Transcript Janeway`s Immunology - Cal State LA

MICR 304 Immunology &
Serology
Lecture 14
Hypersensitivities
Chapter 9.24, 9.25;13.1 – 13.4, 13.6 –
13.12, 13.14, 13.16 –19
Overview of Today’s Lecture
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Definition
Classification of hypersensitivities
Key players in hypersensitivities
Immunopathology of hypersensitivities
Definition of Hypersensitivity
• Hypersensitivity reactions are immune
responses to innocuous, non-infectious,
environmental antigen that lead to
symptomatic reactions upon re-exposure
• Harmful immune responses
• Hypersensitivity diseases result from
repetitively occurring reactions
• Antigen is in this context “allergen”
Key Players in Hypersensitivities
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IgE
Eosinophils
IgG
Complement
Mast cells
Basophils
Eosinophils
Phagocytes, Dendritic cells, NK cells
T-cells
Properties of IgE and IgG
IgE
IgG
180 kD, no hinge
150 kD, hinge
0.00003
14
Mast Cell Sensitization
+++
-
Basophil sensitization
+
-
Binding to eosinophils*,
basophils, mast cells
+
(+)
NK-Binding
-
++
Neutralization, complement
activation, opsonization
-
+++
Placenta transport
-
+++
Size, structure
Blood levels [mg/ml]
* activated
Two Types of IgE Receptors
• High affinity (FceRI)
– IgE is captured
without antigen
binding
– Present on resting
mast cells, basophils
– Present on activated
eosinophils
– Cross-linking with
antigen granule
release
• Low affinity (FceRII)
– Present on many
cells
– B-Lymphocytes
– Activated Tlymphocytes
– Phagocytes
– Dendritic cells
– Thymic epithelial
cells
Production of IgE
• Under primary influence of IL4, also IL13
• Antigen-dependent dendritic cells promote development of
TH0 to TH2 in the absence of inflammation
• Exposure of TH0 to certain cytokines will promote TH2
development
– IL4, IL5, IL9, and IL13
• Mast cells and TH2 secrete IL4
• TH2 secrete IL4, IL5, IL9, and IL13
• B-cell respond to IL4 , IL13, CD40 (B-ly): CD40L (TH)
– JAK signal transduction pathway
– phosphorylation of STAT (signal transducer and activator of
transcription)
– Ig- class switch to IgE
Mast Cells
• Mast cells derive from bone marrow, myeloid
lineage
• Prominent histamine rich granules
• Line body surfaces
– In vascularized connective tissues just beneath
epithelial surfaces
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Primary function is to alert to local infection
High affinity IgE receptor
Release granules upon receptor cross-linking
Role in defense against parasites, allergy
Mast Cells are Activated Upon
IgE Cross-Linking
Mast Cell Products
• Histamine, Heparin
– Toxic
– Endothelial permeability increase, edema
– Smooth muscle contraction
• Chymase, tryptase
– Tissue remodeling
• Cytokines
– IL4, IL13: IgE, TH2 response
– TNFa: Proinflammatory
– Chemokines: Recruit eosinophils, basophils
• Lipid mediators
– PAF: recruit leukocytes, activates neutrophils, eosinophils,
platelets
– Leukotriene, prostaglandins: smooth muscle cell contraction,
mucus secretion, increased vascular permeability
Mast Cells Amplify IgE Production
Mast Cell Effects Depend on
Site of Activation
Anaphylaxis
• Disseminated mast cell
activation
• Widespread increase in
vasopermeability leads
to catastrophic drop in
blood pressure (shock)
• Airway constriction
causes breathing
problems
• Swelling of epiglottis
can cause suffocation
Basophils
• Myeloid cell lineage
• Develop under the influence of IL3, IL5,
GM-CSF, TGFb
– IL3 + TGFb increase basophil production
and decrease eosinophil production
• Polymorphonuclear
• Basophil granules
– Histamin
Differences Between Basophils
and Mast Cells
Basophils
• In peripheral blood (but
enter tissue during
inflammation)
• Lobular nucleus
• Tryptase +/?
