Hypersensitivity

1. Hypersensitivity Láng, Orsolya MD, PhD Dept. Genetics, Cell & Immunobiology, Semmelweis University www.gsi.semmelweis.hu Lecture ED 2017

2. Hypersensitivity - Tolerance Hypersensitivity: Immune reaction leads to pathology upon recognition of either harmless environmental antigens or self-antigens Tolerance: immunological unresponsiveness to (self)-antigens (tolerogen) that have the capacity to elicit an immune response Autoimmunity: Autoreactivity is inevitable Dysregulation or failure of self-tolerance => autoimmune disorder Common: adaptive immune system

3. Hypersensitivity (HS) – Allergy • The most common immunological abnormality. • Increasing number of affected people (25-40%) • Potential reasons: Environmental pollution (?) • Lack of selection (?)

4. General mechanism First exposure Repeat exposure Tissue injury or disease Sensitization • Robert Royston Amos ("Robin") Coombs: • British immunologist, • co-discoverer of the Coombs test (Arthur Mourant and Rob Race) in 1945 Gell - Coombs classification of hypersensitivity in 1963

5. Four classifications • Type I (Immediate) hypersensitivity • Type II (cytotoxic) hypersensitivity • Type III (immune complex mediated) hypersensitivity • Type IV (delayed) hypersensitivity

6. Types of hypersensitivities (Gell - Coombs classification)

7. Type I. hypersensitivity (HS) Immediate HS or Allergy , Atopy Atopy – inherited tendency to respond immunologically to inhaled or ingested allergens with increased IgE production

8. Commontypes of immediate HS Skin contact Inhaled allergens Ingestion Hives Urticaria Food allergies Hay fever or injection Bronchial asthma Anaphylaxis

9. Main characteristics of the allergenes • Smallsizeproteinsorglycoproteins: • Carried on desiccated particles (pollen grains or mite feces), where they are very stable • Haveenzymeactivitythatfacilitatethetransmucosalpenetrance • Small, molecularwheight is 5 to 70 kDa (dustmite: der p1 15 kD), • Highsolubility • Smalldose (ragweed: 1µg/year) • MHCII binding

10. What do they have in common? ? Hevein domain

11. Cross-reactive allergenes orbetweenfoods cross-reactivity between aeroallergens and foods … cross-reactivity between aeroallergens and foods http://ainotes.wikispaces.com/Pollen+Food+Allergy+Syndrome

12. Type I. hypersensitivity Afferent phase IgEproduction Hypersensitivity IL4, IL13 Degranulation Firstexposure APC and Th2 activation Classswitch IgEproduction IgE+ memoryB-cells cross-linkedIgE Mastcells Basophils FcᵋRI receptor Repeatexposure ACTIVATION and DEGRANULATION Nature Review, Drug Discoverys alapján

13. Class switching of B cells during differentiation IL- 13

14. Fcereceptors onmastcellsand basophils FcƐRI(highaffinity) Kd= 10-11 M [IgE] = 10-9 M MC arealwayscoatedwith IgEboundreceptors FcƐRIIa on B cells FcƐRII(lowaffinity) FcƐRIIb (CD23) on B cells, T cells, Mφ-s, DC-s and basophils

15. Signalinginducedbycross-linking of IgE

16. Effects of IgE cross-linking (phospholipids)

17. Degranulation of MC • Other degranulators • Immune • Anaphylatoxins: C5a, C3a • Modulator • IL3 • Non Immune • Bacterial products, gastrine, physical (cold), stress, chemical (gases, smoke), etc. • Intracellular signalling: Ca++ • Inhibitors of degranulation • Pharmacotherapy: cromoglicic acid

18. Pro-inflammatory mediators released by mast cells, basophils and eosinophils Primary mediators are in preformed granules Gilfillan et al.Nature Reviews Immunology 6, 218-230 (March 2006) | doi:10.1038/nri1782

19. Physiological effect of mast cell degranulation

20. Histaminereceptors

21. Histamine is thekeymediator and theirreceptors H1: e.g GIT, bronchoconstriction↑; vesselpermeabilty↑ H2: e.g. vasodilataion ↑; secretion of exocrinegland(e.g. gastricacid)↑; secretion (H3: neuralsystem) H4: eosinophilchemotaxis

22. Role of the Mast cells (MC) MC (Connectivetissue) MucosalMCs Intravenous , high dose Subcutanous, low dose Ingestion Inhalation, low dose capillaries capillaries SM in brochus SM in intestin Systemic anaphylaxis urticaria Hay fever, Bronchial asthma Food allergy: diarrhea, vomiting utricaria, anaphylaxis

23. Immediate reaction in respiratory tract Nature Medicine 18, 693–704 (2012) doi:10.1038/nm.2755

24. Immediate and late phase symptoms PEFR = peak expiratory flow rate After 2 hrs After 1 day

25. Chronic inflammation and complications (tissue remodelling) Nature Medicine 18, 693–704 (2012) doi:10.1038/nm.2755

26. 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.

