New understanding mast cell function

NEW UNDERSTANDING OF
MAST CELL

SURASARIT KHAWLAOR

OUTLINES
 Mast cell ontogeny and tissue localization
 Human mast cell heterogeneity
 Progress in understanding mast cell functions
Mast cell homeostasis
Interface between innate & adaptive immunity
mast cell in infection
Role in diseases: food allergy, functional GI
disorders, cancer
asthma, other allergic disorders

History of mast cell
• Identified as granular cells in mesentery of frog by
Dr von Recklinghausen in 1863
• Dr Paul Ehrlich in 1878 named these cells as
“Mastzellen”
• Initail studies focused on their histological
characteristics, distribution & abundance in health
and dz.
• In 1910, discovery of histamine, In 1938, of slow-
reacting substance of anaphylaxis & In 1966, of
IgE  provided initial insights into the role of MCs
in allergic reactions

Mast cell ontogeny and
tissue localization

Ontogeny and tissue localization
 Human mast cell (MC) originate from
CD34+/CD117+/CD13+ multipotent hematopoietic
progenitor in BM and migrate through blood to
tissue where they mature
 In human, detail of their differentiation &
phenotypic diversification are incompletely known
 Several studies on mechanism of MCs localization
 MC progenitor are abundant in small intestine

TC Moon et al.Mucosal Immunology 2010; 3(2):111-128

Granulocyte/
macrophage
progenitor

mast cell
progenitor

Common
myeloid
progenitor


Middleton’s Allergy Principle & Practice 7th ed

transcription
factors

Kit
ligand
with T cell
cytokine
(IL3,4,5,9

Distribution of mast cell
Fresh camel tissue from 9 healty male
camels (9-12 Mo old) 6 full thickness
section of duodenum, jejunum, ileum

Either fixed in 10% phosphate-buffered
formaldehyde over night or in Carnoy’s
fluid for 4 hrs  serial section at thickness
of 4 m

-1 section of each was stained with H&E
for histopathological evaluation

-other sections were stained by
1.Metachromatic staining : MB
2.immunohistochemistry : mouse Ab to
human tryptase

M.B. Al-Aghoul et al. Euro J Histochemistry 2008; 52(4): 237-42

Distribution of mast cell


-no significant difference
was observed in MC
among lamina propria,
muscularis mucosae,
muscularis externa &
serosa
-only significant
difference observed was
in submucosa region
1.highest MC in
jejunual submucosa
2.lowest MC in ileal
submucosa

Stephan C. Bischoff. Semin Immunopathol 2009; 31: 185-205

Localization to small intestine reliant on
oAdhesive interaction which is controlled by
- 4 (CD49d) 7 integrin
-vascular cell adhesion molecule 1
(VCAM-1:CD106)
-mucosal addressin cell adhesion
molecule 1 (MAdCAM-1)
oExpression of CXCR2 (CD182) is critical
for localization of MC progenitors in gut

 MC progenitor are not abundant in lung
Pulmonary inflammation  increased numbers of
MC are detected in bronchial epithelium, airway
smooth muscle
Localization to lung
o Adhesive interaction
-Vascular cell adhesion molecule 1
- 4 7 or 4 1 integrin
but not mucosal addressin cell adhesion
molecule 1

Human mast cell
heterogeneity

Cell type MCT MCTC

Granule proteases Tryptase Tryptase, chymase,
carboxypeptidase,
cathepsin-G

Tissue distribution Mucosal, alveoli, Skin, submucosa,
bronchi, allergic normal conjunctiva,
conjunctiva synovium, heart,
vascular wall

T-cell dependency Yes no

Arachidonic acid PGD2, LTC4 PGD2
metabolism


Human mast cell mediators


Progress in understanding
mast cell functions

Progress in understanding mast
cell functions : homeostasis (1)
 MC’s mediator influence many sites involved in
 All phase of wound healing
 Acute inflammatory
 Promote influx of inflammatory cells to injury site
 Proliferative phase
 Re-epithelialization & angiogenesis
 Release many angiogenic factors to induce revasculaization of
damage tissue
 Heparin from MC stimulates endothelial cell migration to form
new blood vessel


