF, NGF, or other mechanisms.

DISTRIBUTION
Mast cells are found predominantly in skin, respiratory mucosa, and gastrointestinal tract.
Mast cells populate connective tissue, particularly in subepithelial regions.
In the connective tissue- surrounding blood vessels, nerves, smooth muscle cells, mucus glands,
and hair follicles

HETEROGENEITY
Variation in the morphologic, biochemical, and/or functional characteristics of mast cells from
different anatomic locations or from the same organ or site has been reported in several
mammalian species, including humans.
This phenomenon, often referred to as mast cell heterogeneity.

DIFFERENTIATION
After tissue localization, mast cells can undergo
further differentiation into distinct subsets.
Two mast cell subtypes have been described in
tissue— MCT and MCCT.
These subtypes are based on structural,
biochemical, and functional differences and have
been well characterized by several researchers.

RELEASE OF MEDIATORS FROM MAST CELL

ACTIVATION
Mast cells may be activated by several distinct stimuli acting on numerous receptors on the
mast cell surface.
The range and nature of mast cell responses to different stimuli can be influenced by intrinsic
and microenvironmental factors that affect the expression or functionality of surface receptors
and/or signaling molecules that contribute to these responses.

MULTIPLE ROLES OF HUMAN MAST CELLS IN IMMUNE
PHYSIOLOGY AND DISEASE STATES

HOMEOSTASIS
MCs are important in the homoeostasis of organs that undergo continuous growth and
remodelling such as hair follicles and bones.
MC-derived histamine, TNF and substance P are implicated in regulating growth and regression of
hair follicles between periods of hair growth and rest.
MCs also contribute to bone remodelling. It has been speculated that MC IL-1, TGF-β, IL-6 and
histamine could influence osteoclast recruitment and development. Recently, MCs were found to
produce OPN (osteopontin), a secreted glycoprotein that controls bone metabolism and also has a
role in immune responses.

NERVOUS SYSTEM
MCs localize near nerve endings in many different tissues, including the lungs, skin, intestinal
mucosa and CNS (central nervous system).
MCs and neurons can communicate through the mediators they release In certain situations of
wound healing and stress response MCs and neurons work cooperatively.
For example, in the gut, MCs and neurons maintain homoeostasis by regulating ion transport,
secretory activity of mucous epithelial cells, vascular permeability and intestinal motility.

HOST DEFENCE
First, these cells can directly phagocytose foreign particles (and bacteria).
Second, they enhance the development of Th2 cells and allow B cells to class switch to IgE. A role as
antigen presenting cells has also been proposed for mast cells.
Third, activated complement products often generated during an innate immune response to an
infectious event, induce mast cell degranulation.
Fourth, mast cells are themselves capable of secreting a plethora of cytokines, chemokines, and other
mediators that can activate lymphocytes and macrophages.

DEFENCE AGAINST PARASITES
MCs facilitate host clearance of ecto- and endoparasitic infections that include worms, ticks, and
protozoa.
Parasitic infections are often associated with high levels of IgE (parasite-specific or non-specific),
increased MC numbers and redistribution and evidence of MC activation, which all point strongly to
MC involvement in host response to parasite infection.
MCs play role in the recruitment of key immune cells, the regulation of gut permeability and parasite
expulsion, containment, chronic inflammation and nematode fecundity.

DEFENCE AGAINST BACTERIA
MCs can be activated by bacteria via TLRs and by other mediators to kill bacteria directly, recruit
neutrophils and degrade potentially toxic endogenous mediators such as ET-1 and neurotensin.
Although MCs can participate in direct killing of bacteria by phagocytosis and reactive oxygen species
production, gaining access to an intracellular compartment also may constitute a pathogenic strategy
to escape the extracellular antimicrobial activity.

DEFENCE AGAINST BACTERIA
MCs contribute indirectly to antigen capture after bacterial activation through their release of
IL-6 that mobilizes certain subsets of DCs to lymph nodes.
MCs influence T cell and B cell migration directly through the release of cytokines and indirectly
through mediators, such as TNFα, that increase cell adhesion molecules expressed on
vasculature and increase vascular permeability.
Finally, MCs also regulate B cell-dependent IgE production.

