1. Hypersensitivities1 Immune Hypersensitivity Chapter 18 Self-Test Questions: Intro: all A1-2: all A3: 1, 3, 5 A4: all B: 1, 2, 4, 5 C: 1 - 4 D: 1 - 4

2. Hypersensitivities2 What characteristics are shared by all hypersensitivies? Immune responses: Primary (sensitization) response Secondary (activation) response Abnormal (hyper-) response to antigens (allergens) Symptoms: localized or systemic Onset can be: Early, Late or Chronic

3. Hypersensitivities3 What are hypersensitivities? 4 types of hypersensitivities (Gel and Combs classification) Immune Namesystem involvedEffectorsEffects Onset Type 1“Atopic” Humoral (IgE)mast cellsinflammationseconds eosinophils(anaphylaxsis) Type II “Cytotoxic” Humoral/macrophages cell destruction hours Complementcomplement (hemolysis) Type III“Im. Complex” Humoral/ granulocytesinflammation hours Complement Type IV“Delayed type” Cell-mediatedmacrophagesinflammation days -- T H 1

4. Hypersensitivities4 Type I – Atopic hypersensitivities AG presentation DCs, even Basos & Eosinos activate T H 2 cells IgE production class switching to IgE Mast cell sensitization IgE binding to Fc receptors Mast cell activation Degranulation secretion synthesis Early phase & late phase responses McGraw-Hill Type-I

5. Hypersensitivities5 Early phase responses Molecular Mediators: Primary – in granules Secondary – synthesized later (w/in 1- few minutes) Localized clinical response (Atopy) atopic asthma: urticaria (hives) eczema (skin lesions) atopic rhinitis food allergies Systemic clinical response (anaphylaxis) anaphylatic shock

6. Hypersensitivities6 e.g., Erythema, etc “peak flow rate” measurements Due to: -- Cytokines from mast cells -- Recruited eosinophils & T H 2 -- degranulation Chronic Type I -- eosinophilia -- inflammation: damaged airways & mucous membranes Late phase responses -- 4-6 hours later Early phase Late phase

7. Hypersensitivities7 What factors affect predisposition toward Type I hypersensitivities? Genetic factors Environmental factors Hygiene hypothesis

8. Hypersensitivities8 Treatment Skin testing -- carries some risk Drugs therapies -- Theophylline (blocks degranulation) -- antihistamines (block histamine receptors) -- epinephrine (reverses trachael & bronchiole SM and contracts arteriole SM) Desensitization Desensitization Therapy

9. Hypersensitivities9 Type II hypersensitivity -- “Cytotoxic” Ig binding to AG on cells -- triggers cell lysis Complement mediated Macrophage mediated Various types of hemolytic disorders e.g., Blood transfusion incompatibility {see section in chapter 17} Autoimmune disorders e.g.. Goodpasture’s syndrome RBC being phagocytosed in fetal erythroblastosis 1967 Science 158: cover

10. Hypersensitivities10 Type III hypersensitivity -- “immune complex” Localized : (Arthus reaction) -- could result from an insect bite 1)Ag-Ab complex Excess AG  small complexes  complement activation 2) mast cell degranulation 3) neutrophil recruitment 4) Triggering of inflammation Systemic : S erum sickness Vasculitis Hypersensity pneumonitis -- Pigeon breeders disease (pigeon feces dust) -- Farmers lung (Actinomycetes) -- Mushroom picker’s… -- Cheese washer’s… -- Chicken plucker’s… -- etc., … disease Adapted from Majno and Joris, 2004, Cells, Tissues and Disease Type III Hyper C3a, C5a

11. Hypersensitivities11 Type IV hypersensitivity “Delayed-type” -- slow onset ~day(s) (if sensitized) T H 1-cell mediated Sensitization phase -- week(s) onset -- T H 1 expansion Effector stage – day(s) onset -- T H 1 & macrophage activation -- inflammation Latex type IV hypersensitivity

12. Hypersensitivities12 Type IV hypersensitivities, con’t Contact dermatis reactions Often involves hapten production e.g. to: hair sprays, plant toxins, turpentine TH1TH1

13. Hypersensitivities13 Tuberculosis (see Chapter 14 pp 212-213) -- Persistent Mycobacterium tuberculosis Granuloma (tubercule) formation T H 1 cells and activated macrophages ‘caseous’ regions extended tissue destruction