27. Allergy – Multifactorial disorder Genetics FcƐRI beta chain - 11q13 IL-3, IL-4, IL5, IL-9, IL-13 and GMCSF coding genes - 5q31 MHCII allels - 6p Allergy Environmental factors Failure of tolerance during childhood Dysregulaion of the Immune system Activation of Th1 and Th2 subpopulation IgE production Immunodeficiency Increased eosinophil count

28. DER p1 in the faeces of the house dust mite penetrates the airway epithelium

29. Bronchialasthma normalbronchiole severe asthma

30. Anaphylaxis • Anaphylactic shock is the most serious • Symptoms are directly related to the massive release of vasoactive substances leading to fall in blood pressure, shock, difficulty in breathing and even death. • It can be due to the following: • Horse gamma globulin given to patients who are sensitized to horse protein. • Injection of a drug that is capable of acting as a hapten into a patient who is sensitive, i.e.penicillin. • Following a wasp or bee sting in highly sensitive individuals. • Foods – peanuts, shellfish, etc.

31. StaphylococcusexotoxinsmayserveeitherassuperantigensorallergensStaphylococcusexotoxinsmayserveeitherassuperantigensorallergens Non specific T-cell activation May lead to toxic shock syndrome !

32. Therapy • Avoidance of known allergens • Localized reactions use OTC (Over-the-Counter) antihistamines and decongestants. • Asthma uses combination – antihistamines, bronchodilators and corticosteroids. • Systemic use epinephrine • Hyposensitization – inject antigen to cause production of IgG which binds to antigen (allergen) before it reaches IgE coated cells. • Monocolonal anti-IgE– inject, binds to receptors on mast cells blocking them from the IgE.

33. Administration of increasing doses of antigen desensitization

34. DESENSITIZATION – Allergen-specific immunotherapy Repeated administration of the sensitizing allergen usually by subcutaneous injection or, more recently, by sublingual application. Both IgE- and IgG-specific antibodies increase during postdesensitization therapy. IgGactsasblocking Ab http://www.fpnotebook.com http://www.voedselallergie.nl/allergic-and-non-allergic-hypersensitivity-to-food

35. Anti-IgE therapy Monoclonal antibody anti-IgE therapy significantly reduces severe exacerbations in moderate and severe persistent asthma Nature Reviews Immunology 8, 218-230 (March 2008)

36. In vivo test - Intradermalallergy test (Pricktest) • Small amount of allergen injected into skin • Look for wheal formation of 3mm or greater in diameter • Simple, inexpensive, can screen for multiple allergens. • Stop anti-histamines 24-72 hours before test. • Danger of systemic reaction • Not for children under 3

37. In vitro test • Measure total IgE or antigen-specific IgE in serum • Less sensitive than skin tests. • RIST, RAST, Allergen specific and Microarray will be covered later. Protein array RAST RadioAllergoSorbent Test

38. Anaphylaxis vs. Anaphylactoidreaction (pseudoallergy) Ibuprofen v. COX1 inhibitor No test! 4 type of pseudoallergybasedon COX1 inhibition http://allergycases.blogspot.hu/2010/07/allergic-and-pseudoallergic-reactions.html

39. Type II. hypersensitivity (HS)

40. Type II. hypersensitivity Cell surface antigen (IgG v. IgM) Antigens: Intrinsic - autoantigen, Membrane component(receptor) Extrinsic antigen RBC – tarnsfusion, Rh incompatibility Absorbed drugs or metabolits

41. Pathomechanisms of type II. hypersensitivity Opsonization => phagocytozis Fc-receptor mediated phagocytosis/ cell lysis (macrophage, NK cell, neutrophil & eozinophil) Complement activation=> cell lysis ADCC (antibody dependent cellular cytotoxicity) Abnormal physiologic response: Ab inhibits binding of neurotransmitter anti Ach R: myasthenia gravis Ab stimulate receptor anti-TSH R: autoimmune thyroiditis

42. Hemolysis Transfusion reaction Incompatible transfusion - IgM Polytransfused - IgG Multipara - IgG Rh incompatibility Complication: Erythroblastosis fetalis Not only RBC, but platelets or leukocytes

43. Erythroblastosis fetalis Haemolytical disease of the newborn

44. Erythroblastosis fetalis Passive immunization with anti-Rh

45. Haemolytic anaemia and thrombocytopeny Drugs/ metabolits can act as a hapten – e.g. penicillin

46. Drug allergy (penicillin)

47. Autoimmune thyroiditis Graves- Basedow + exophtalmus Altering signal transduction Myastenia Gravis - ptosis 3 hrsaftermethylprednisolontreatment

48. Type III. HS Soluble antigen-antibody complex - IMMUNE COMPLEX disease

49. Pathomechanism Solubile Ag - Ab (IgG or IgM) => IC => Complement activation=> inflammation and tissue injury Mechanism of the tissue destruction similar in all tissue Severity depends upon: size of the IC, ratio of Ag/Ab, affinity of Ab, isotype of Ab

50. The consequence of the tissue damage depends on the site of deposition  1. Local immune complex disease Arthus reaction – skin necrotic vasculitis – vascular wall pneumonitis – farmer’s lung 2. Acute-systemic immune complex disease    acute serum disease (7-10 days) 3. Chronic immune complex disease SLE Rheumatoid arthritis