DEFENCE AGAINST VIRUSES
Following recognition of viruses or viral components such as double- stranded through TLR3, MCs
can release a panel of antiviral response cytokines and chemokines that promote CD8 + T cell, natural
killer (NK) T cell, and NK cell recruitment.
MCs may participate in viral immunity by directly presenting major Histocompatibility complex
(MHC) class-I antigens to activate CD8 + T cells and by inducing DC maturation and enhancing DC-
cytokine release leading to downstream activation and proliferation of CD4 + T cells.
However, MCs may also act as a reservoir for virus.

VENOMS
Studies indicate that mast cells can enhance the resistance of mice to diverse animal venoms and/or
their toxic components, including the venoms of three poisonous snakes, the honey bee, the Gila
monster, and two species of scorpions.
Carboxypeptidase A3 (CPA3) or mouse mast cell protease (mMCP-4, the functional counterpart in
the mouse to human chymase) appeared to account for much or all of the protective effects against
various venoms that were attributable to mast cells.
CPA3 and mMCP-4 can degrade both endogenous biologically active peptides (endothelin-1 [ET-1]
and vasoactive intestinal polypeptide [VIP], respectively) and similar peptides present in animal
venoms.

ASTHMA
MCs have long been implicated in asthma pathogenesis due to their localization near blood vessels,
beneath the basement membrane, and near smooth muscle fibers throughout the lung
airways(ASM).
MC preformed mediators recruit eosinophils and T H 2 cells and can have direct and rapid effects
on ASM, leading to bronchoconstriction.
MC accumulation in the ASM of asthmatics correlates with increasing severity of airway
hyperresponsiveness, and the number of degranulated MCs is higher in fatal asthma.

TISSUE REMODELING AND FIBROSIS
Mast cells are increased in numbers in many fibrotic diseases and may play a crucial role in
development of fibrosis.
Liebler et al., found mast cell hyperplasia during the later reparative stages of the lungs of
patients with the adult respiratory distress syndrome but not in the early stage.
The percentages of mast cells in bronchoalveolar lavage fluid from patients with sarcoidosis or
interstitial fibrosis are greater than from control individuals.
Patients with idiopathic interstitial pulmonary fibrosis show evidence of mast cell
degranulation and elevated mast cell numbers.

TISSUE REMODELING AND FIBROSIS
Mast cell - dominant source of bFGF in patients with fibrotic lung disease.
Thus it appears that mast cells play a pivotal role in fibrotic disorders.
The dominant mechanisms behind the regulation of fibroblast function and proliferation by
human mast cells are uncertain. It is clear that mast cell products such as tryptase and cytokines
(TNF-a, bFGF) induce fibroblast proliferation.
On the other hand, fibroblasts appear to enhance mast cell survival. Thus a bidirectional
relationship between mast cells and fibroblasts has been proposed

INFLAMMATORY BOWEL DISEASE
IBD patients frequently display an increased number of intestinal MCs when compared to healthy
patients.
Intestinal MCs from CD patients are functionally different from those isolated from healthy
individuals and show increased expression of TNFα, IL-16, and substance- P.
In the context of IBD, MC degranulation is likely triggered by food or commensal bacterial antigens,
and their activation exacerbates a pro-inflammatory cascade with detrimental physiological effects.

AUTOIMMUNE AND AUTOINFLAMMATORY
DISEASE
MCs have been implicated in the pathophysiology of several human autoimmune and autoinflammatory
diseases including arthritis, multiple sclerosis (MS), autoimmune glomerulonephritis, lupus, scleroderma,
pemphigus, pemphigoid, psoriasis, dermatopolymyositis and polymyositis, Sjögren’s syndrome, and
cryopyrin- associated periodic syndromes.
Release of mast cell mediators (α- and β-tryptase and histamine) has been demonstrated in the joint of
various forms of inflammatory arthritis.
In osteoarthritis, a degenerative but potentially inflammatory disorder, mast cell counts and tryptase and
histamine levels are elevated in synovial fluid.

