micr 304 immunology & serology
DESCRIPTION
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. Definition Classification of hypersensitivities Key players in hypersensitivities Immunopathology of hypersensitivities. - PowerPoint PPT PresentationTRANSCRIPT
MICR 304 Immunology &
Serology
MICR 304 Immunology &
Serology
Lecture 14Hypersensitivities
Chapter 9.24, 9.25;13.1 – 13.4, 13.6 – 13.12, 13.14, 13.16 –19
Lecture 14Hypersensitivities
Chapter 9.24, 9.25;13.1 – 13.4, 13.6 – 13.12, 13.14, 13.16 –19
Overview of Today’s Lecture
• 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
• IgE• IgG• Complement• Mast cells• Basophils• Eosinophils• Phagocytes, Dendritic cells, NK cells• T-cells
Eosinophils
Properties of IgE and IgG
IgE IgGSize, structure 180 kD, no hinge 150 kD, hinge
Blood levels [mg/ml] 0.00003 14
Mast Cell Sensitization +++ -
Basophil sensitization + -
Binding to eosinophils*, basophils, mast cells
+ (+)
NK-Binding - ++
Neutralization, complement activation,
opsonization
- +++
Placenta transport - +++* activated
Two Types of IgE Receptors
• High affinity (FcRI)– IgE is captured
without antigen binding
– Present on resting mast cells, basophils
– Present on activated eosinophils
– Cross-linking with antigen granule release
• Low affinity (FcRII)– Present on many
cells– B-Lymphocytes– Activated T-
lymphocytes– 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
• 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– TNFProinflammatory– 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, TGF– IL3 + TGF 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
• 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 • 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– Soluble antigen Antigen-Antibody complexes
• Type IV– T-cell mediated
An
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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.)
92608A
dust mitefecal pellet pollen
mineral
plant debris
dead skin / dander
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– IL4, IL4 receptor– High affinity IgE receptor– MHC II allele– TCR locus
Allergies!!
Less allergies!!
Allergic Reactions Can be Divided into 2 Phases
Immediate within minutes•Histamine mediated•Smooth muscle cell contraction•Vascular endothelium leakage
Late after several hours•Chemokine mediated•Inflammatory cell influx
PFER:Peak expiratory flow rate
Skin
Lung
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 Fc 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
Antigenabsorbed through gut
Injected Allergen and TH1 Mediated Type IV Hypersensitivity
Example: Tuberculin skin test
Cell infiltrate!!
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 Eosinophils!!
Example: Chronic asthma
Chronic Asthma Can Lead to Complete Airway
Occlusion
Dense inflammatory infiltrate with eosinophils,
neutrophils, and lymphocytes
Mucus plug in the airways
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
http://www.denniskunkel.com/product_info.php?products_id=9797