New understanding mast cell function
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Transcript of 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 homeostasisInterface between innate & adaptive immunitymast cell in infectionRole in diseases: food allergy, functional GI
disorders, cancer
asthma, other allergic disorders
2
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
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Mast cell ontogeny and tissue localization
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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
5TC Moon et al.Mucosal Immunology 2010; 3(2):111-128
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mast cell progenitor
Common myeloid
progenitor
Granulocyte/macrophage progenitor
TC Moon et al.Mucosal Immunology 2010; 3(2):111-128
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Middleton’s Allergy Principle & Practice 7th ed
transcription factors
Kit ligand with T cell
cytokine(IL3,4,5,9
8Middleton’s Allergy Principle & Practice 7th ed
9
Distribution of mast cell
10M.B. Al-Aghoul et al. Euro J Histochemistry 2008; 52(4): 237-42
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
Distribution of mast cell
11M.B. Al-Aghoul et al. Euro J Histochemistry 2008; 52(4): 237-42
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-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
14Stephan C. Bischoff. Semin Immunopathol 2009; 31: 185-205
Ontogeny and tissue localizationLocalization 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
15TC Moon et al.Mucosal Immunology 2010; 3(2):111-128
Ontogeny and tissue localization MC progenitor are not abundant in lung
Pulmonary inflammation increased numbers of MC are detected in bronchial epithelium, airway smooth muscle
Localization to lungoAdhesive interaction
-Vascular cell adhesion molecule 1
-47 or 41 integrin
but not mucosal addressin cell adhesion
molecule 1
16TC Moon et al.Mucosal Immunology 2010; 3(2):111-128
Human mast cell heterogeneity
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18Middleton’s Allergy Principle & Practice 7th ed
Cell type MCT MCTC
Granule proteases Tryptase Tryptase, chymase, carboxypeptidase,
cathepsin-G
Tissue distribution Mucosal, alveoli, bronchi, allergic
conjunctiva
Skin, submucosa, normal conjunctiva,
synovium, heart, vascular wall
T-cell dependency Yes no
Arachidonic acid metabolism
PGD2, LTC4 PGD2
19Stephan C. Bischoff. Semin Immunopathol 2009; 31: 185-205
Human mast cell mediators
Progress in understanding mast cell functions
20
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
21TC Moon et al.Mucosal Immunology 2010; 3(2):111-128
Progress in understanding mast cell functions : homeostasis (2)
All phase of wound healing 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
22TC Moon et al.Mucosal Immunology 2010; 3(2):111-128
Progress in understanding mast cell functions : homeostasis (3)
All phase of wound healing 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)
23TC Moon et al.Mucosal Immunology 2010; 3(2):111-128
Progress in understanding mast cell functions : homeostasis (3)
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
24TC Moon et al.Mucosal Immunology 2010; 3(2):111-128
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
25Radia Tamarat et al. Lab Invest 2002, 82:747–756
Mechanism of angiotensin II in angiogenesis (2)
second : By regulating matrix metalloproteinases
(MMP) production and activation2 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
26Radia Tamarat et al. Lab Invest 2002, 82:747–756
Mechanism of angiotensin II in angiogenesis (3)
Third :exerts several direct effects to
stimulation of monocyte recruitment, activation of M, and enhanced COX-2 protein expression
27Radia Tamarat et al. Lab Invest 2002, 82:747–756
28TC Moon et al.Mucosal Immunology 2010; 3(2):111-128
mast cell homeostasis
mast cell functions : interface between innate & acquired immunity
Various pathogen & their products activate MCs through TLRs, complement Rc, Fc Rco 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 LNo Increasing evidence that function as APC (express
MHC class I and upregulate expression of MHC class II when stimulated with IFN-, TNF, LPS)
29TC Moon et al.Mucosal Immunology 2010; 3(2):111-128
mast cell functions : interface between innate & acquired immunity
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mast cell functions : interface between innate & acquired immunity
In addition to MHCo 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
31TC Moon et al.Mucosal Immunology 2010; 3(2):111-128
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
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Middleton’s Allergy Principle & Practice 7th edTC Moon et al.Mucosal Immunology 2010; 3(2):111-128
mast cell in infection 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
33
Middleton’s Allergy Principle & Practice 7th edTC Moon et al.Mucosal Immunology 2010; 3(2):111-128
mast cell in infection 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
34TC Moon et al.Mucosal Immunology 2010; 3(2):111-128
mast cell in infection 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 AIDSindicate 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
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mast cell in infection 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
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37TC Moon et al.Mucosal Immunology 2010; 3(2):111-128
mechanism of MC responses to pathogens
Role in diseases: food allergy, functional GI
disorders, cancer
38
39Stephan C. Bischoff. Semin Immunopathol 2009; 31: 185-205
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
40Terez She-Donohue et al. Curr Gastroenterol Rep 2010; 12: 349-57
Role in disease : food allergy(2) 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
41Terez She-Donohue et al. Curr Gastroenterol Rep 2010; 12: 349-57
Role in disease : food allergy(3) 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
42Terez She-Donohue et al. Curr Gastroenterol Rep 2010; 12: 349-57
Role in disease : food allergy(4) 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
43Terez She-Donohue et al. Curr Gastroenterol Rep 2010; 12: 349-57
Role in disease : food allergy(5) Prominent result of MC/nerve/smooth muscle
interaction is hypersensitivity of nerves resulting in elevated smooth muscle contractility
44Terez She-Donohue et al. Curr Gastroenterol Rep 2010; 12: 349-57
Role of mast cells in intestinal allergy
45Stephan C. Bischoff. Semin Immunopathol 2009; 31: 185-205
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
46Terez She-Donohue et al. Curr Gastroenterol Rep 2010; 12: 349-57
Role in disease : functional 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)
47Terez She-Donohue et al. Curr Gastroenterol Rep 2010; 12: 349-57
Role in disease : functional 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
48Terez She-Donohue et al. Curr Gastroenterol Rep 2010; 12: 349-57
Role in disease : functional 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)
49Terez She-Donohue et al. Curr Gastroenterol Rep 2010; 12: 349-57
Role in disease : functional 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.
50Terez She-Donohue et al. Curr Gastroenterol Rep 2010; 12: 349-57
Role in disease : functional 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
51Terez She-Donohue et al. Curr Gastroenterol Rep 2010; 12: 349-57
Role in disease : functional 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
52Terez She-Donohue et al. Curr Gastroenterol Rep 2010; 12: 349-57
Role in disease : cancer(1)
Gounaris et al.’s work found thatColon 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 polypno longer produce IL-10 (IL-10 suppress inflammation which critical component of tumor progression)
53Terez She-Donohue et al. Curr Gastroenterol Rep 2010; 12: 349-57
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
54Terez She-Donohue et al. Curr Gastroenterol Rep 2010; 12: 349-57
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
55
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
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