1. MICR 304 Immunology & Serology Lecture 14 Hypersensitivities Chapter 9.24, 9.25;13.1 – 13.4, 13.6 – 13.12, 13.14, 13.16 –19 Lecture 14 Hypersensitivities Chapter 9.24, 9.25;13.1 – 13.4, 13.6 – 13.12, 13.14, 13.16 –19

2. Overview of Today’s Lecture Definition Classification of hypersensitivities Key players in hypersensitivities Immunopathology of hypersensitivities

3. 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”

4. Key Players in Hypersensitivities IgE IgG Complement Mast cells Basophils Eosinophils Phagocytes, Dendritic cells, NK cells T-cells Eosinophils

5. Properties of IgE and IgG IgEIgG Size, structure 180 kD, no hinge150 kD, hinge Blood levels [mg/ml] 0.0000314 Mast Cell Sensitization +++- Basophil sensitization +- Binding to eosinophils*, basophils, mast cells +(+) NK-Binding -++ Neutralization, complement activation, opsonization -+++ Placenta transport -+++ * activated

6. Two Types of IgE Receptors High affinity (Fc  RI) –IgE is captured without antigen binding –Present on resting mast cells, basophils –Present on activated eosinophils –Cross-linking with antigen  granule release Low affinity (Fc  RII) –Present on many cells –B-Lymphocytes –Activated T- lymphocytes –Phagocytes –Dendritic cells –Thymic epithelial cells

7. 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

8. 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

9. Mast Cells are Activated Upon IgE Cross-Linking

10. Mast Cell Products Histamine, Heparin –Toxic –Endothelial permeability increase, edema –Smooth muscle contraction Chymase, tryptase –Tissue remodeling Cytokines –IL4, IL13: IgE, TH2 response –TNF  Proinflammatory –Chemokines: Recruit eosinophils, basophils Lipid mediators –PAF: recruit leukocytes, activates neutrophils, eosinophils, platelets –Leukotriene, prostaglandins: smooth muscle cell contraction, mucus secretion, increased vascular permeability

11. Mast Cells Amplify IgE Production

12. Mast Cell Effects Depend on Site of Activation

13. 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

14. 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

15. 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

16. 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

17. 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

18. 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 Antibody Cell

19. Immunological Mechanisms of Hypersensitivities

20. Type I Hypersensitivities (Allergies)

21. Pathogenesis of Type I Hypersensitivity Antigen is soluble Antibody is IgE Mast cell degranulation

22. IgE Mediated Reactions to Allergens Always involve mast cell mast cell degranulation Symptomatic depends on site of entry and mast cell activation and dose

23. Examples for Inhaled Allergens Dust mite (Dermatophagoides sp.) 92608A dust mite fecal pellet pollen mineral plant debris dead skin / dander

24. Allergens Promote TH2 Development Can easily spread in tissue and reach subepithelial APC (primarily DC) with subsequent Th2 priming Typical for inhaled allergens

25. 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.

26. 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!!

27. 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

28. Immediate and Late Phase in Acute Allergy

29. 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

30. Approaches to Treat Allergies

31. 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

32. Pathogenesis of Type III Hypersensitivity Soluble antigen Antibody is IgG Deposition of immune complexes Activation of complement Inflammation –Local (Arthus reaction) –Systemic (serum sickness)

33. Arthus Reaction: Local Type III Hypersensitivity

34. Serum sickness: Systemic Type III Hypersensitivity

35. Pathogenesis of Type IV Hypersensitivity Mediated by T-cells Soluble antigen: TH mediated –TH1 –TH2 Cell associated antigen: CTL mediated

36. Type IV Hypersensitivity Responses are Mediated by Antigen-specific Effector T cells Antigen injected into skin Antigen absorbed through skin Antigen absorbed through gut

37. Injected Allergen and TH1 Mediated Type IV Hypersensitivity Example: Tuberculin skin test Cell infiltrate!!

38. Examples for Positive Tuberculin Tests

39. TH1 Cytokines in Type IV Hypersensitivity Response

40. Absorbed Allergen and TH1 Mediated Type IV Hypersensitivity Example: Contact dermatitis

41. TH2 Mediated Type IV Hypersensitivity ImmediateLateEosinophils!! Example: Chronic asthma

42. Chronic Asthma Can Lead to Complete Airway Occlusion Dense inflammatory infiltrate with eosinophils, neutrophils, and lymphocytes Mucus plug in the airways

43. 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

44. Additional Resources Accessed 5/17/2008 http://medicalimages.allrefer.com/large/epiglottis.jpg http://www.denniskunkel.com/product_info.php?products_id=9797