Aims

1. Aims • Explain the mechanisms of hypersensitivity reactions. • Define anaphylaxis • Readings: Abbas & Lichtman, Chapter 11

2. Hypersensitivity • Hypersensitivity reactions refer to adaptive immune responses that occur in exaggerated or inappropriate forms and result in disease. • Four types of hypersensitivity reactions.

3. Pathologic immune Mechanism of Type of hypersensitivity mechanism tissue injury Type I - IgE antibody mast cell immediate hypersensitivity degranulation (hay fever, asthma) Type I Immediate Hypersensitivity Adapted from Abbas & Lichtman’s Basic Immunology 11-1

4. Pathologic immune Mechanism of Type of hypersensitivity mechanism tissue injury Type II - IgG or IgM bound to C’ activation antibody-mediated host cells phagocyte cytotoxic or cytolytic reactions activity (HDN, transfusion reactions, abnormalities in autoimmune) membrane receptor functions Type II Antibody-mediated Adapted from Abbas & Lichtman’s Basic Immunology 11-1

5. Pathologic immune Mechanism of Type of hypersensitivity mechanism tissue injury Type III - Deposition of IgG or C’ activation Immune complex-mediated IgM IC phagocyte activity (Arthus reaction, serum sickness) Type III Immune complex-mediated Adapted from Abbas & Lichtman’s Basic Immunology 11-1

6. Pathologic immune Mechanism of Type of hypersensitivity mechanism tissue injury Type IV - Activation of CD4+ Mf activation Delayed hypersensitivityandCD8+ T cells CTL lysis of cells (PPD, contact dermatitis) Type IV T cell-mediated Adapted from Abbas & Lichtman’s Basic Immunology 11-1

7. Type I Hypersensitivity“Immediate Hypersensitivity” • Biologic role in the control of helminth infections (schistosomiasis). • Reactions include: • Hay fever • Food allergies • allergic asthma • ___________________________________

8. Predisposing Factors to Type I Reactions • Type of allergens • Route of exposure • Genetic predisposition • Age

9. fecal pellets Dust mite Airborne Allergens • Low dose antigens. • Can become airborne due to small size (10-40 µm in diameter). Pollen Adapted from Roitt’s Immunology 15-4

10. Pathogenesis of Type I • IgE- mediated • Due to low dose antigen resulting in CD4+ T cells differentiating into IL-4 producing TH2 cells. • IL-4 enhances the growth of B cells and induces their class switch from IgM to IgE. Abbas & Lichtman’s Basic Immunology 11-2

11. Pathogenesis of Type I • Initial Exposure • IgE binds to high-affinity Fc receptors on mast cells and basophils. • Repeat Exposure • Allergen is multi-valent meaning it can bind multiple IgEs at the same time. • Mast cell and basophil are activated. Abbas & Lichtman’s Basic Immunology 11-2

12. Pathogenesis of Type I • Activated cell releases: • ____________________ • constricts bronchial and intestinal smooth muscle. • Increases vascular dilation and permeability. • Causes sneezing, itching (pruritis), and runny nose (rhinorrhea). Adapted from Abbas & Lichtman’s Basic Immunology 11-4

13. Pathogenesis of Type I • Activated cell releases: • Leukotrienes and Prostaglandins • generated from membrane phospholipids. • Prolonged bronchial constriction. • Vasodilation. Adapted from Abbas & Lichtman’s Basic Immunology 11-4

14. Pathogenesis of Type I • Activated cell releases: • Cytokines • IL-4 • IL-5 • Eosinophil activation. • TNFa Adapted from Abbas & Lichtman’s Basic Immunology 11-4

15. Clinical Manifestations of Type 1 Hypersensitivity • Mild local • “wheal and flare” • Mosquito bite • nasal congestion • Pruritis (itching) • Rhinitis • Conjunctivitis • Asthma

16. Allergic Asthma • Mast cell activation resulting in: • ________________________________________. • Increased inflammation and mucus. • Chronic bronchospasm. Adapted from Roitt’s Immunology 21-22

17. Clinical Manifestations of Type 1 Hypersensitivity • Mild systemic • generalized pruritis (itching) • urticaria (hives) • Nausea • Vomiting • Diarrhea Roitt’s Immunology 26-2

18. Clinical Manifestations of Type 1 Hypersensitivity • Anaphylaxis • Extreme systemic form of Type I hypersensitivity reaction • Immediate reaction (<20 minutes). • Can be local reaction or general leading to fall in blood pressure due to vasodilation and edema, airway obstruction and broncospasm. Adapted from Roitt’s Immunology 21-2

19. Clinical Manifestations of Type 1 Hypersensitivity • Severe anaphylaxis - laryngeal edema, hypotension, shock, bronchospasm, cardiac arrhythmia, arrest and death. • Three possible outcomes that can lead to death: • asphyxiation from laryngeal edema. • suffocation from bronchiolar constriction/contraction • loss of adequate blood pressure from an overwhelming edema

20. Sensitization phase Activation phase Effector phase Review of Normal Sequence of Events • Exposure to allergen • Th2 activation and IgE production • IgE binds to mast cell Fc receptors • 2nd exposure to allergen • Allergen binds to mast cell-associated IgE • Signal transduction • Mediator release (e.g. histamine) • End organ effects of mediators

21. Management of the Allergic Patient • Identify the allergen(s): • in vivo challenge tests • in vitro tests

22. Management of the Allergic Patient • Environmental intervention • Pharmacological intervention • antihistamines • corticosteroids • epinephrine • Hyposensitization therapy • blocking antibodies • Th2 to Th1 switch • specific suppressor T cells

23. Type II Hypersensitivity“Antibody-Mediated” • Caused by _____________________________ antibodies against cell and tissues. Adapted from Abbas & Lichtman’s Basic Immunology 11-7A

24. Effector Mechanisms of Type II Hypersensitivity • Binding of antibody induces inflammation. • By attracting and activating leukocytes. • Via Macrophages and neutrophils Fc receptors. • By activating the classical pathway of the complement cascade. Abbas & Lichtman’s Basic Immunology 11-8A

25. Effector Mechanisms of Type II Hypersensitivity • Binding of antibody to cells results in opsonization and phagocytosis. • Through phagocytic cells Fc receptor. • Through phagocytic cells C3b receptor. Abbas & Lichtman’s Basic Immunology 11-8B

26. Effector Mechanisms of Type II Hypersensitivity • Binding of antibody interferes in normal cell functions. • Binding to receptors resulting in their stimulation (Graves disease). • Binding to receptors resulting in their inhibition (Myasthenia Gravis). Abbas & Lichtman’s Basic Immunology 11-8C

27. Next Time • Compare and contrast the ABO and Rho(D) alloantigens. • Describe an Arthus reaction. • List the cells involved in a DTH response. • Describe ocular immune privilege • Describe the role Anterior Chamber AssociatedImmune Deviation (ACAID) is believed to play in an ocular immune response. • Readings: Abbas & Lichtman, Chapter 11

28. Objectives • Describe the 4 types of hypersensitivity reactions. • Similarities & differences • Pathogenesis • Clinical implications • Describe the management of the allergic patient.