Type I-III Hypersensitivity Reactions

1. Type I-III Hypersensitivity Reactions Parham – Chapter 12 pp 365-392 H. HogenEsch, 2009

2. Hypersensitivity reactions – Gell and Coombs classification (1963) • Antibody-mediated • Type I – IgE • Type II – IgG (cell-bound antigens) • Type III – IgG/IgM (soluble antigens) • Cell-mediated • Type IV • Broad classification of immune responses to pathogens as well as “innocuous” antigens H. HogenEsch, 2009

3. Hypersensitivity reactions H. HogenEsch, 2009

4. Atopic triad Type I hypersensitivity - allergies • At least 50 million Americans suffer from allergies • Most common allergies: • Asthma – prevalence: 7% of population • Atopic dermatitis (“eczema”) • Most common skin disease in infants and children < 12 years • Up to 20% prevalence • Allergic rhinitis (“hay-fever”) – 20 -30 % prevalence • Food allergy • Insect bites/stings • Sensitization followed by challenge/effector phase H. HogenEsch, 2009

5. Asthma PrevalenceUnited States, 1980-2004 Lifetime Current 12-Month Attack Source: National Health Interview Survey; National Center for Health Statistics H. HogenEsch, 2009

6. Child and Adult Asthma PrevalenceUnited States, 1980-2004 • Child • Adult Lifetime Current 12-Month Attack Source: National Health Interview Survey; National Center for Health Statistics H. HogenEsch, 2009

7. Cause of increasing prevalence of allergies • Hygiene hypothesis • Shift from Th1 to Th2 • Decreased number/activity of regulatory T cells • Changes in indoor air quality • Changes in life style H. HogenEsch, 2009

8. Components of allergic reactions • Sensitization • production of TH2 CD4 T cells and IgE • Binding of IgE to FcRI on mast cells and basophils • Effector phase • Acute (immediate reaction) • Mast cell/basophil degranulation • Late phase reaction - chronic • Influx of eosinophils and eosinophil degranulation • Influx of TH2 CD4 T cells H. HogenEsch, 2009

9. Mast cells • Derived from hemopoietic stem cells in bone marrow • Precursors develop into mast cells in tissues under influence of c-kit (CD117) and Stem Cell Factor (SCF) . • Mast cells are most numerous in the skin and mucosal tissues • Express high affinity FcRI H. HogenEsch, 2009

10. Mast cell activation by IgE crosslinking H. HogenEsch, 2009

11. Mast cell activation • Pre-formed mediators stored in granules • Histamine, heparin • Cytokines (Tumor necrosis factor) • Enzymes • Newly synthesized mediators • Prostaglandins, leukotrienes • Cytokines and chemokines H. HogenEsch, 2009

12. Contents of mast cell granules H. HogenEsch, 2009

13. Histamine histidine CO2 • H1 receptors • endothelial cells • smooth muscle cells histamine H1-antagonists H. HogenEsch, 2009

14. Leukotrienes and prostaglandins aspirin Montelukast (Singulair) receptor H. HogenEsch, 2009

15. Basophils • Granulocytes with very similar function to mast cells • Express FcRI • Secrete IL-4 and IL-13 • Role in TH2-differentiation H. HogenEsch, 2009

16. Eosinophils • Granules rich in basic proteins • Major basic protein, eosinophil cationic protein, neurotoxin • Toxic to cells and parasites • Production in bone marrow is stimulated by IL-5, influx into tissues by chemokine, e.g., eotaxin. • Activated eosinophils express FcRI • Degranulation is induced by eotaxin, C5a, and antigens (via IgE) H. HogenEsch, 2009

17. Mediators secreted by eosinophils H. HogenEsch, 2009

18. Regulation of IgE synthesis IgE+ memory cell IL-4 (IL-13) CD40-CD40L IgE+ B cell IgM+/IgD+ naïve B cell IgE+ plasma cell H. HogenEsch, 2009

19. + + Regulation of CD4 T cell differentiation IFN-g IL-12 DC TH1 naïve TH TH0 IL-4 IL-5 IL-13 TH2 IL-4 allergies H. HogenEsch, 2009

20. Atopy • Genetic predisposition to IgE production H. HogenEsch, 2009

21. Some properties of inhaled allergens • Examples: • pollen • dust mite feces • cockroach antigens H. HogenEsch, 2009

22. Sensitization to inhaled allergens H. HogenEsch, 2009

23. Late phase reactions H. HogenEsch, 2009

24. Clinical manifestations of allergy H. HogenEsch, 2009

25. Diagnosis of allergies • Skin testing • Avoidance • Antigen-specific IgE • Radio allergosorbent test (RAST) • ELISA (ImmunoCap) • Total IgE H. HogenEsch, 2009

