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Mast cells in health and disease final dr karishma
1. Presenter :Dr Karishma A. Korgaonker
Moderator : Dr . Gauri Metkar
MAST CELLS IN HEALTH AND DISEASE
2. Introduction
Activation of mast cells
Mast cell mediators
Mast cell in health
>Wound healing
>Angiogenesis
Mast cell in disease
>Immediate hypersensitivity reaction
>Infection
>Inflammation
• Mast cell disorders
• Summary
3. Introduction
Dr Paul Ehrlich in 1878
Large mononuclear cells
Cytoplasmic membrane bound granules - contain a variety of
biologically active mediators and sulphated
glycosaminoglycans
Bone marrow–derived cells-- originate from CD34+/CD117+
multipotent hematopoietic progenitor
They are abundant near blood vessels and nerves and in
subepithelial tissues
4.
5. Mast cells function
Participate in defence against bacterial and parasitic
infection
Develop immediate hypersensitivity reactions
Take part in reparation of tissues - angiogenesis,
production of intercellular substances
6. Introduction
Activation of mast cells
Mast cell mediators
Mast cell in health
>Wound healing
>Angiogenesis
Mast cell in disease
>Immediate hypersensitivity reaction
>Infection
>Inflammation
• Mast cell disorders
• Summary
7. Activation of mast cells
Cross-linking of high-affinity IgE Fc receptors
Complement components C5a and C3a
Mast cell secretagogues include some chemokines (e.g.,
IL-8), drugs such as codeine and morphine, adenosine,
mellitin (present in bee venom), and physical stimuli (e.g.,
heat, cold, sunlight).
8. Activation of mast cells
Mast cells express a high-affinity receptor, called FcεRI,
that is specific for the Fc portion of IgE, and avidly binds
IgE antibodies.
In the first step in this sequence, antigen (allergen) binds
to the IgE antibodies previously attached to the mast cells
The bridging of the Fcε receptors activates signal
transduction pathways from the cytoplasmic portion of the
receptors.
9. Activation of mast cells
These signals lead to mast cell degranulation with the
discharge of preformed (primary) mediators that are stored
in the granules, and de novo synthesis of secondary
mediators
16. Mast cell mediators
• Vasoactive amines:
The most important mast cell–derived amine is histamine.
= intense smooth muscle contraction,
=increased vascular permeability, and
=increased mucus secretion by nasal, bronchial, and gastric
glands.
17. Mast cell mediators
• Enzymes:
= contained in the granule matrix
= include neutral proteases (chymase, tryptase) and several
acid hydrolases.
= cause tissue damage and lead to the generation of kinins
and activated components of complement (e.g., C3a)
18. Mast cell mediators
Proteoglycans:
= include heparin (anticoagulant) and chondroitin sulfate.
= serve to package and store the amines in the granules.
19. Lipid Mediators.
are synthesized by sequential reactions in the mast cell
membranes
= lead to activation of phospholipase A2, an enzyme that
acts on membrane phospholipids to yield arachidonic
acid.
=This is the parent compound from which leukotrienes
and prostaglandins are derived by the 5-lipoxygenase and
cyclooxygenase pathways
20. Lipid Mediators.
Leukotrienes:
C4 and D4 --the most potent vasoactive and spasmogenic
agents known.
B4 --is highly chemotactic for neutrophils, eosinophils, and
monocytes.
21. Lipid Mediators.
Prostaglandin D2 :
= most abundant mediator produced in mast cells by the
cyclooxygenase pathway.
= intense bronchospasm as well as increased mucus
secretion.
22. Lipid Mediators.
• Platelet-activating factor (PAF):
= platelet aggregation, release of histamine, bronchospasm,
increased vascular permeability, and vasodilation.
=chemotactic for neutrophils and eosinophils,
=at high concentrations it activates the inflammatory cells,
causing them to degranulate.
23. Cytokines.
play an important role in immediate hypersensitivity
reactions.
The cytokines include:
>TNF, IL-1, and chemokines - promote leukocyte
recruitment
>IL-4- which amplifies the TH2 response.
