Hypersensitivity is an excessive immune response that leads to undesirable tissue or organ damage and dysfunction. There are four main types: type I is antibody-mediated and involves IgE, type II also involves antibodies and can cause hemolysis, type III involves immune complex deposition and complement activation, and type IV is T-cell mediated and causes delayed hypersensitivity reactions. Therapy for type I hypersensitivity focuses on allergen avoidance, desensitization treatments, and drugs like antihistamines and adrenaline.

1. Hypersensitivity

2. Introduction What is hypersensitivity? It is excessive immune response which leads to undesirable consequences, i.e. tissue or organ damage/ dysfunction . Type: typeⅠ, Ⅱ, Ⅲ, Ⅳ hypersensitivity Ab mediated: typeⅠ, Ⅱ, Ⅲ T-cell mediated: type Ⅳ

3. Type Ⅰ hypersensitivity IgE mediated, immediate hypersensitivity/ allergy Major features: React and disappear quickly on re-exposure to Ag Dysfunction rather than severe tissue and cell damage occurs Obvious individual difference and genetic correlation

4. Component and cells Allergen: An antigen that causes allergy. Hapten can turn into allergen by carrier effect (hapten +carrier ->immunogen) Common allergen: inhalant allergen (grass pollen, animal dander, feces from mites in house dust, etc.), some kinds of food and drugs

5. Reaginic antibody (IgE) The main anaphylactic Ab in human IgE can bind FcεRⅠon mast cells and basophils by its CH4 domain, cause anaphylaxis

6. Mast cells Express high affinity IgE Fc receptor FcεRⅠ, granules contain mediators. Distribution: connective tissues, mucosa, skin Anaphylaxis is triggered by clustering of IgE receptors (FcεRⅠ) on mast cells and basophils through cross-linking

7. IgE-binding Fc recepors FcεRⅠ: high affinity receptor of IgE on mast cell/ basophil, activate mast cell/ basophil FcεRⅡ:low affinity

8. Mediators released by mast cells Primary mediators (preformed): heparin, histamine, neutral protease, eo-sinophil & neutrophil chemotactic factors, provoke early phase(immediate) reaction Secondary mediators (newly synthesi-zed) : leukotrienes(LTB4, LTC4 and LTD4), PGD2, PAF, CKs(IL-4, GM-CSF), induce late phase reaction

9. Mechanism of typeⅠhypersensitivity Allergen->host->specific B-cell->IgE->Fc fragment of IgE binding FcεRⅠon mast cells/ basophils Allergen once again enter the host ->binding IgE ->cross-linking of IgE -> cross-linking of FcεRⅠ -> mast cell activation -> degranulation-> mediators release-> anaphylaxis symptoms

10. Early phase response : short-lived, resolve within 1 hr. Increase of vasopermeability, smooth muscle contraction, gland hypersecretion and vasodilation Late phase response : inflammation, peak at around 5 hrs, last for several days. Eosinophils, mast cells, basophils, T-cells and neutrophils infiltration.

11. The mechanism of typeⅠhypersensitivity

12. Typical diseases of anaphylaxis Systemic anaphylaxis( anaphylactic shock ): fatal, venom from bee, wasp; drugs such as penicillin, antitoxins, etc. Localized anaphylaxis( atopy ): the tend-ency to manifest localized anaphylaxis is inherited and called atopy. typical diseases: asthma, hayfever, eczema, food allergy, etc.

13. Atopy Allergic rhinitis: Hay fever, airborn allergens, symptoms include shedding tears, sneezing, coughing, etc. Asthma : airborn/blood-born allergens. Occur in lower respiratory tract Cardinal clinic and physiological features: variable airflow obstruction, bronchial hyper-responsiveness.

14. Food allergies : diarrhea, vomiting, wheal and flare reaction Atopic dermatitis : eczema , urticaria. itch, desquamation, pachyderma

16. Therapy of typeⅠhypersensitivity Allergen avoidance : best if possible, but often impractical. Skin test Hyposensitivity : repeated injection of increasing doses of allergen. Allergic rhinitis Drug: antihistamines; epinephrine (also called adrenaline), etc. Immediate injection of adrenaline could rescue anaphylactic shock

17. Atopic allergies and their treatment

18. Mediated by IgG and/or IgM Mechanism : Ag present on the surface of cells-> im-munity activation->Ab->tissue damage/ dysfunction Tissue damage caused by: Opsonic adherence : phagocytosis Complement : membrane damage ADCC : cell destruction Type Ⅱ hypersensitivity

