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

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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