24. Introduction
Activation of mast cells
Mast cell mediators
Mast cell in health
>Wound healing
>Angiogenesis
Mast cell in disease
>Immediate hypersensitivity reaction
>Infection
>Inflammation
• Mast cell disorders
• Summary
25. Woundhealingandangiogenesis
MC’s mediator influence-
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
26. Woundhealingandangiogenesis
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
27. Woundhealingandangiogenesis
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
28. Woundhealingandangiogenesis
Bone remodeling
MCs are source of osteopontin, glycoprotein component of bone
matrix, that contributes to bone resorption & calcification
In human systemic mastocytosis, bone turnover is accelerated
enhance bone loss
29. Introduction
Activation of mast cells
Mast cell mediators
Mast cell in health
>Wound healing
>Angiogenesis
Mast cell in disease
>Immediate hypersensitivity reaction
>Infection
>Inflammation
• Mast cell disorders
• Summary
30.
31. Immediate hypersensitivityreactions
Histamine and leukotrienes, are released rapidly from
sensitized mast cells and are responsible for the intense
immediate reactions characterized by edema, mucus
secretion, and smooth muscle contraction
32. Mast Cells vs. Allergens
Allergen detection leads to mast cell histamine
release
In skin, this leads to wheal and flare reactions.
In the gut ,leads to intestinal hyper-permeability,
smooth muscle contraction, altered water and ion
transport, and intestinal symptoms.
• In the lungs, this leads to smooth muscle
contraction, mucus production, and airway
remodeling.
33. Introduction
Activation of mast cells
Mast cell mediators
Mast cell in health
>Wound healing
>Angiogenesis
Mast cell in disease
>Immediate hypersensitivity reaction
>Infection
>Inflammation
• Mast cell disorders
• Summary
34. Mast Cells vs. Parasites
Mast cells offer a first line of defense against parasitic
pathogens.
They are preferentially located in organs targeted
by parasites, where they release proteases, recruit neutrophils,
and regulate vessel permeability.
Mast cells release antimicrobial peptides.
35. mastcell in infection
Helminth infection
MCs are activated by
helminth & MC hyperplasia
is observed in helminth
infection
36. Mast Cells vs. Bacteria
Mast cells express most TLRs on their membrane
surfaces.
TLR binding triggers distinctive patterns of mast cell
activation including the release of antimicrobial peptides
and the production of complement-mediated membrane
attack complexes.
37. mastcell in infection
Bacterial infection
MC-derived TNF, together with LTC4 & LTB4 contributed to recruitment
neutrophils to clearance Klebsiella pneumoniae, Listeria monocytogenes,
Pseudomonas aeruginosa
38. Mast Cells vs. Yeast
and Fungal Forms
Parasite antigen stimulation of TLRs) and C-type
lectin
receptors (CLRs) initiates a wide range of mast cell
IgE
receptors resulting in the release of pro-
inflammatory
cytokines, chemokines, and other pre-stored
mediators of
inflammation.
The release of pre-formed mediators of
inflammation is
39. mastcell in infection
Fungal infection
Human MCs respond to zymosan, but not peptidoglycan,
Trichoderma viridae, indoor fungus, induce MC degranulation
(high dose) but low dose enhance histamine secretion from MCs
Aspergillus fumigatus induce IgE-independent MC degranulation
40. Mast Cells vs. Viruses
Upper respiratory viral infections worsen allergic
asthma,
suggesting increased activation of mast cells during
infection.
Mast cells recognize the presence of double-stranded
viral RNA and respond by releasing: IL-29, interferon-
alpha, interferon-beta, and tumor necrosis factor
alpha.
Virally infected mast cells respond by releasing the
anti-viral
proteins.
41. mastcell in infection
41
Viral infection
This aspect is emerging field
Report from HIV-infected patients
Increased serum IgE predict worse prognosis
Israël-Biet D et al.JACI 1992 Jan;89:68-75
42. mastcell in infection
Viral infection
Dengue virus can activate MCs to release IL-1, IL-6,
RANTES, MIP-1 and MIP-1
Respiratory syncytial virus (major cause of LRT in infant &
associated with development of asthma later in life
Airway MC numbers increase in parainfluenza infection
43. Mast Cells vs. Toxins
Mast cells are known to initiate an immediate IgE-
dependent
hypersensitivity response to venoms.