DISEASE
Activated mast cells also are seen in the lesions present in patients with rheumatoid arthritis, whereas
mast cell chemotactic activity and their expression of VEGF have been demonstrated in rheumatoid
synovium.
Mast cell infiltration of the minor salivary glands is observed in patients with Sjögren’s syndrome, and
this infiltration often is associated with fibrosis and c-kit expression.
Patients with fibromyalgia demonstrate higher dermal deposits of IgG and Increased dermal mast cell
numbers, but the role these play in pathogenesis of the disease is unknown.

DISEASE
In CNS tissue derived from MS patients, MCs are found at the border regions of demyelinated
lesions, next to vessels with associated immune cell infiltrates and, in some cases, deep within
the CNS parenchyma.
MCs are more common in lesions of patients with “chronic active” or relapsing-remitting”
disease but not prevalent in the case of acute or newly formed lesions.
MC-associated transcripts are enriched in plaques of MS patients.

PROGRESSIVE KIDNEY DISEASE
MCs are rare in healthy kidney but are greatly expanded (~6 to 7-fold) in GN patients regardless of
disease etiology.
MCs in GN kidney tissue are primarily located in the interstitial tissue rather than the glomerulus.
MC abundance correlates with extent of fibrosis, decline in glomerular filtration rate, rapid disease
progression, and poor outcome.
MC chymases, as angiotensin II (Ang II)-converting enzymes, may promote fibrosis via conversion of Ang
II and activation of transforming growth factor beta (TGFβ). In addition, MC tryptase acts as a mitogen for
smooth muscle cells and fibroblasts.

TRANSPLANT
Abundant MC presence correlates with tissue fibrosis and acute and chronic rejection of
transplanted heart, lung, liver, kidney, and intestine.
Participation of MCs in the mechanisms of chronic rejection parallels the processes of tissue
fibrosis. Specifically, MC degranulation releases ACE and TGFβ-elaborating proteases that
promote activation of fibroblasts and chronic graft failure.

CANCER
There is evidence for MCs both in promoting, but also in protecting against, tumour growth.
MCs may directly mediate cytotoxic effects, by releasing cytokines such as IL-1, IL-4, IL-6, and TNFα,
thereby initiating an antitumor response.
MCs may promote tumor development through release of a number of molecules and enzymes such as
histamine, VEGF, proteases (MMP9), and leukotrienes that act indirectly to promote tumor
proliferation, angiogenesis, invasion, and remodeling of the ECM.

DISORDERS AFFECTING MAST CELLS
Increases in tissue mast cells can occur by a combination of enhanced progenitor influx and
proliferation of resident mast cells in tissues.
A number of disorders are associated with small to up to several fold increases in mast cell
numbers in or near the tissues affected by the disorder.

MASTOCYTOSIS
Mastocytosis is due to a clonal, neoplastic proliferation of mast cells that accumulate in one or
more organ systems. It is characterized by the presence of multifocal compact clusters or cohesive
aggregates/infiltrates of abnormal mast cells.
cutaneous mastocytosis / CM
● maculopapular cutaneous mastocytosis / MPCM = urticaria pigmentosa / UP
● diffuse cutaneous mastocytosis / DCM
● mastocytoma of the skin / cutaneous mastocytoma
systemic mastocytosis / SM
● indolent systemic mastocytosis
● smoldering systemic mastocytosis
● SM with associated hematologic neoplasm / SM-AHN / SH-AHNMD
● aggressive systemic mastocytosis
● mast cell leukemia / MCL
mast cell sarcoma / MCS

EPIDEMIOLOGY
Mastocytosis may occur at any age
Cutaneous mastocytosis is most common in children and may be present at birth.
About 50% of afflicted children develop typical skin lesions before 6 months of age .
In adults CM is less frequently diagnosed than in children.
A slight male predominance has been reported in CM.
SM is generally diagnosed after the second decade of life ; the male to female ratio has been
reported to vary from 1:1 to 1:3

ETIOLOGY
Activating mutations in KIT, which encodes the SCF receptor, a member of the type III receptor
tyrosine kinase family, have been documented in patients with mastocytosis. The most common of
these mutations (Asp816Val), which results in ligand-independent activation of the KIT receptor.
Additional genetic lesions have been reported in aggressive mastocytosis including mutations in
PRKG2-PDGFRB fusion, JAK2, TET2, NRAS, and KRAS.

