Hypersensitivity

1. Hypersensitivity A damage to the host, mediated by preexisting immunity to self or foreign antigen. Dr. Sudheer Kher Kher

2. What is hypersensitivity? • Injurious consequences in the sensitized host, following contact with specific antigen • Deals with injurious aspect of heightened and exaggerated immune response leading to tissue damage, disease or even death • Concerned with what happens to the host rather than what happens to the antigen. Kher

3. Musts for Hypersensitivity • Contact with allergen • Sensitizing/priming dose • Induction of AMI/CMI • Shocking dose Kher

4. Classification:Hypersensitivity reactions • Immediate hypersensitivity • Anaphylaxis • Atopy • Antibody mediated cell damage • Arthus phenomenon • Serum sickness • Delayed hypersensitivity • Infection (Tuberculin) type • Contact dermatitis type Kher

5. Classification: Gell & Coombs(1963) Kher

6. Kher

7. Type I (Anaphylactic) Reactions • Occur within minutes of exposure to antigen • Antigens combine with IgE antibodies bound to mast cells and basophils, causing them to undergo degranulation and release several mediators: • Histamine: Dilates and increases permeability of blood vessels (swelling and redness), increases mucus secretion (runny nose), smooth muscle contraction (bronchi). • Prostaglandins: Contraction of smooth muscle of respiratory system and increased mucus secretion. • Leukotrienes: Bronchial spasms. • Anaphylactic shock: Massive drop in blood pressure. Can be fatal in minutes.

8. Type I Reactions ( IgE Mediated) • Anaphylaxis – • Classical immediate reaction • Sensitization • Most effective when Ag introduced parenterally • May occur by any route exposure to Ag • Minute quantities are enough • Interval of 2-3 wks needed between sensitizing & shocking dose • Once sensitized it remains so for long time • Shocking dose most effective by IV route then IP, then SC then ID • The shocking Ag must be same or similar to Sensitizing Ag Kher

9. Mast Cells and the Allergic Response Kher

10. B cell IL13 TH2 Newly synthesized mediators Sensitization against allergens and type-I hypersensitivity Histamine, tryptase, kininegenase, ECFA Leukotriene-B4, C4, D4, prostaglandin D, PAF Kher

11. Type I Reactions • Humans – • Itching of scalp & tongue, flushing of skin, difficulty in breathing, nausea, vomiting, diarrhea, acute hypotension, loss of consciousness, death (rare) • Causes • Serum therapy, antibiotics, insect stings • Treatment • Adrenalin 0.5 ml (1 in 1000 solution) SC/IM repeated up to 2 ml in 15 min Kher

12. Cutaneous anaphylaxis • If small shocking dose is given ID to sensitized host, there is a local weal & flare reaction (local anaphylaxis). • Used for • Testing for hypersensitivity • Identification of allergens for atopy • Precaution – Keep adrenalin injection ready to combat severe fatal reaction. Kher

13. Mechanism of anaphylaxis • Mediators of anaphylaxis – • Primary mediators • Preformed contents of Mast cells & Basophils • Histamine, serotonin, eosinophils chemotactic factor of anaphylaxis (ECF-A), Neutrophil chemotactic factor (NCF), Heparin & various proteolytic enzymes • Secondary mediators – • Newly formed after stimulation by Mast cells, Basophils & other leucocytes • Slow reacting substance of anaphylaxix (SRS-A), Prostaglandins & Platelet activating factors (PAF) Kher

14. Primary Mediators of Anaphylaxis • Histamine – • Most important vasoactive amine of Human anaphylaxis, formed from histidine found in granules. Released into skin, causes burning & itching. Causes vasodilatation & hyperemia by an axon reflex (Flare) and edema by increasing capillary permeability (Weal). Induces smooth muscle contraction of diverse tissues & organs. Kher

15. Primary Mediators of Anaphylaxis • Serotonin (5-HT) – • Base derived by decarbolxylation of Tryptophan. • Found in intestinal mucosa, brain & platelets. • Causes smooth muscle contraction, ↑ Vascular permeability & vasoconstriction. • Important in rats & mice. • Role in human not clear. Kher

16. Primary Mediators of Anaphylaxis • Chemotactic factors – • ECF-A released from mast cell granules are strongly chemotactic for eosinophils. Accounts for high eosinophil counts in many hypersensitivity reactions. • NCF – Attracts neutrophils • Heparin – Acidic mucopolysaccharide. Contributes to anaphylaxis in dogs but apparently not in man. • Enzymatic mediatores such as proteases & hydrolases are also released from the mast cell granules. Kher

17. Secondary mediators of anaphylaxis • Prostaglandins & leukotrienes – • Derived from Arachidonic acid formed from the disruption of mast cell membrane other leucocytes • Lipoxygenase pathway - Leukotrienes • Cycloxygenase pathway - Prostaglandins • One of the family of Leukotrienes is SRS-A (slow reacting substance of anaphylaxis) • Prostaglandins are bronchoconstrictors/broncodilators, affect secretions of mucus glands, platelet adhesion, permeability, dilatation of capillaries & pain threshold. Kher

18. Secondary mediators of anaphylaxis • Platelet activating factor – PAF • Low mol wt lipid released from basophils • Causes aggregation of platelets and release of their vasoactive amines • Other mediators – • Anaphylatoxin – Released by complement activation • Bradykinin & Other kinins formed from plasma kininigens Kher

19. Type-I hypersensitivity The common allergy Kher

20. Anaphylactoid reaction • Intravenous injection of peptone, trypsin & certain other substances causes clinical reaction like anaphylaxis. • Resemblance due to participation of same chemical mediators. • Difference – Anaphylactoid shock has no immunological basis. It is nonspecific reaction involving activation of complement & release of anaphylatoxin. Kher

21. Type II (Cytotoxic) Reactions • Involve activation of complement by IgG or IgM binding to an antigenic cell. • Antigenic cell is lysed. • Transfusion reactions: • ABO Blood group system: Type O is universal donor. Incompatible donor cells are lysed as they enter bloodstream. • Rh Blood Group System: 85% of population is Rh positive. Those who are Rh negative can be sensitized to destroy Rh positive blood cells. • Hemolytic disease of newborn: Fetal cells are destroyed by maternal anti-Rh antibodies that cross the placenta.