Mast cells can also be activated by various
endotoxins and
exotoxins.
It is not known whether mold or bacterial toxins
activate mast cell responses, but mast cells
release VEGF and MMP-9,
markers affected in biotoxin-mediated
44. Introduction
Activation of mast cells
Mast cell mediators
Mast cell in health
>Wound healing
>Angiogenesis
Mast cell in disease
>Immediate hypersensitivity reaction
>Infection
>Inflammation
• Mast cell disorders
• Summary
45. Mast cell- skin inflammation
Skin mast cells are located close to sensory nerve
endings and triggered by neuropeptides released by
dermal neurons
Acute stress releases CRH in the skin inducing local
response , increases vascular permeability
Acute stress induces redistribution of leukocytes from
the sytemic circulation into the skin and excerbates
skin delayed hypersensitivity reactions
46. Mast cell – inflammatory arthritis
Fluid aspirated from joints of patients with
arthrosynovitis contains RANTES and MCP-
1(chemoattractants)
Mast cells in the joints of RA patients express CRH
receptors
CRH and CRH receptors are increased in the joints of
inflammatory and RA patients symptoms of which
worsen by stress
47. Mast cell – Coronary inflammation
Cardiac mast cells participate in the development of
artherosclerosis , coronary inflammation, and cardiac
ishemia
Mast cells are prominent in coronary arteries during
spasm
The human mast cell proteolytic enzyme chymase is
the main cardiac source of coronary constrictor
angiotensin II
Cardiac mast cell derived histamine constrict the
coronary arteries
48. Mast Cells and
Coronary Artery Disease
People with mastocytosis or myalgic encephaplitis/chronic
fatigue syndrome are particularly prone to coronary
hypersensitivity reactions.
• Stress precipitates and worsens activation of mast cells via
activation of surface receptors by corticotropin releasing
hormone (CRH) and other hypothalamic neuropeptide
regulators.
49.
50. Mast cells and
Irritable Bowel Syndrome
Mast cell activation plays a role in post-infectious IBS.
• Mast cell degranulation associates with cytokine
alterations and intestinal hyperpermeability in patients
with IBS.
• Mast cell hyperplasia is seen in inflammatory bowel
disorders.
51. Mast Cells and the
Blood-Brain Barrier
Acute stress triggers CRH production which activates
histamine release by mast cells, which leads to increased
blood-brain barrier permeability.
This implicates mast cells in neuroinflammatory disorders
including multiple sclerosis.
53. Rolein cancer
In connective tissue of certain tumours mast cells occur in
great quantities
Cutaneous carcinomas especially basal cell cancers
Enormous accumulation of mast cells is in cutaneous
papilloma these are precancerous lesions
The moment tumour grow malignant the mast cells
disappear and escape detection
Mast cells and their products play a part in the local tissue
resistance against development and growth of the tumour
55. Introduction
Activation of mast cells
Mast cell mediators
Mast cell in health
>Wound healing
>Angiogenesis
Mast cell in disease
>Immediate hypersensitivity reaction
>Infection
>Inflammation
• Mast cell disorders
• Summary
56. MASTOCYTOSIS
A rare group of disorders
Pathological increase in mast cells in tissues
Mastocytosis can form part of other haematological
disorders, including myelodysplastic syndromes,
myeloproliferative disorders or AML.
Cutaneous mastocytosis: involve just the skin
Systemic mastocytosis: involve multiple tissues and
are associated with systemic symptoms
57. MASTOCYTOSIS
A c-kit point mutation leads to a single amino acid
substitution (Asp816Val) .
This mutation leads to ligand-independent
phosphorylation of c-Kit and a consequent clonal
expansion of mast cells.
58.
59.
60. MASTOCYTOSIS
Cutaneous manifestations
Urticaria pigmentosa is the usual presenting feature in
children and adults.