SYSTEMIC MASTOCYTOSIS
Symptoms in SM at presentation have been grouped into 4 categories:
1) constitutional symptoms (fatigue, weight loss, fever, diaphoresis).
2) skin manifestations (pruritus, urticaria, dermatographism).
3) mediator-related systemic events (abdominal pain. gastrointestinal distress , flushing.
syncope, headache, hypotension, tachycardia. respiratory symptoms) and
4) musculoskeletal complaints (bone pain, osteopenia/osteoporosis. Fractures, Arthralgias,
myalgias)

CRITERIA FOR SYSTEMIC MASTOCYTOSIS

Lymph nodes
Lymphadenopathy is most prominent in patients
with SM-AHNMD or ASM.
Mast cell infiltrates are observed in the node’s
paracortex, follicles, medullary cords, and
sinuses.
Additional findings include infiltrates of
eosinophils, blood vessel proliferation in
association with mast cells in the paracortical
areas, and extramedullary hematopoiesis.
Fibrosis may be observed in lymph nodes
involved by mast cell infiltrates.

Liver
Patients frequently exhibit infiltration of the liver with mast cells. When severe liver disease
does occur, it typically affects patients with SM-AHNMD or ASM.
● Elevated serum levels of alkaline phosphatase, amino transaminases, 5′-nucleotidase, or
γ-glutamyl transpeptidase.
● Hepatomegaly, prominent infiltration of the liver with mast cells.
● Hepatic fibrosis
● Ascites or portal hypertension.

Spleen
Splenic involvement at diagnosis has been
reported in approximately half of patients with
systemic disease.
Mast cells most commonly occurred in a
paratrabecular distribution, followed by
perifollicular, follicular, and diffuse infiltrates.
Trabecular and capsular fibrosis and eosinophilic
infiltration also were observed, and
extramedullary hematopoiesis was present in most
cases.

Bone Marrow
The majority of adults with systemic mast cell disease have focal mast cell lesions in the marrow, typically
appearing as foci of spindle-shaped mast cells in a fibrotic background, sometimes with associated
eosinophils and T and B lymphocytes.
These focal mast cell lesions are the major criterion in the diagnosis of systemic mastocytosis.
Reticulin staining may be increased, and Masson trichrome staining may reveal collagen deposition.

INVESTIGATIONS
Diagnosis usually requires histological and biochemical confirmation
Routine investigations should include a full blood count, liver function tests and a random serum
tryptase.
Plasma levels of soluble CD25 and CD117 (kit) have shown promise as novel markers of mast cell
disease.

INVESTIGATIONS
Bone marrow aspiration and trephine biopsy
Mast cell aggregates can be visualized on conventional haematoxylin and eosin-stained sections
but stand out clearly with stains such as toluidine blue .
Immunochemistry using anti tryptase antibodies highly specific for mast cells.
Flow cytometry to look for expression of CD2 and CD25 in bone marrow mast cells may be useful
as this phenotype is not seen in normal mast cells.

INVESTIGATIONS
Abdominal ultrasound or computerized tomography (CT) scanning should be performed to look for
hepatosplenomegaly and lymphadenopathy.
Plain radiography and bone densitometry can be used to assess bone involvement and the
presence of osteoporosis.
Endoscopy and biopsy can be useful if gut involvement is suspected.

PROGNOSIS
Age and disease category are the most important determinants of outcome.
The most benign syndrome is paediatric mastocytoma, which disappears with time in over 50% of
cases.
Paediatric urticaria pigmentosa also has a good prognosis and resolves in about one-half of the
cases.
Indolent systemic mastocytosis carries a favourable prognosis and usually persists as a chronic
low-grade disorder.

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Mast cells in health and disease

Mast cells in health and disease

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