• Life span hours
Mast Cells
• In tissue around blood
vessels
• (skin, epithelial mucosa,
in particular gut, lung)
• Round nucleus
• Tryptase (a serine
protease) +++
• Survive months to years
Eosinophils
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Derive from bone marrow
Myeloid lineage
Granules contain major basic protein (arginine rich)
Predominant in connective tissue, subepithelial in
respiratory, intestinal and urogenital tract
Express high affinity IgE receptor after activation
Can present antigen to T cells
Promote TH1 apotosis
Two major effector functions
– Direct killing via exocytosis
– Orchestrating an inflammatory response
Eosinophils Secrete a Range of
Highly Toxic Molecules
• Tissue remodeling
– Peroxidase
– Collagenase
– Matrix metalloprotease
• Direct Killing
– Toxic proteins
• Major basic protein
• Cationic protein
• Neurotoxin
– Oxidative burst
• Inflammation
– Cytokines
• IL3, IL5, GM-CSF
• CXCL-8
– Lipid mediators
Anti-parasitic, activate mast cells, proinflammatory
Classification of Hypersensitivities
by Mechanism in Four Types
Antibody
• Type I (“Allergy”)
– Soluble antigen: IgE: Mastcells
– Immediate-type
– Atopy: Exaggerated tendency to mount an IgE
response
• Type II
– Cell associated antigen: IgG: phagocytes, NK cells
• Type III
Cell
– Soluble antigen  Antigen-Antibody complexes
• Type IV
– T-cell mediated
Immunological Mechanisms of
Hypersensitivities
Type I Hypersensitivities
(Allergies)
Pathogenesis of Type I
Hypersensitivity
• Antigen is soluble
• Antibody is IgE
• Mast cell
degranulation
IgE Mediated Reactions to Allergens
•Always involve mast cell mast cell degranulation
•Symptomatic depends on site of entry and mast cell activation and dose
Examples for Inhaled Allergens
Dust mite (Dermatophagoides sp.)
dust mite
fecal pellet
dead skin / dander
pollen
mineral
92608A
plant debris
Allergens Promote TH2 Development
Can easily spread in tissue
and reach subepithelial APC
(primarily DC) with
subsequent Th2 priming
Typical for inhaled allergens
Enzymatic Activity of Some Allergens Enables
Easy Penetration of Epithelial Cell Barriers
The cysteine protease Der p 1 is from fecal pellets of house dust mite.
Protease inhibitors may be a novel therapeutic approach for allergies.
Genes and Environment in Allergies
• Both environmental and inherited
factors are important
• Environment:
– Exposure to infectious agents in early
childhood drives a TH1 response
– Too hygienic environment with too little
infectious agents drive a TH2 response
• Susceptibility genes for asthma
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IL4, IL4 receptor
High affinity IgE receptor
MHC II allele
TCR a locus
Allergies!!
Less allergies!!
Allergic Reactions Can be
Divided into 2 Phases
Immediate within minutes
•Histamine mediated
•Smooth muscle cell
contraction
•Vascular endothelium
leakage
Lung
Skin
Late after several hours
•Chemokine mediated
•Inflammatory cell influx
PFER:
Peak expiratory flow rate
Immediate and Late Phase in
Acute Allergy
Food Allergies
• About 1 – 4 % of European and
US population suffers from true
food allergies
• 25% of true food allergies are
against peanuts
– 30,000 anaphylactic reactions and
200 deaths per year in US
• Food allergens have high
resistance against gastric pepsin
• Allergens are resorbed and
activate resident mast cells
• Urticaria and asthma after
systemic dissemination the
allergen
Approaches to Treat Allergies
Pathogenesis of Type II
Hypersensitivity
• Antigen is cell-or matrix
associated
• Antibody is IgG
 Activation of complement
– Hemolysis, platelet lysis
 Binding through Fcg
receptors
– Phagocytosis
 Antibody itself induces cell
changes
Pathogenesis of Type III
Hypersensitivity
• Soluble antigen
• Antibody is IgG
• Deposition of immune
complexes
• Activation of complement
• Inflammation
– Local (Arthus reaction)
– Systemic (serum sickness)
Arthus Reaction: Local Type III
Hypersensitivity
Serum sickness: Systemic
Type III Hypersensitivity
Pathogenesis of Type IV
Hypersensitivity
• Mediated by T-cells
• Soluble antigen: TH
mediated
– TH1
– TH2
• Cell associated
antigen: CTL
mediated
Type IV Hypersensitivity Responses are
Mediated by Antigen-specific Effector T cells
Antigen injected into skin
Antigen absorbed through skin
Antigen
absorbed
through gut
Injected Allergen and TH1 Mediated
Type IV Hypersensitivity
Cell infiltrate!!
Example: Tuberculin skin test
Examples for Positive Tuberculin Tests
TH1 Cytokines in Type IV
Hypersensitivity Response
Absorbed Allergen and TH1 Mediated
Type IV Hypersensitivity
Example: Contact dermatitis
TH2 Mediated Type IV
Hypersensitivity
Immediate
Late
Example: Chronic asthma
Eosinophils!!
Chronic Asthma Can Lead to
Complete Airway Occlusion
Mucus plug in the airways
Dense inflammatory infiltrate
with eosinophils, neutrophils,
and lymphocytes
CTL Mediated Type IV
Hypersensitivity
• Example: Poison ivy contact
dermatitis
• Lipid soluble allergen is
absorbed through skin and
crosses cell membranes
• Allergen modifies self
peptides
• Presentation of modified self
peptide via MHC I to CTL
• Destruction of modified cell
Additional Resources
Accessed 5/17/2008
http://medicalimages.allrefer.com/large/epiglottis.jpg
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