26. Systemic anaphylaxis • Allergen • insect venom • drugs • food allergens blood circulation H. HogenEsch, 2009

27. Treatment of anaphylactic shock H. HogenEsch, 2009

28. Allergic rhinitis H. HogenEsch, 2009

29. Treatment of allergic rhinitis • Avoidance • Antihistamines • Corticosteroids • Prevention of mast cell degranulation H. HogenEsch, 2009

30. Asthma • Extrinsic – IgE-mediated • Intrinsic – no evidence of IgE involvement H. HogenEsch, 2009

31. Pathogenesis of asthma Type I hypersensitivity Type IV hypersensitivity “remodeling” H. HogenEsch, 2009

32. Clinical symptoms of asthma • Coughing • Wheezing • Hypersensitive airways H. HogenEsch, 2009

33. Treatment of allergic reactions • Avoidance • Foods • Pets • Dust • Drugs • Inhibitors of inflammation • Corticosteroids (systemic or inhalation) • Anti-LTC4-R (Montelukast) • Chromolyn sodium (prevents mast cell degranulation) • Bronchodilators • Antihistamines • Anti-IgE (omalizumab (Xolair) • Desensitization • Increasing doses of allergen via subcutaneous injection • Shift response to TH1 or induction of IL-10/TGF-β-secreting regulatory T cells • Risk: induce/enhance allergy or type III hypersensitivity H. HogenEsch, 2009

34. Type II hypersensitivity H. HogenEsch, 2009

35. Drug-induced blood cell dyscrasias • Related to pharmacologic action of the drug • Idiosyncratic – often immune-mediated • Thrombocytopenia most common H. HogenEsch, 2009

36. Mechanism of antibody-mediated blood cell destruction • Type II hypersensitivity • Antibodies: • Drug (hapten)-specific • Antibody binds to cells in presence of drug or drug metabolite • True autoantibodies • Immune complexes, e.g., heparin • Fibrinogen receptor (gp IIb/IIIa) antagonists H. HogenEsch, 2009

37. Modification of RBC by penicillin H. HogenEsch, 2009

38. Production of anti-penicillin antibodies H. HogenEsch, 2009

39. Lysis and phagocytosis of penicillin-modified RBC H. HogenEsch, 2009

40. Clinical Case • Cynthia Waymarsh was 31 years old when she became pregnant for the 3rd time • First pregnancy was normal • Second pregnancy – positive indirect Coombs test. Normal delivery. Father Rh+, Cynthia Rh-. • Third pregnancy – positive Coombs test. Bilirubin in amniotic fluid at 22 and 29 weeks of gestation. Hematocrit of umbilical vein was 6.2% • Transfusion of packed type O, Rh-, red blood cells into umbilical vein twice, followed by induction of labor at 35 weeks of gestation. H. HogenEsch, 2009

41. Coombs reagent Rhesus factor H. HogenEsch, 2009

42. Questions? • Rh antigens are sparsely scattered across RBC surface and complement fixation does not occur. What is mechanism for RBC destruction? • A preventive treatment is IV treatment of pregnant women with anti-Rh antibodies (Rhogam). How does this work? Why does it not harm the fetus? H. HogenEsch, 2009

43. Passive immunization against Rh prevents hemolytic anemia of the newborn H. HogenEsch, 2009

44. Type III hypersensitivity • Caused by immune complexes of IgG and soluble antigen • Clinical symptoms depend on size and localization of immune complexes • Inflammation induced by complement activation and neutrophils H. HogenEsch, 2009

45. Arthus reaction • Localized response • Induced by injection of soluble antigen in patient with pre-existing IgG antibodies • Example: • Desensitization of IgE-mediated allergies H. HogenEsch, 2009

46. Systemic immune complex disease • Serum sickness • Induced by repeated injection of foreign proteins (horse immunoglobulins) • Chronic infections • Subacute endocarditis • Chronic autoimmune disease • Rheumatoid arthritis • Systemic lupus erythematosus H. HogenEsch, 2009

47. Pathology and symptoms of systemic type III hypersensitivity depends on the localization of immune complexes H. HogenEsch, 2009

48. Serum sickness H. HogenEsch, 2009