22. Type II Reactions : Cytolytic, Cytotoxic & Cell Stimulatory • Involve reaction between IgG (rarely IgM) & Ag determinant on the surface of cells. • Leads to cytolytic or cytotoxic effect. • Autoimmune anemias • Hemolytic disease of the new born • Drug induced hemolytic anemias • Drug induced thrombocytopenic purpura • Drug induced agranulocytosis • Rarely normal cell function may be disrupted • Agonist effect -Cell stimulatory effect seen (LATS in Graves’ disease). • Antagonist effect – Myasthenia gravis Kher

23. Type III (Immune Complex) Reactions • Involve reactions against soluble antigens circulating in serum. • Usually involve IgA antibodies. • Antibody-Antigen immune complexes are deposited in organs, activate complement, and cause inflammatory damage. • Glomerulonephritis: Inflammatory kidney damage. • Occurs when slightly high antigen-antibody ratio is present.

24. Immune Complex Mediated Hypersensitivity Kher

25. Type III Reaction: Immune Complex Disease • Arthus Reaction – Localized manifestation of generalized hypersensitivity • Ag+Ab precipitates cause C activation and release of inflammatory molecules. Leads to ↑ vascular permeability & neutrophil infiltrate. Leucocyte-platelet thrombi formed which reduce blood supply leading to necrosis. • Clinical example – Farmer’s lung & other hypersensitivity pneumonitis following inhaled Ag like Actinomycetes. Kher

26. Arthus reaction Arthus reaction Type-III Weal & flare reaction Type-I Kher

27. Type III Reaction: Immune Complex Disease • Serum Sickness – Systemic form of Type III reaction. • Takes place following serum therapy • e.g. ADS, ATS, AGGS, Hyperimmune globulin, Anti Snake venum. • Clinically Fever, lymphadenopathy, splenomegaly, arthritis, glomerulonephritis, endocarditis, vasculitis, urticarial rashes, abdominal pain, nausea, vomiting. • Pathogenesis – Formation of immune complexes, its deposition on the endothelial lining of BVs all over the body, leads to inflammation. Kher

28. Serum Sickness (contd) • Plasma concentration of C falls due to massive activation and fixation to Ag+Ab complexes. • Disease self limited. • Single dose of Antiserum can serve both as sensitizing & shocking dose. • Can also be seen after administration of penicillin or other antibiotics. • Immune complexes occur in many bacterial, viral, parasitic infections e.g. poststreptococcal glomerulonephritis, Hepatitis B & Malaria. Also seen in disseminated malignancies & autoimmunity. Kher

29. Serum sickness Kher

30. Type IV (Cell-Mediated) Reactions • Involve reactions by TD memory cells. • First contact sensitizes person. • Subsequent contacts elicit a reaction. • Reactions are delayed by one or more days (delayed type hypersensitivity). • Delay is due to migration of macrophages and T cells to site of foreign antigens. • Reactions are frequently displayed on the skin: itching, redness, swelling, pain. • Tuberculosis skin test • Poison ivy • Metals • Latex in gloves and condoms (3% of health care workers) • Anaphylactic shock may occur.

31. Type IV Reactions: Delayed Hypersensitivity • One aspect of CMI • Provoked by specific Ag, involves lymphocytes & Macrophages. • Not induced by circulating Ab but by sensitized lymphocytes. • Sensitized lymphocytes release lymphokines which have biological effects on leucocytes, macrophages & tissue cells. • Transfer possible thru’ lymphocytes / transfer factor. Kher

32. Type IV Reactions: Delayed Hypersensitivity • Two types – • Tuberculin (Infection) type • Contact dermatitis type • Tuberculin type – • ID inoculation of PPD in sensitized indivisual leads to induration & inflammation in 48-72 hrs. This is not same as skin test done for Type I hypersensitivity. • Used for diagnosis / exclusion of diagnosis of many bacterial / fungal / parasitic / viral and autoimmune diseases. Kher

33. Granuloma in a leprosy patient Kher

34. Contact dermatitis • Ag possibly enters thru’ sebaceous glands • Lesions vary from macules & papules to vesicles which subsequently breakdown leaving weeping surface typical of acute eczematous dermatitis. • Detected by patch test Kher

35. Contact dermatitis reaction Kher

36. Allergic Contact Dermatitis Response to Poison Ivy Hapten Kher

37. characteristic Type-I Type-II Type-III Type-IV antibody IgE IgG, IgM IgG, IgM none exogenous cell surface soluble intracellular antigen response time 15-30 min. Min.-hrs 3-8 hours 48-72 hours or longer Erythema & edema Erythema & induration Lysis & necrosis appearance Weal & flare baso- and eosinophils Ab and complement Monocytes & lymphocytes histology PMN and complement antibody T-cells antibody transfer with antibody examples hay fever, asthma pemphigus, Goodpasture farmers’ lung, SLE TB test, poison ivy, granuloma Comparison of hypersensitivity reactions Kher