Immunopathology

1. Immunopathology Ahmad Shihada Silmi Hematologist & Immunologist IUG

3. Section A Hypersensitivity

5. Gell and Coombs Classification of Hypersensitivities

6. Adapted from: Kuby Immunology, Sixth Edition Types of Hypersensitivity

7. Type I HypersensitivityClassic allergy • Mediated by IgE attached to Mast cells. • The symptoms resulting from allergic responses are known as anaphylaxis. • Includes: Hay fever, asthma, eczema, bee stings, food allergies.

8. Allergens • Allergens are nonparasite antigens that can stimulate a type I hypersensitivity response • Allergens bind to IgE and trigger degranulation of chemical mediators.

9. Allergens

10. Characteristics of allergens • Small 15-40,000 MW proteins. • Specific protein components • Often enzymes. • Low dose of allergen • Mucosal exposure. • Most allergens promote a Th2 immune response.

11. Allergens Example: Der P1 • Der P1 is an enzyme allergen • from the fecal pellets of the dust mite.

12. Der P1 Allergen Allergen is easily aerosolized and inhaled. Der P1 breaks down components of tight junctions which helps it to cross mucosa.

13. Atopy • Atopy is the term for the genetic trait to have a predisposition for localized anaphylaxis. • Atopic individuals have higher levels of IgE and eosinophils.

14. Genetic PredispositionType I hypersensitivity • Candidate polymorphic genes include: • IL-4 Receptor. • IL-4 cytokine (promoter region). • FcεRI. High affinity IgE receptor. • Class II MHC (present peptides promoting Th2 response). • Inflammation genes.

15. Mechanisms of allergic response Sensitization • Repeated exposure to allergens initiates immune response that generates IgE isotype. • Th2 cells required to provide the IL-4 • required to get isotype switching to IgE.

16. Mechanisms of allergic response Sensitization • Th2/B cell interaction Drive B cell Activation and IgE secretion

17. Mechanisms of allergic response Sensitization • The IgE can attach to Mast cells by Fc receptor, which increases the life span of the IgE. • Half-life of IgE in serum is days whereas • attached to FcεR it is increased to months.

18. Mechanisms of allergic response Fc ε receptors (FcεR) FcεR1 • High affinity IgE receptor found on • mast cells/basophils/activated eosinophils. • Allergen binding to IgE attached to FcεR1 • triggers release of granules from cell.

19. Mechanisms of allergic response Effector Stage of Hypersensitivity Secondary exposure to allergen • Mast cells are primed with IgE on surface. • Allergen binds IgE and cross-links to activate • signal with tyrosine phosphorylation, Ca++ • influx, degranulation and release of mediators.

20. Type I hypersensitivity. IgE produced in response to initial allergen exposure binds to Fc receptors on mast cells and basophils. Rechallenge with the same allergen leads to release of histamine and other mediators, which produce various symptoms of localized atopic reaction or generalized anaphylaxis.

21. Type I: Effects of Degranulation

22. Mediators of Type I Hypersensitivity Immediate effects • Histamine • Constriction of smooth muscles. • Bronchiole constriction = wheezing. • Constriction of intestine = cramps-diarrhea. • Vasodilation with increased fluid into tissues causing increased swelling or fluid in mucosa. • Activates enzymes for tissue breakdown. • Leukotrienes • Prostaglandins

23. Immediate vs. late effects

24. Mediators of Type I HypersensitivityPrimary Mediators Pre-formed mediators in granules • Histamine • Cytokines TNF-α, IL-1, IL-6. • Chemoattractants for Neutrophils and • Eosinophils. • Enzymes • tryptase, chymase, cathepsin. • Changes in connective tissue matrix, tissue breakdown.

25. Type I Hypersensitivity Secondary mediatorsformed after activation • Leukotrienes • Prostaglandins • Th2 cytokines- IL-4, IL-5, IL-13, GM-CSF

26. Continuation of sensitization cycle • Mast cells control the immediate response. • Eosinophils and neutrophils drive late or chronic response. • More IgE production further driven by activated Mast cells, basophils, eosinophils.

27. Continuation of sensitization cycleEosinophils • Eosinophils play key role in late phase reaction. • Eosinophils make: • enzymes, • cytokines (IL-3, IL-5, GM-CSF), • Lipid mediators (LTC4, LTD4, PAF) • Eosinophils can provide CD40L and IL-4 • for B cell activation.