19. Mechanism of tissue damage of typeⅡ hypersensitivity

20. Type Ⅱ associated diseases Transfusion reaction: mismatched blood transfusion cause complement-mediated hemolysis. ABO blood group : isohemagglutinins(IgM) Prevention: cross-matching between donor and recipient blood

21. Heamolytic diseases of newborn Rh incompatibility: Rh blood groups Rh- mother has the first Rh+ baby-> mother sensitized by baby’s erythrocy-tes ->anti-Rh IgG Mother has the second Rh+ baby-> IgG enter the fetus through placenta-> destruction of fetal RBC

22. Hemolytic disease of the newborn due to rhesus incompatibility

23. Drug-induced hemolytic anemia Drug adsorb RBC proteins->Anti-RBC IgG/IgM->complement, opsonization, ADCC ->RBC lysis, anemia

24. Grave’s disease and myasthenia gravis Special class of type Ⅱ hypersensitivity, Autoimmune diseases, tissue/organ dysfunction Grave’s disease: anti-TSH receptor Myasthenia gravis: anti-acetylcholine receptors

25. Myasthenia gravis Grave’s disease

26. Type Ⅲ hypersensitivity Participate by IgG/IgM, induced by de-position of immune complex (IC) Formation of IC: Excess of antigen over a protracted period Deposition frequently observed: blood-vessel walls, synovial membrane of joints, glomerular basement of kidney

27. Mechanism of type Ⅲ hypersensitivity

28. Tissue damage caused by: Complement activation and attraction of neu-trophils : release tissue damaging mediators Stimulation of Mφ : release proinflammatory cytokines Aggregation of plate-lets : cause microthrombi and vasoactive amine release

29. Immune complex-mediated (type Ⅲ) hypersensitivity

30. Type Ⅲ associated diseases Localized type Ⅲ reaction: the Arthus reaction , erythematous and edematous, intense neutrophil infiltration Generalized type Ⅲ reaction: Serum sickness: injection of foreign protein (horse serum) SLE: systemic lupus erythematosus , DNA/ anti-DNA/ complement

31. Rheumatoid arthritis: rheumatoid factor (RF): anti-IgG autoantibodies, usually IgM. IgM-IgG complex deposit in joints Immune complex glomerulonephritis : Ag-Ab-C3 deposit glomerular basement membrane Others: drug reactions, infectious diseases Type Ⅲ associated diseases

32. Type Ⅳ hypersensitivity Delayed-type(DTH), T-cell mediated, 24-72 hr after Ag contact, Ab not involve Results from excessive CMI, secondary response, chronic granuloma Mechanism: CD4 + Th1: Tm->Ag:MHCⅡ->effector T-cell->MCP-1, IFN-γ, TNF, IL-2->Mφ attraction and activation->tissue damage

33. Immune pathogenesis CD8+CTL: primed CTL->Ag:MHCⅠ-> perforin/ Fas-FasL->target cell death

35. Insulin-dependent diabetes mellitus (IDDM): insulin-producing βcells Multiple sclerosis(MS): central nervous system, myelin Ag Contact dermatitis : foreign low molecular weight materials, hapten-carrier, topical Infectious diseases: tuberculosis Others: hashimoto’s thyroiditis, IBD Type Ⅳ associated diseases

36. Summary Hypersensitivity is excessive immune response which leads to undesirable consequences, i.e. tissue or organ damage/ dysfunction . Type: typeⅠ, Ⅱ, Ⅲ, Ⅳ hypersensitivity Ab mediated: typeⅠ, Ⅱ, Ⅲ T-cell mediated: type Ⅳ

39. Summary Therapy for typeⅠhypersensitivity: Allergen avoidance Hyposensitivity Drug treatment: antihistamines, adrenaline

40. Thanks!

41. Clustering of IgE receptors

42. Patholo-gical changes in asthma

43. An atopic eczema reaction

44. ADCC mediated by NK

45. The ABO system Phenotype genotype Ag on RBC (agglutinins) Ab to ABO in serum (isohem-agglutinins) A AA, AO A Anti-B B BB, BO B Anti-A AB AB A and B none O OO H Anti-A and anti-B

46. Histology of acute inflammatory reaction in type Ⅲ hypersensitivity

47. IgE mediated mast cell activation and degranulation

48. Skin reaction of atopic allergy (Skin prick tests)

49. Deposition of immune complex in the kidney glomerulus

50. Vasculitic skin rashes due to immune complex deposition

51. Granuloma in tuberculosis infection