 MC tryptase stimulates vessel tube formation &
enhances growth of microvascular endothelial cells
 MC chymase promotes angiogenesis through
effects of angiotensin II
 Generate growth factors : fibroblast growth factor,
vascular endothelial growth factor (VEGF), platelet-
derived growth factor (PDGF), nerve growth factor
(NGF)
all growth factors induce proliferation of
epithelial cells & fibroblasts

 Remodeling phase
 As fibroblast expand in previous phase, they deposit
collagen & other extracellular matrix proteins  molded and
remodeled into scar tissue
 Hair follicle recycling
 MC histamine, TNF, substance P involved are
thought to contribute in hair follicle recycling (where
hair growth & regression continuously occur)


 Bone remodeling
 MC-deficient mice have femurs that are lighter &
thinner than WT mice  be validated with MC
reconstituted mice
 MCs are source of osteopontin, glycoprotein
component of bone matrix, that contributes to bone
resorption & calcification (mechanism of bone
remodeling)
 In human systemic mastocytosis, bone turnover is
accelerated  enhance bone loss


Mechanism of angiotensin II in
angiogenesis (1)
 First :
 increasing vascular endothelial growth factor
(VEGF) and basic fibroblast growth factor (bFGF)
synthesis
 But angiogenic response to VEGF might involve the
production of nitric oxide (NO) by increasing
expression of both endothelial (eNOS) and inducible
(iNOS) NO synthase
 bFGF modulate eNOS level and NO production
leading to endothelial cell differentiation into
vascular tubes
Radia Tamarat et al. Lab Invest 2002, 82:747–756

angiogenesis (2)
 second :
By regulating matrix metalloproteinases
(MMP) production and activation
2 members of MMP endopeptidase family,
MMP-9 (92 KD) and MMP-2 (72 KD), are
able to degrade extracellular matrix
components of basement membrane
(proteins that keep the vessel walls solid)
This proteolysis allows the endothelial cells
to escape into the interstitial matrix

angiogenesis (3)
 Third :
exerts several direct effects to
stimulation of monocyte recruitment,
activation of M , and enhanced COX-2
protein expression


mast cell homeostasis

mast cell functions : interface between
innate & acquired immunity
 Various pathogen & their products activate MCs
through TLRs, complement Rc, Fc Rc
o In early phase, MCs release performed mediators that
recruit effector cells ( e.g. Neutrophil) to clearance of
pathogen
o Activate DCs & T cells and their migration to LN
o Increasing evidence that function as APC (express
MHC class I and upregulate expression of MHC class II
when stimulated with IFN- , TNF, LPS)



 In addition to MHC
o Costimulatory molecules CD28, CD80, CD86,
intercellular adhesion molecule-1, OX-40 ligand (act on
T cells) and CD40 ligand (act on B cells) are also
expressed on MCs


mast cell in infection
 Helminth infection
 MC degranulation influence DC activation of T cells
away from Th1, toward Th2 response (mechanism of
this function due to PGD2 or histamine which can
suppress IL-12 release by DC)
 MCs are actvated by helminth & MC hyperplasia is
observed in helminth infection
 but critical involvement in pathogenesis has shown in
few types of these infection e.g. trichinella spiralis is
expulsed by MC-derived MMCP-1, TNF, IL-4. Nippostrongylus
brasiliensis also induces MC hyperplasia

 Bacterial infection
 MC-derived TNF, together with LTC4 & LTB4
contributed to recruitment neutrophils to clearance
Klebsiella pneumoniae, Listeria monocytogenes,
Pseudomonas aeruginosa
 MC can produce antimicrobial nets containing
proteases and LL37 (Cathelicidin antimicrobial peptide
,polypeptides found in lysosomes in macrophages and
polymorphonuclear leukocytes (PMNs))
 Further studies are needed to completely understand


