• Share
  • Email
  • Embed
  • Like
  • Save
  • Private Content
New understanding mast cell function
 

New understanding mast cell function

on

  • 3,238 views

 

Statistics

Views

Total Views
3,238
Views on SlideShare
3,236
Embed Views
2

Actions

Likes
2
Downloads
69
Comments
0

1 Embed 2

https://twitter.com 2

Accessibility

Categories

Upload Details

Uploaded via as Microsoft PowerPoint

Usage Rights

© All Rights Reserved

Report content

Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
  • Full Name Full Name Comment goes here.
    Are you sure you want to
    Your message goes here
    Processing…
Post Comment
Edit your comment

    New understanding mast cell function New understanding mast cell function Presentation Transcript

    • 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 progenitorTC Moon et al.Mucosal Immunology 2010; 3(2):111-128
    • Middleton’s Allergy Principle & Practice 7th ed transcription factors Kit ligand with T cell cytokine (IL3,4,5,9
    • Middleton’s Allergy Principle & Practice 7th ed
    • Distribution of mast cellFresh camel tissue from 9 healty malecamels (9-12 Mo old) 6 full thicknesssection 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 M.B. Al-Aghoul et al. Euro J Histochemistry 2008; 52(4): 237-42
    • M.B. Al-Aghoul et al. Euro J Histochemistry 2008; 52(4): 237-42-no significant differencewas observed in MCamong lamina propria,muscularis mucosae,muscularis externa &serosa-only significantdifference observed wasin submucosa region 1.highest MC injejunual submucosa 2.lowest MC in ilealsubmucosa
    • Stephan C. Bischoff. Semin Immunopathol 2009; 31: 185-205
    • Ontogeny and tissue localization 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 TC 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 lung o Adhesive interaction -Vascular cell adhesion molecule 1 - 4 7 or 4 1 integrin but not mucosal addressin cell adhesion molecule 1 TC Moon et al.Mucosal Immunology 2010; 3(2):111-128
    • Human mast cell heterogeneity
    • Cell type MCT MCTCGranule proteases Tryptase Tryptase, chymase, carboxypeptidase, cathepsin-GTissue distribution Mucosal, alveoli, Skin, submucosa, bronchi, allergic normal conjunctiva, conjunctiva synovium, heart, vascular wallT-cell dependency Yes noArachidonic acid PGD2, LTC4 PGD2 metabolism Middleton’s Allergy Principle & Practice 7th ed
    • Human mast cell mediatorsStephan C. Bischoff. Semin Immunopathol 2009; 31: 185-205
    • 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 TC Moon et al.Mucosal Immunology 2010; 3(2):111-128
    • Progress in understanding mastcell 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 TC Moon et al.Mucosal Immunology 2010; 3(2):111-128
    • Progress in understanding mastcell 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) TC Moon et al.Mucosal Immunology 2010; 3(2):111-128
    • Progress in understanding mastcell 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 TC 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 Radia Tamarat et al. Lab Invest 2002, 82:747–756
    • Mechanism of angiotensin II in 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 Radia 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 Radia Tamarat et al. Lab Invest 2002, 82:747–756
    • mast cell homeostasisTC Moon et al.Mucosal Immunology 2010; 3(2):111-128
    • 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) TC Moon et al.Mucosal Immunology 2010; 3(2):111-128
    • mast cell functions : interface between innate & acquired immunity
    • mast cell functions : interface between innate & acquired immunity 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 TC 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 Middleton’s Allergy Principle & Practice 7th ed TC 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 Middleton’s Allergy Principle & Practice 7th ed TC 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 TC 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 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
    • 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
    • mechanism of MC responses to pathogens TC Moon et al.Mucosal Immunology 2010; 3(2):111-128
    • Role in diseases: foodallergy, functional GI disorders, cancer
    • intestinal mast cells regulate GI tissue homeostasisStephan C. Bischoff. Semin Immunopathol 2009; 31: 185-205
    • 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
    • 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 Terez 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 Terez 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 Terez 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 Terez She-Donohue et al. Curr Gastroenterol Rep 2010; 12: 349-57
    • Role of mast cells in intestinal allergy Stephan 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 Terez 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) Terez 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 Terez 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 bodys 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) Terez 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, mechanicalor 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 instomach wall, called enterochromaffin-like cells (ECL) look like EC cells but do not contain 5-HT produce Gastrin at antrum of stomach. Terez 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 Terez 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 Terez She-Donohue et al. Curr Gastroenterol Rep 2010; 12: 349-57
    • 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) Terez 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 environmentMC were recruited by “IL-17 switched” Treg cells,further increasing proinflammatory environment Terez 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
    • 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