Hypersensitivity Reactions Gell & Coombs 1963

1. Hypersensitivity ReactionsGell & Coombs 1963

2. Based on effector mechanisms and antigens Type I Mediated by IgE on mast cells, basophils and eosinophils(time: 2-30 min) Type II Mediated by IgG and IgM against cell surface / matrix antigens (time: hours- 1 day) Type III Mediated by IgG against soluble antigens(time: hours- days) Type IV Mediated by CD4 and CD8 cells against soluble and cell surface antigens (time: 24-72 hours) Classification of Hypersensitivity Reactions (Gell and Coombs)

3. Subtypes IV a ‐ eczematous IV b – maculopapular or bullousexanthem IV c – Eczematous, maculopapular, bullous, pustularexanthem IV d – Pustularexanthem. Type V: Stimulation of Receptors Hypersensitivity afterGell & Coombs 1963

6. Normal physiological role of IgE • Defense against parasites • Pathophysiological role of IgE • Type I hypersensitivity reaction • Type I reactions follow sensitization to allergens • Sensitization • First exposure to allergen elicits an IgE response • Genetic predisposition (Atopy - 10% of population are atopic) TYPE I - IMMEDIATEHypersensitivityIgemediated

7. Sensitization

8. History of Discoveries • Anaphylaxis: Portier and Richet, 1902 • Histamine: Dale and Laidlaw, 1911 • Mast cells as main tissue source ofhistamine: Riley and West, 1952 • IgEimmunoglobulin: Ishizakaand Ishizaka, 1966 Type I Hypersensitivity:

9. Atopy • Genetic propensity to produce IgE antibodies in response to allergens • Atopic response characterized by elevated levels • IgE and eosinophils • Multiple genes are involved • Chromosome 2 • Regulation of T cell activation • Chromsome 5 • Gene cluster for IL-3, IL-4 and IL-13 • Chromosome 11 • Beta chain of FceRI receptor GENETIC PREDISPOSITION TO TYPE I HYPERSENSITIVITY

10. FceRI receptor expressed constitutively • Mast cells and Basophils • Activated eosinophils • Allergen binding results in cross-linking of receptors • Cross-linked receptors signal degranulation of cytoplasmic granules • Degranulation results in release and synthesis • Inflammatory mediators, toxins, enzymes MECHANISM OF TYPE I HYPERSENSITIVITY REACTIONS

13. AtopicDiseases (Triad of atopy): AllergicAsthma, AllergicRhinoconjunctivitis- Hay Fever,AllergicDermatitis (eczema), & Urticaria *, Foodallergy Type I - IgE mediatedreaction

15. Mechanism of type I hypersensitivity Generation Primary Individual Allergen IgE Adhesion Secondary IgE binds to the FceRI on mast cell and basophil Allergen binds to the IgEon primed target cell Crosslikage of FceRI Degranulate and release the biological mediators Preformed granule mediators New generated mediators Histamine Bradykinin Leukotrienes PAF Prostaglandin D2 Dilate capillaries,increase permeability, increase mucus secretion, contract smooth muscle Systemic anaphylaxis Skin Respiratory tract GI tract

16. Immediate reaction (Stage 1) • Appears within 30 minutes • Subsides within 30 minutes • Late phase reaction (Stage 2) • Appears 6 to 8 hours after immediate reaction has subsided • Subsides within 24 hours • Examples • Wheal and flare (skin) • Breathing capacity (lungs) • Forced expiratory volume in 1 second (FEV1) TWO STAGES OF TYPE I HYPERSENSITIVITY REACTIONS

18. MAST CELL • DEGRANULATION- Release of preformed mediators • SYNTHESIS OF LIPID MEDIATORS EARLY PHASE RESPONSE

20. MEDIATORS & CeLls Mast cells

21. Originate in bone marrow from CD34 progenitor • Basophils may have same progenitor • Development of immature cells at tissue sites • Types • Mucosal • Tryptaseproduction • Development T cell dependent • Connective tissue • Chymotryptase production • Express high levels of IgE receptor MAST CELLS (MASTOCYTES)

22. • Preformed – Vasoactiveamines: histamine – Neutralproteases: tryptase, chymase – Acidhydrolases: β-hexoseaminidase – Proteoglycans: heparin, chondroitinsulfate • Newlyformed – Eicosanoids: PGD2, LTC4 – Cytokines: TNFα, IL-4, IL-5, IL-6 Mast CellMediators