 Fungal infection
 Animal MCs respond to yeast cell wall zymosan and
peptidoglycan by releasing cysteinyl LT & by production of
ROS
 Human MCs respond to zymosan, but not peptidoglycan,
through dectin-1, -glucan Rc for C-type lectin family
 Trichoderma viridae, indoor fungus, induce MC
degranulation (high dose) but low dose enhance histamine
secretion from MCs
 Aspergillus fumigatus induce IgE-independent MC
degranulation
 In vivo requires additional study

 Viral infection
 This aspect is emerging field
 Report from HIV-infected patients
 Increased serum IgE & higher levels predict worse prognosis

Israël-Biet D et al.JACI 1992 Jan;89:68-75

 Fewer MCT in intestinal mucosa of patients with
AIDSindicate a role for functional T lymphocytes in the
development of the T mast cell type in humans

Irani AM et al. J Immunol. 1987; 138(12): 4381-6

 Viral infection (2)
 Dengue virus can activate MCs to release IL-1 , IL-6,
RANTES, MIP-1 and MIP-1
 Dengue virus also induce caspase-dependent MC
apoptosis, but not apoptosis of other Fc -expressing cell
types
 Respiratory syncytial virus (major cause of LRT in infant &
associated with development of asthma later in life
 MD density and levels of LT are increasesed in lungs of this
infected rat  implicating MCs in response to this viral
infection
 Airway MC numbers increase in parainfluenza infection

mechanism of MC responses to pathogens


Role in diseases: food
allergy, functional GI
disorders, cancer

intestinal mast cells regulate GI tissue homeostasis


Role in disease : food allergy(1)
 Increased intestinal permeability is common
outcome of immune-mediated dz. Including DM,
IBS, food allergy, celiac dz.
 Contribution of MC to barrier functions in
homeostasis is not well defined, mediators which
effect on epithelial barrier function including
histamine, proteases, IL-4, IL-13, TNF- , IL-1
Exposure to human MC chymase increased cultured
epithelial cell permeability  providing support role of
chymase in regulation barrier function

Terez She-Donohue et al. Curr Gastroenterol Rep 2010; 12: 349-57

 Infiltration of MC to mucosal site of small or large
intestine following oral challenge is common
feature observed in all food allergies
 May associated with constipation
 Number of MC & their proximity to nerve fibers is significantly
reduced by removal of allergen from diet in children suffering
from chronic constipation
 MC influence intestinal smooth muscle function as a result of
their close approximation with enteric nerve
 Histamine, tryptase, LTs directly cause smooth muscle
contraction / relaxation


 Cell adhesion molecule-1 (CADM1) promote
communication between nerves or smooth muscle
and MC
 May associated with diarrhea
 sphingosine 1-phosphate (S1P) was identified as
potential therapeutic target for allergy-induced
diarrhea due to
• There has report that FTY720 (inhibitor of S1P
signaling) can reduce MC infiltration to large
intestine


 sphingosine 1-phosphate (S1P) cont.
• S1P is blood borne lipid mediator regulates
angiogenesis, vascular stability, and
permeability
• In immune system, it is now recognized as a
major regulator of trafficking of T- and B-cells
• S1P interaction with its receptor S1PR1 is
needed for the egress of immune cells from the
lymphoid organs (such as thymus and lymph
nodes) into the lymphatic vessels,
• S1PR1 highly expression in endothelial cell

 Prominent result of MC/nerve/smooth muscle
interaction is hypersensitivity of nerves resulting
in elevated smooth muscle contractility


Role of mast cells in intestinal allergy


Role in disease : functional
GI disorders (1)
 Diagnosis of IBS is based on symptoms due to
absence of specific pathology
 Common feature of IBS is visceral hypersensitivity
from stimuli in lumen of gut
 Chronic stress caused release of norepineprine 
lesd to increased expression of nerve growth
factor (product of MC) key role in sensitizing
visceral afferent neurons