28. Localized anaphylaxis • Target organ responds to direct contact with allergen. • Digestive tract contact results in vomiting, cramping, diarrhea. • Skin sensitivity usually reddened inflamed area resulting in itching. • Airway sensitivity results in sneezing and rhinitis OR wheezing and asthma.

29. Systemic anaphylaxis • Systemic vasodilation and smooth muscle contraction leading to severe bronchiole constriction, edema, and shock. • Similar to systemic inflammation.

30. Treatment for Type I Pharmacotherapy • Drugs • Non-steroidal anti-inflammatories • Antihistamines block histamine receptors. • Steroids • Theophylline OR epinephrine -prolongs or increases cAMP levels in mast cells which inhibits degranulation.

31. Treatment for Type I Immunotherapy • Desensitization (hyposensitization) also known as allergy shots. • Repeated injections of allergen to reduce the IgE on Mast cells and produce IgG.

32. Treatment for Type I Effect of allergy shots Allergen Specific Antibodies

33. Hypersensitivity

34. Type II: Antibody-Mediated Cytotoxic Hypersensitivity • Players • Cell-surface antigens • Antibodies  IgM, IgG • Inappropriate response • Normally: eliminate foreign cells • But: autoimmunity, or when foreign cells should be tolerated

35. Type II: Mechanism Antigen on cell surface  Antibody bind to antigens  • Activate complements  membrane attach complex 2. Antibody-dependent cell-mediated cytotoxicity (ADCC)  cytotoxic cells with Fc receptors bind to Fc region of antibodies on cell 3. Opsonization  phagocytosis

36. Type II: Example - Autoimmunity • Goodpasture’s Syndrome • Antigen = α3 chain of basement membrane collagen • Found in kidneys and lungs • Auto-antibodies binds to α3 on own cells  crosslink Fc receptors on cytotoxic cells  activates monocytes, neutrophils, tissue basophils  chemokines  rescuit more neutrophils  self tissue destruction

37. From: Dokkyo Medical University http://www.dokkyomed.ac.jp/dep-k/cli-path/a-super/vasculitis/vas-html/vas-63.html Type II: Example - Autoimmunity

38. From: http://www.collectmedicalantiques.com/images/bloodletting/4_transfusion.jpg Type II: Example – Foreign Antigen • Transfusion reaction  ABO blood-group incompatibility

39. TYPE II HypersensitivityAntibody mediated cytotoxicity Blood Transfusion reactions Innocuous antigens on red blood cells EXAMPLE: ABO blood group antigens

40. ABO Blood Groups • Antibody against RBC antigen binds and mediates killing of RBCs via C’or ADCC causes systemic inflammation.

41. TYPE IIAntibody mediated cytotoxicity Drug reactions • Drug binds to RBC surface and antibody against drug binds and causes lysis of RBCs. • Immune system sees antibody bound to "foreign antigen" on cell. ADCC

42. Drug-induced Thrombocytopenic Purpura

43. TYPE IIHemolytic disease of newborn Rh factor incompatibility • IgG Abs to Rh an innocuous RBC antigen • Rh+ baby born to Rh- mother first time fine. 2nd time can have abs to Rh from 1st pregnancy. • Ab crosses placenta and baby kills its own RBCs. • Treat mother with Ab to Rh antigen right after birth and mother never makes its own immune response.

44. TYPE IIRh factor incompatibility

45. Hypersensitivity

46. Adapted from: Kuby Immunology, Sixth Edition Type III: Immune Complex-Mediated Hypersensitivity

47. Type III: Immune Complex-Mediated Hypersensitivity • Players • Soluble antigens • Antibodies  IgG • Complements Inappropriate response • Normally: antibody-antigen immune complex helps antigen phagocytosis + clearance • But: when large amount of complexes present  tissue damage

48. Type III: Localized Reaction Also called “Arthus reaction” Previously sensitized host  Antigen exposure to specific site (ex. Inhalation, injection, etc.)  Immunoglobuin-antigen complex (IgG)  • Complement activation (C3a/C5aanaphlytoxins, chemotactic agents, membrane attack complex) 2. Bind Fc receptor on leukocytes (lytic enzyme secretion, phagocytosis)

49. Type III: Localized Reaction • Similar to type I hypersensitivity except for • IgG, complement activation, inflammation, phagocytosis

50. TYPE IIIAntigen antibody immune complexes IgG mediated Immune Complex Disease • Large amount of antigen and antibodies form complexes in blood. • If not eliminated can deposit in capillaries or joints and trigger inflammation.