23. HISTAMINE • Stimulation of irritant nerve receptors • Smoothmusclecontraction • Increaseinvascularpermeability KALLIKREIN • Activates bradykinin - similar actions to histamine TRYPTASE - role unclear PREFORMED MEDIATORS

24. Exerts a variety of physiological effects following binding to specific receptors (H1, H2, H3) • Allergic reactions • Histamine binds to H1 receptors • Physiological effects • Constriction of bronchial / intestinal smooth muscle • Increased permeability of blood vessels • Increased secretion of mucus by goblet cells • Leukocyte chemotaxis HISTAMINE (BIOGENIC AMINE)

25. • Produced almost exclusively by basophils and mast cells (3-8 pg/cell) • Immediate pharmacologiceffects: – pruritus (H1) – ↑ vascularpermeability/vasodilatation (H1) – smoothmusclecontraction (H1) – gastricacidsecretion (H2) Histamine

26. Tetramericserineprotease • Found only in mast cells, not basophils • Peaks in 1-2 hoursand remains elevated 4-6-12hours inserum following release in anaphylaxis • Alpha isoform is predominant in blood: most mastocytosis patients with systemic disease have total tryptase levels that are elevated (> 20 ng/ml) and are at least 10-fold greater than their β tryptaselevel. Mast CellTryptase

27. Arachidonicacidpathway

28. Allergen Hydroxyl phosphalipid Phosphatidylcholine Phosphalipid Phosphoration of ITAM MAPK Activated PKC Arachidonic acid Activation of PTK Inactivated PKC Myosin Acetyl- transferases COX LOX Phosphoration of Light chain Endoplasmic reticulum Degranulation Lipid mediatiors Cell membrane Histamine Degranulation ,release and synthesis of biological mediators of primed target cells

29. Prostaglandins produced by two different enzymes • Cyclooxygenase-1 (Cox-1) • Cyclooxygenase-2 (Cox-2) • Cox-1 involved in normal physiological functions • Stomach mucus production • Kidney water excretion • Platelet formation • Cox-2 involved in inflammatory response LIPID MEDIATORS- CYCLOOXYGENASE PATHWAY

30. Classified as lipid mediators of inflammation • Derived from arachidonic acid • Act locally and rapidly metabolized • Located in virtually all tissues / organs • Produced following activation of • Mast cells, basophils, macrophages • PGD2 is major mediator • Levels increased by Cox-2 in inflammation • Physiological effects similar to histamine • Vasodilation, bronchoconstriction, neutrophilchemotaxis LIPID MEDIATORS PROSTAGLANDINS

31. Synthesized and released following activation of • Mast cells, eosinophils, basophils, neutrophils, macrophages • Classified as lipid mediators of inflammation • Derived from arachidonic acid • Leukotrienes (LTA4 – LTE4) • Sustain inflammatory response in allergic disease • C, D and E are cysteinylleukotrienes • Receptors (CysLT 1 & 2) on mast cells, eosinophils, endothelial cells • Increased levels induce anaphylaxis • Physiological effects similar to histamine • More potent / longer lasting than histamine • Vasodilation, bronchoconstriction, neutrophilchemotaxis LIPID MEDIATORS LEUKOTRIENES

32. BASOPHILS • Similar properties to mast cells over longer time scale EOSINOPHILS • granulescontaincytotoxicproteins (ECP) • In tissues, releasecontents of granules – majorsource of tissue damage in allergic response T cells • cytokine- activityis the major source ofpathogenesisinallergicresponses LATE-PHASE RESPONSE -

33. Granulocytic leukocytes (1 – 6% in blood) • Level variation (down in a.m., up in p.m.) • Granules • Orange to reddish-orange in color • Uniform in size and evenly distributed • Toxins, enzymes, cytokines and inflammatory mediators • Mature cells reside in • Blood and lower GI tract EOSINOPHILS

34. • Irritation of nerveendings • Blood vessels dilate and leak • Airways contract • Hypersecretion • Recruitment of immunecells Actions of Mediators

35. • Irritation of nerve endings - Itch • Bloodvesselsdilate, leak- Urticaria/ angiooedema, lowbloodpressure • Airways contract- Wheeze /asthma • Hypersecretion - Runnynose/eyes • Recruitment of immune cells - Late phase reaction Consequences

