1. Hypersensitivity and Autoimmunity

2. Aims & Objectives: Understand the terms hypersensitivity, allergy, autoimmunity and autoimmune disease Understand the classification and mechanisms of immunologically mediated tissue damage (hypersensitivity reactions), and know examples of diseases reflecting each of these Understand what we mean by organ specific and non-organ specific autoimmune diseases, and know examples of both

3. Definitions: Hypersensitivity: exaggerated or inappropriate immune reaction resulting in tissue damage Allergy: hypersensitivity reaction to an extrinsic (often innocuous) antigen Autoimmunity: immune response with specificity for self antigen(s) Autoimmune disease: disease in which an autoimmune response plays a pathogenetic role

4. Hypersensitivity reactions – the mechanisms of allergy and autoimmunity (Gell and Coombs classification)

5. 5 Types of hypersensitivity reactions Type I: anaphylactic or immediate Type II:cytotoxic Type III:Immune complex Type IV:cell mediated or delayed Type I: anaphylactic or immediate Type II:cytotoxic Type III:Immune complex Type IV:cell mediated or delayed

6. Type I (immediate) hypersensitivity reactions

7. Mechanism of type I hypersensitivity Extrinsic allergen pollenshouse dust mite animal dander foods (eg peanut) wasp / bee venom Th2 response IgE mast cells IL-4 / IL-13 Priming sensitization elicitation

8. Mediators of type I hypersensitivity vasodilatation increased vascular permeability tissue oedema smooth muscle contraction chemoattraction Most allergic reactions occur at mucosal sites (site of interaction with allergen)

9. 9 Sensitization against allergens and type-I hypersensitivity B cell Histamine, tryptase, kininegenase, ECFA Leukotriene-B4, C4, D4, prostaglandin D, PAF Newly synthesized mediators TH2

10. Allergic rhinitis (Hay fever)

11. Anaphylaxis – systemic type I hypersensitivity: a medical emergency Clinical features of anaphylaxis: Generalized urticaria Angioedema esp. around eyes, lips, tongue and larynx Gastrointestinal symptoms (nausea, cramps, vomiting, diarrheoa) Bronchospasm Hypotension Loss of consciousness Death i.m. injection of adrenaline (1:1000) plus i.v. antihistamine, i.v.hydrocortisone and oxygen

12. 12 Skin (prick) test for allergy

13. Type II (antibody mediated) hypersensitivity Antibody to tissue bound or cellular antigen:

14. 14 Type II hypersensitivity role of complement and phagocytes

15. 15 Type II hypersensitivity induced by exogenous agents

16. Mechanism and prevention of Rhesus disease

17. Rhesus disease of the newborn – a type II hypersensitivity disease

18. Stimulatory and blocking antibodies in type II hypersensitivity Stimulatory Abs TSH receptor in Grave’s disease Blocking Abs ACh R in myasthenia gravis intrinsic factor in pernicious anaemia insulin receptor in diabetes

19. Myasthenia gravis the mechanism

20. Grave’s disease

21. Type III (immune complex) mediated hypersensitivity Soluble antigen Immune complexes deposit in small vessels (esp joints, kidneys, skin) Complement activation Neutrophil attraction and activation Platelet aggregation and microthrombus formation

22. 22 Type III hypersensitivity mechanism

23. 23 Arthus reaction Type-III Weal & flare reaction Type-I

24. 24 Serum sickness

25. Early and late joint changes in rheumatoid arthritis

26. Typical “butterfly” malar rash in SLE

27. Type IV (delayed) hypersensitivity

28. 28 Type IV hypersensitivity ãDelayed reaction ã36 to 48 hours ãCharacterized by induration and erythema ãAlso known as cell mediated hypersensitivity ãTuberculin test is the most common example ãDelayed reaction ã36 to 48 hours ãCharacterized by induration and erythema ãAlso known as cell mediated hypersensitivity ãTuberculin test is the most common example

29. 29 Tuberculin test

30. Contact hypersensitivity (to nickel)

31. 31 Contact dermatitis reaction to leather

32. 32 Granuloma in a leprosy patient

33. Type IV hypersensitivity and coeliac disease

34. 34 Type IV hypersensitivity the three forms

35. “Patch” testing for contact hypersensitivity

36. Summary or hypersensitivity reactions

37. Autoimmunity and autoimmune disease

38. Peripheral tolerance

39. Autoantibodies and disease presence of antibodies to self antigens indicates an autoimmune process or reaction but does not necessarily equate with presence of disease (eg low titre ANA in elderly or after infection) some (but not all) autoantibodies cause disease (pathogenetic) some autoantibodies provide useful diagnostic markers of disease (often in association with other clinical features) some autoantibodies can be used to monitor disease activity (often pathogenetic antibodies) some autoantibodies have a higher predictive value than others (eg IgA endomysial Ab vs IgA gliadin Ab vs reticulin Ab in coeliac disease) autoantibodies to many autoantigens are found (in low titres) in the elderly in the absence of disease (eg ANA)

40. Comparison of organ specific and non-organ specific autoimmune diseases Organ specific Non-organ specific Antigenlocalized to given organ widespread distribution or tissue throughout the body Lesionsconfined to target organ multiple organs / tissues affected; or tissue immune complexes deposit in joints, skin and kidneys Overlapwith other organ specific overlap with other non-organ antibodies and diseases specific antibodies and diseases Examples autoimmune thyroid disease SLE (Grave’s; Hashimoto’s) rheumatoid arthritis myasthenia gravis systemic sclerosis pernicious anaemia systemic vascultitis diabetes mellitus

41. Autoantibodies and autoimmunity (Some) autoantibodies of clinical significance in organ specific and non-organ specific autoimmune disease: AntigenDistributionDisease thyroid peroxidasethyroid glandHashimoto’s thyroiditis TSH receptorthyroid glandGrave’s disease islet cellpancreastype I diabetes acetyl choline Rneuromuscular junctionmyasthenia gravis t transglutaminase /GI tractcoeliac disease endomysial basement membranekidney / lungGoodpastures syndrome mitochondrial (M2)all cells1 o biliary cirrhosis ANCA (MPO / PR3) neutrophilssystemic vasculitis “rheumatoid factor”immunoglobulin Fcrheumatoid arthritis dsDNAall cellsSLE

42. Causes of autoimmunity – breakdown of self tolerance Molecular mimicry:cross reactivity between pathogen and self antigen Defective immunoregulation:aberrant Ag presentation by dendritic cells (failure of) regulatory T cells cytokines: excess immune stimulation lack of suppression Exposure of “hidden” self antigens:eg sympathetic opthalmia T cell bypass / hapten:eg drug induced autoimmune cytopenias Genetic susceptibility:HLA and non-HLA genes In most cases, trigger not known

43. Summary autoimmune reactions and diseases are relatively common, and represent a breakdown of immunological tolerance autoimmunity can be organ-specific or non-organ specific, depending on the distribution of the autoantigen allergic represents an exaggerated immune response to extrinsic antigen. Allergic diseases are common, and are becoming more common (especially in children) allergic and autoimmune diseases are mediated by mechanisms of hypersensitivity hypersensitivity reactions represent exaggerated or inappropriate immune reactions, resulting in tissue damage

44. Summary Four major types of hypersensitivity reaction have been defined, depending on the underlying immunological mechanism Type IIgE Type IIIgG Type IIIAg-Ab complexes Type IVdelayed / T cell mediated Anaphylaxis (systemic type I hypersensitivity reaction) represents a medical emergency, is potentially life- threatening, and is effectively treated with i.m. adrenaline In many autoimmune diseases, there is overlap between different types of hypersensitivity reaction