Yellowish-brown lesions,usually macular and
sometimes papular, appear in a patchy distribution.
Pruritus is common, as is flushing, and some cases
develop haemorrhagic bullous disease.
Whealing of lesions upon rubbing is known as
Darier’s sign.
61. MASTOCYTOSIS
Systemic disease
Systemic manifestations are very heterogeneous and are
secondary to mast cell mediator release.
Episodes of flushing, angioedema, or even anaphylaxis
with or without any specific trigger, can arise as a result of
systemic histamine release.
Gastrointestinal symptoms include abdominal
pain,diarrhoea, nausea and vomiting. Gastritis and peptic
ulceration may occur secondary to hyperhistaminaemia
and severe cases may develop malabsorption.
62. MASTOCYTOSIS
Osteoporosis leading to pathological fractures.
Peripheral blood cytopenias.
Hepatosplenomegaly.
Fever, fatigue and weight loss
Symptoms of organ failure due to organ infiltration are
characteristic of aggressive systemic mastocytosis.
63. 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.
64. 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 antitryptase
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.
65. 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
involvementis suspected
66. Treatment
No curative treatment exists for mastocytosis,
The management of which remain symptomatic
67. 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
68. other Mast Cells Disorders
The Most Common Forms of Mast Cell Activation
Syndrome
===Idiopathic (non-clonal) mast cell activation syndrome
(also known as nc-MCAS):
- occurs more often in women
MC triggers are usually unknown.
Idiopathic anaphylaxis and mastocytosis should be ruled
out.
69. other Mast Cells Disorders
Monoclonal mast cell activation syndrome (MMAS): ----
systemic reactions to hymenoptera stings or
-- unexplained anaphylaxis with high baseline tryptase.
Bone marrow biopsy shows monoclonal MCs but not
mastocytosis.
Thought to be rare.
70. Histamine-Overdrive Mast Cell Disorders
Histaminosis: commonly induced by exposure to
histamine from foods; rarely, an acute syndrome caused
by scromboid poisoning (due to seafood high in
histamine).
• Histamine intolerance: sensitivity to histamine from foods
and/or from reduced histamine breakdown.
71. Histamine Intolerance
Reduced central or peripheral breakdown of histamine
can lead to:
Rashes
Headaches
Fatigue
Hives or flushing
Allergies
Dysmenorrhea
Estrogen dominance
GI disturbances
Dysrhythmias
Arthritis
Central, peripheral and/or autonomic neurologic
72. Diet and Nutrition in the
Treatment of Mast Cell Disorders
Some high histamine foods
Pickles , beer, mayonnaise, nuts, wine ,chocolate,
champagne ,vinegar ,cocoa, shellfish ,dried fruits
processed meats, tofu, cheese, yeast, canned vegetables,
mushrooms food additives, egg whites, aged cheeses
, tomatoes ,spices ,spinach
73. Diet and Nutrition in the
Treatment of Mast Cell Disorders
Apples: rich in quercitin
Carrots: rich in vitamin A
Watercress: inhibits histamine release
Broccoli: H2 receptor antagonist
Ginger: H2 receptor antagonist
Thyme: anaphylaxis inhibitor
Fennel: antioxidants, antihistamine, anti-
inflammatory
Turmeric: stabilizes mast cells, inhibits histamine
release me foods with anti-histamine effects
74. Introduction
Activation of mast cells
Mast cell mediators
Mast cell in health
>Wound healing
>Angiogenesis
Mast cell in disease
>Immediate hypersensitivity reaction
>Infection
>Inflammation
• Mast cell disorders
• Summary
75. Mast Cells: The Good,
the Bad, and the Ugly
The Good
An essential player in the body’s innate immune response.
They patrol the front lines: skin, connective tissues and
mucus membranes.
They release chemical alarms to summon defenses against
pathogens, allergens, toxins, and other noxious incitants.
