1. IMMUNOLOGICAL DISEASES AN INTRODUCTION TO HYPERSENSITIVITY

2. Allergy & hypersensitivity HYPERSENSITIVITY = harmful immune responses autoimmunity (self antigen) allergy ( foreign antigen) Distinct from: pharmacological intolerance / hypersensitivity toxicity

3. Classification of Hypersensitivity TypeMechanismExample I IgE mediatedSystemic anaphylaxis eg peanut allergy Asthma IIAntibody mediatedHaemolytic disease of the newborn IIIImmune complex mediated Arthus reaction Glomerular nephritis IVCell mediated (delayed) Contact dermatitis Anaphylactic hypersensitivity Cytotoxic hypersensitivity Immune complex hypersensitivity Cell-mediated hypersensitivity

4. Type I hypersensitivity reaction Dependant on IgE and Mast cells. Requires prior sensitisation to antigen.

5. Mast cell degranulation

6. Key Event. Mast cell activation (elicitation phase) Histamine Prostaglandin D2 Leukotriene C4 Cytokines (TNF-  ) Y Y Y Y Y IgE antigen

7. Scanning electron micrographs of RBL-2H3 (rat basophilic leukemia) cells (A) before and (B) after crosslinking IgE-primed FceRI with polyvalent antigen

8. Effector mechanisms Mast cell activation: – preformed mediators histamine enzymes (e.g. tryptase) TNF-α – synthesis leukotrienes C4, D4 IL-4, IL-5 Results: – vasodilation and increased permeability – increased mucus secretion – bronchoconstriction – Cough – chemotaxis of other inflammatory cells

9. HYPERSENSITIVITY TYPE II Caused by IgM or IgG antibodies to cell surface and extracellular matrix proteins. Abs interact with complement components and effector cells such as macrophages and neutrophils. This results in tissue damage via mechanisms normally active against foreign antigens.

10. EXAMPLES 1.Reactions against incompatible blood transfusions. 2.Autoimmune haemolytic anaemia. Sensitised to patients’ own RBCs. Often drug induced. 3.Goodpastures Syndrome. Ab against basement membrane proteins produce nephritis. 4.Myasthenia Gravis. Muscular weakness associated with Abs to acetylcholine receptors. 5. Haemolytic disease of the newborn. Pregnant woman is sensitised to the fetal erythrocytes.

11. HAEMOLYTIC DISEASE OF THE NEWBORN Occurs when mother has become sensitised to Ag on the infant’s erythrocytes. Rhesus D commonly. Often Rh –ve mother carrying a second or subsequent rhesus +ve infant. Sensitisation of the mother during the birth of the first Rh +ve baby. Subsequent children have an increased risk of being affected.

12. HAEMOLYTIC DISEASE OF THE NEWBORN First birthPostpartumSubsequent pregnancy RhD+ foetus RhD- mother Exposure sensitisation disease

13. Exposure no sensitisation no disease RhD+ foetus Ag removed prevents sensitisation Anti D Abs given immediately after birth First birthPostpartumSubsequent pregnancy

14. Muscle fibres Acetyl choline from nerve impulse Acetyl choline receptors Normal nerve signal

15. MYASTHENIA GRAVIS Ab against the receptor is only part of the disease process Muscle weakness from reduced signal transmission Antibodies to the receptor block acetylcholine binding

16. HYPERSENSITIVITY TYPE III Caused by IgM or IgG Abs against soluble antigens. Ab/Ag immune complexes normally removed effectively. In these reactions complexes that persist are deposited in the circulation or tissue and cause inflammation. Frequent complication in autoimmune disease.

17. Type III Hypersensitivity results from immune complex formation Can accumulate in tissues leading to increased local concentrations which may be pathogenic

18. 3 basic categories CausePersistent Infection AutoimmunityInhaled Antigen AntigenMicrobialSelf-antigenMould plant or animal antigen SiteKidney and infected organs Kidney, joints and skin Lung

19. MECHANISMS IN TYPE III HYPERSENSITIVITY Complexes interact with basophils and platelets to induce release of vasoactive amines. Macrophage stimulation results in cytokine release (TNFα IL-1). Complement activation and inflammation.

20. MECHANISMS IN TYPE III HYPERSENSITIVITY

21. Experimentally induced Type III hypersensitivity Immune complex deposition in the skin and resultant pathology is known as the Arthus reaction

22. TYPE IV HYPERSENSITIVITY Delayed type hypersensitivity. Typically mediated by T H 1 cells and/or macrophages which produce and respond to cytokines including TNFα and IFNγ Can be shown experimentally by transferring T cells between animals.

23. 3 BASIC TYPES Contact hypersensitivity48-72 hours Tuberculin reaction48-72 hours Granulomatous reaction21 days

26. ANAPHYLAXIS An immediate, severe, systemic hypersensitivity or allergic reaction, sometimes fatal, usually characterised by at least one or other of the following symptoms, respiratory difficulty, hypotension or circulatory failure. Generalised urticaria and tissue swelling also common. Mediated by IgE antibodies and Mast cells Immunologically disease. ‘Type One hypersensitivity’

27. Common causes of anaphylaxis Foods Serum/vaccines Bee and wasp stings Drugs Latex rubber - gloves

28. Foods commonly causing anaphylaxis Peanuts Tree nuts (eg. brazil nut, almond, hazlenut) Fish Shellfish Egg Milk Sesame

29. Drugs causing anaphylaxis Antibiotics (especially penicillin) Intravenous anaesthetic drugs Aspirin Non-steroidal anti-inflammatory drugs

30. Features of Anaphylaxis Erythema itching Urticaria Asthma Rhinitis Conjunctivitis Nausea, vomiting, abdominal pain Fainting, lightheadedness Collapse Lose of consciousness Hypotension/reduced blood pressure Circulatory/heart failure

31. Urticaria Raised, erythematous intensely itchy skin eruption caused by IgE-mediated histamine release from mast cells. Causes: DrugsFood allergens penicillinEnvironmental allergens cephalosporinsInsect bites latex

32. Is this allergy? “Please see this patient who is: obviously allergic to something...... clearly having allergy-like episodes......presumably to something he/she is eating............but can’t tell what he/she is allergic to.”

33. Case 1 Clinical diagnosis “oral allergy syndrome” allergy to birch pollen causing symptoms on exposure to cross-reacting allergens in a variety of fruits (particularly peach, pear, apple and plum) other plant-derived foods are sometimes involved, as in this case Tests skin prick testing showed a very strong response to birch pollen. Strong responses were also obtained to hazel nut, almond, carrot and celery. Extracts of the relevant fruits gave negative results. IgE results were: –total 52.4 –birch pollen 22.3 –apple 1.01 –carrot 1.3 –celery 0.8(peach, pear and plum were negative)

34. The End