GI disorders (2)
 IBS can be classified as
diarrhea-predominant (IBS-D)
constipation-predominant (IBS-C) or IBS with
alternating stool pattern (IBS-A)
In some individuals, IBS may have acute onset and
develop after infectious illness characterized by two or
more of the following:
fever, vomiting, diarrhea, or positive stool culture
This post-infective syndrome has been termed "post-infectious
IBS" (IBS-PI)


GI disorders (3)
 In IBS-PI, there is evidence that several
inflammatory cells are elevated e.g. MC, (5-HT)-
containing enterochromaffin cells(EC), T cells
 In small cohort study, control groups were
compared with non IBS-PI and IBS-PI
Non IBS-PI, there were elevated levels of 5-HT-
containing EC cells & intraepithelial lymphocytes
IBS-PI, demonstrated elevated number of MC & 5-HT-
containing EC cells  MC are important component as
distinguishing feature of IBS-PI

GI disorders (4)
 Enterochromaffin (EC) cells (Kulchitsky cells) are
type of enteroendocrine cell occurring in the
epithelia lining lumen of the digestive tract and the
respiratory tract
produce and contain about 90% of body's store of
serotonin (5-HT)
called “entero” meaning related to gut & “chromaffin”
because of chromium salt reaction that they share with
chromaffin cells of the adrenal medulla (adrenal glands)


GI disorders (5)
5-HT is important in response to chemical, mechanical
or pathological stimuli in the lumen
It activates both secretory and peristaltic reflexes
activates vagal afferents (via 5-HT3 receptors) that signal to
brain (important in the generation of nausea)
Ondansetron is antagonist of 5-HT3 receptor and is an
effective anti-emetic.
Another population of chromaffin cells is found only in
stomach wall, called enterochromaffin-like cells (ECL)
look like EC cells but do not contain 5-HT
produce Gastrin at antrum of stomach.


GI disorders (6)
 IBS-D pts. have significantly elevated MC
numbers in jejunum with corresponding higher
levels of MC tryptase indicating that mucosal
inflammation of IBS is not restricted to lower gut
MC tryptase activated protease-activated-
receptor-2 (PAR2)
PAR2 is expressed on epithelial, smooth
muscles , nerves, MC, APC


GI disorders (7)
PAR2 is expressed on epithelial, smooth muscles
, nerves, MC, APC
 In IBS-C, it was found increasing numbers of MC in
duodenum


Role in disease : cancer(1)
 Gounaris et al.’s work found that
Colon cancer develop from nonmalignant adenomatous
polyps
MC is an essential hematopoietic component in polyp
development
Genetic or pharmacologic depletion of MC resulted in
remission of polyps
Treg, which expand in adenomatous polyp
no longer produce IL-10 (IL-10 suppress inflammation which
critical component of tumor progression)


Role in disease : cancer(2)
And same time not suppress mastocytosis (normally Treg will
suppress MC activity via IL-10)
Switch from producing IL-10 to IL-17  promoting
proinflammatory rather than immunosuppressive environment
MC were recruited by “IL-17 switched” Treg cells,
further increasing proinflammatory environment


Take Home Messages
 Mast cells are functionally diverse cells that have
a constitutive presence at mucosal surfaces and
elaborate impressive array of mediators, making
them an attractive therapeutic target
 mast cell proteases,their well-documented ability
to alter intestinal permeability, a key factor in
several GI autoimmune/inflammatory pathologies

Take Home Messages
 role of mast cells in IBS and food allergy is well-
documented and represents a convergence of
mast cell actions on immune and intestinal
functioneral GI autoimmune/inflammatory
pathologies
 Role of mast cells in human needs further studies

New understanding mast cell function

New understanding mast cell function

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