76. Mast Cells: The Good,
the Bad, and the Ugly
The Bad
Over-activation of mast cells can lead to:
• Allergic disease/Asthma/Anaphylaxis
• Eczema/atopic dermatitis
• Migraines/neurological disorders
• Autoimmune disorders
• Gastrointestinal disorders
• Unexplained multi-symptom illnesses
Histamine is only one of many inflammatory elements
released by mast cells. Excess release of mast cell-derived
chemicals results in mast cell-related inflammation.
77. Mast Cells: The Good,
the Bad, and the Ugly
The Ugly
Abnormal mast cell proliferation results in mastocytosis,
which can lead to mast cell tumors and severe forms of
cutaneous or systemic disease.
Systemic mastocytosis commonly results in an
unexplained multi-system, multi-symptom illness
with damage to multiple organ systems that can go
unrecognized in multiple medical settings.
78. Take Home Message
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, is a key factor in several GI
autoimmune/inflammatory pathologies
79. Take Home Message
Mast cells have emerged as unique immune cells that
can be activated by many immune and nonimmune
triggers, including acute stress through CRH
Inhibition of mast cell activation by CRH, therefore,
is a novel target for the development of new treatments
for inflammatory and autoimmune disease
80. References
Robbins and Cotran pathologic basis of disease ,
Eighth Edition p.198-202
A. Victor Hoffbrand ,Daniel Catovsky MD, Edward
G.D. Tuddenham MD, Postgraduate Haematology,
Fifth edition 2005;p-775-778
Beaven M. Our perception of the mast cell from Paul
Ehrlich to now. European Journal of Immunology.
2009 Jan;39(1):11-25.
Moon TC, et al. Advances in mast cell biology: new
understanding of heterogeneity and function.Mucosal
Immunology. 2010;3:111-128.
81. References
Metz M, Maurer M. Mast cells: key effectors in
immune response. Trends in Immunology.
2007;28:234-241.
Theoharis C. Theoharides,and Dimitrios
Kalogeromitros The Critical Role of Mast Cells in
Allergy and InflammationAnn. N.Y. Acad. Sci. 1088:
78–99 (2006). C 2006 New York Academy of
Sciences.doi: 10.1196/annals.1366.025
Gustav Asboe-hansen Mast cells in health and disease
New Understanding Of Mast Cell surasarit Khawlaor
Editor's Notes
(production of IgE antibodies in response to an antigen, binding of IgE to Fc receptors of mast cells, cross-linking of the bound IgE by the antigen and release of mast cell mediators)
. Although the production of PAF is also triggered by the activation of phospholipase A2, it is not a product of arachidonic acid metabolism
The inflammatory cells that are recruited by mast cell–derived TNF and chemokines are additional sources of cytokines and of histamine-releasing factors that cause further mast cell degranulation.
As is evident from this figure, mast cells are capable of signalling to all other immune cells and other cells, the presence of a pathogen.
Mast cells are highly adaptible in nature. Very heterogeous and phenotypically malleable. Originally classified based on staining patterns as mucosal or connective tissue mast cells. These so called types actually differ in their phenotype, their granule composition. For eg. Mucosal mast cells show a different range of proteases than connective tissue mast cells. This composition is further affected based on the stimuli for eg. A cytokine signal that it receives. And based on this stimuli, the response is also quite differently modulated. These features allow mast cells to respond to different pathogens entering different tissues in different ways.
Mast cells functions by virtue of their mediators include increasing vascular permeability and oedema, immune cell recruitment like neutrophils and eosinophils, DCs, T cells and others. Producing antimicrobial peptides and reactive o2 species that have direct bactericidal properties. By its abbility to interact with smooth muscle cells, nerve cells and mucosal cells it can impede colonization of pathogens, and even its physical expulsion for eg. Diarrhoea in response to bacterial toxins. They further activate and modulate Ag presentation of DCs. Mast cells also influence cell trafficking to draining lymph nodes and lymphocyte retention, thus increasing the chances of induction of rare Ag-specific lymphocytes.
With all these functions that mast cells are capable of, they become an attractive addition to vaccines since the clearly enhance the asaptive response by serving as an adjuvant. It was shown 48/80.