36. Inflammation of mucous membranes caused by inhaled allergens • Genetic predisposition for offspring • 1 (30%) or 2 (50%) parents with AR • Classification • Seasonal (tree, grass, ragweed pollens) • Perennial (dust mites, cockroaches, animal dander) • Symptoms • Sneezing, itching, rhinorrhea and nasal congestion • Nasal discharge rich in eosinophils ALLERGIC RHINITIS (HAY FEVER)

37. ALLERGIC RHINITIS (HAY FEVER)

38. Skin PrickTesting Used in the diagnosis ofallergicdisorders. A panel of potentialallergens areintradermally“pricked” intothe skin. After 15-20 minutes if a wheal orflare is seen this is suggestiveof IgE allergy against theallergen. Diagnosis of atopy

39. Prevention • Avoidance of offending allergens • Treatment / Prevention • Antihistamines • Leukotriene receptor antagonists • Anti-inflammatory agents (GCS) • Mast cell stabilizing agents • Immunotherapy (Hyposensitization / Desensitization) PREVENTION AND TREATMENT OF ALLERGICRHINITIS

40. Mechanism of action • Prevent binding of histamine to H1 receptors • Antihistamines (1st generation) • Antazolinum (Phenazolinum), Clemastinum, Hydroxyzinum, Prometazinum- per os, i.m., i.v. • Chlorpheniramine (Chlortrimeton) • Diphenhydramine (Bendryl) • Antihistamines (2nd generation) • Cetirizine (Zyrtec, Allertec)Levocetirizine (Xyzal) • Fexofenadine (Allegra, Fexofast, Telfast) • Loratadine (Claritin), Desloratadine (Clarinex, Aerius) ANTIHISTAMINES FOR ALLERGIC RHINITIS

41. Azelastine (Astelin,Allergodil) • First intra-nasal antihistamine • FDA approval in 1996 • Indicated for seasonal allergic rhinitis • 1 spray per nostril (FDA approval in 2006) • Adverse events • Bitter taste, headache, somnolence • Precaution • Avoid concurrent use with alcohol and other CNS depressants NASAL ANTIHISTAMINE FOR ALLERGIC RHINITIS

42. Leukotriene receptor antagonists • Montelukast (Singulair) • Zafirlukast (Accolate) • Mechanism of action • Binds to CysLT1 receptor with no agonist activity • Leukotriene synthesis inhibitors • Zileuton (Zyflo) • Mechanism of action • Inhibits 5-lipoxygenase (5-LO) ANTI-LEUKOTRIENE AGENTS FOR ALLERGIC RHINITIS

43. Considered most effective for prevention and treatment • Mechanism of action: • Wide range of effects on many inflammatory cells and mediators • Maximum benefit following several days of use • Steroids • Fluticasone propionate (Flonase, Flixonase) • Mometasonefuroate (Nasonex) • Triamcinoloneacetonide (Nasacort) • Beclomethasonedipropionate (Beconase) NASAL STEROIDS FOR ALLERGIC RHINITIS

44. Cromolyn sodium • Cromolyn (Intal) by metered-dose inhaler (MDI) • Cromolyn (Nasalcrom) by nasal spray • Mechanism of action • Calcium ion channel blocker • Intracellular Ca++ essential for degranulation • Not as effective as corticosteroids MAST CELL STABILIZING AGENTS FOR ALLERGIC RHINITIS

45. Goal is to shift immune response from IgE to IgG • Achievement of goal by allergy shots • Injection of small, then increasing doses of allergen • Shots gradually divert TH2 IgE response to • TH1 and / or IgG response • Potential complication • Anaphylaxis IMMUNOTHERAPY FOR ALLERGIC RHINITIS

46. Binding of antibody to cell surface leads to activation ofcomplement and damage to host cell eg. blood cells (penicillin, methyldopa, quinidine) Examples of Diseases: • Transfusionreactions • Hemolytic disease of the newborn (Rh incompatibility) • Hyperacutegraftrejection • Drug-inducedhemolytic anemia Type II - CYTOTOXIC REACTION

47. Allergen Stimulate Antibody Cell A. Opsonicphagocytosis Combined opsonic activities D. ADCC of NK C. Effect of complement Cell injury ways of type II hypersensitivity

48. IgM, IgG1, IgG3 activatecomplement HypersensitivityType II

49. Antigen or hapten on cell Antibody (IgG, IgM) Activate complement Opsonic phagocytosis NK , phagocyte Stimulate / block Lyse target cell Destroy target cell ADCC Target cell injury Change the function ofTarget cell Mechanism of Type II hypersensitivity

50. Transfusionreactions