ALLERGY AND HYPERSENSITIVTY IN IMMUNIZATION

Allergy
Allergens
Allergy causing agents

1. department of oral and maxillofacial surgery Allergy and Hypersensitivity

2. Index Introduction Classification Type I (Anaphylactic, IgE or reagin dependent) Type II (cytotoxic/ cell stimulating) Type III(immune complex or toxic complex disease) Type IV(delayed or cell mediated hypersensitivity) Conclusion References

3. Introduction Immunity is considered a protective process helping body to overcome infectious agents Under certain circumstances inflammatory response can have deleterious effects, resulting in significant tissue damage or even death

4. Hypersensitivity Hypersensitivity refers to undesirable (damaging, discomfort producing and sometimes fatal) reactions produced by the normal immune system. Hypersensitivity reactions require a pre-sensitized (immune) state of the host.

5. Hypersensitivity is what happens to the host as a result of immune reaction Allergy is most commonly a synonym for hypersensitivity Allergy means : altered state of reactivity to an antigen and includes both types of immune responses protective as well as injurious

6. For induction of hypersensitivity reaction host should have had contact with antigen Sensitising /priming dose : Initial contact sensitizes the immune system leading to priming of appropriate T or B lymphocytes Subsequent contact with allergen causes manifestations of hypersensitivity – shocking dose

7. Traditional classification Based on time required for the sensitized host to develop clinical reactions on re-exposure to antigen Immediate hypersensitivity(B cell / antibody mediated) Anaphylaxis Atopy Antibody mediated cell damage Arthus phenomenon Serum sickness

8. Delayed hypersensitivity (t cell mediated) Infection(tuberculin type) Contact dermatitis type

9. Gell and Coombs Classification 1963 Based on different mechanisms of pathogenesis: Type I (Anaphylactic, IgE or reagin dependent) Type II (cytotoxic/ cell stimulating) Type III (immune complex or toxic complex disease) Type IV(delayed or cell mediated hyperensitivity )

10. TYPE I : IgE DEPENDENT

11. Anaphylaxis : (by Richet 1902) Ana=without phylaxis =protection Classical immediate hypersensitivity reaction Sensitization most important when antigen is introduced parenterally In susceptible host very minute amount can sensitize host

12. Antigen as well as hapten can induce hypersensitivity There should be atleast 2-3 weeks between sensitizing dose and shocking dose Shocking dose most effective when injected intravenously and less effective intraperitoneally / subcutaneously and least effective intradermally

13. Shocking antigen should be identical/ immunologically closely related to sensitizing antigen Clinical effects are due to smooth muscle contraction and increased vascular permeability Oedema , decreased coagulability of blood, fall in blood pressure and temperature, leucopenia, thrombocytopenia also occur

14. Symptoms and signs of anaphylactic shock Itching of the scalp and tongue Flushing of the skin over the whole body Difficulty in breathing due to bronchial spasm. Nausea, vomiting, abdominal pain and diarrhoea Sometimes with blood in the stool. Acute hypotension, Loss of consciousness Death

15. IMPORTANT EXAMPLES Urticaria (hives) Angioedema Allergic conjunctivitis Allergic Rhinitis Allergic Asthma Anaphylaxis Seen with Injections of antibiotics Insect sting

16. Characteristics of allergens Small 15-40,000 MW proteins. Specific protein components Often enzymes. Low dose of allergen Mucosal exposure

17. Dermatophagoides pteronyssinus (common dust mite) Allergens Example: Der P1 Der P1 is an enzyme allergen from the fecal pellets of the dust mite.

18. Clinical manifestations

19. Urticaria Angioedema

20. Angioedema of oropharynx

21. Cutaneous anaphylaxis Small shocking dose of an antigen is administered intradermally to sensitised host there will be local wheal and flare response Is useful in testing for hypersensitivity and in identifying the allergen responsible in atopic diseases.

22. Passive cutaneous anaphylaxis (PCA) : Extremely sensitive in vivo method for detection of antibodies Antibody is injected intradermally into a normal animal Antigen, along with a dye such as Evans blue, is injected intravenously 4-24 hours afterwards There will be an immediate blueing at the site of` intradermal injection due to vasodilatation and increased capillary permeability (wheal-and-flare reaction)

23. Mechanism of anaphylaxis The immunologic basis for hypersensitivity is cytotropic IgE antibody IgE molecules are bound to surface receptors on mast cells and basophils. These cells carry large numbers of such receptors called Fc ER receptors

24. Continuation of sensitization cycle Mast cells control the immediate response. Eosinophils and neutrophils drive late or chronic response. More IgE production further driven by activated Mast cells, basophils, eosinophils.

25. Pharmacological Mediators 1)Primary mediators which are the preformed contents of mast cell and basophil granules Histamine, serotonin, Eosinophil chemotactic factor of anaphylaxis Neutrophil chemotactic factor Heparin and various proteolytic enzymes

26. 2) Secondary mediators which are newly formed upon stimulation by mast cells, basophils and other Leucocytes (slow reacting substance of anaphylaxis) Prostaglandins and platelet activating factor, and Cytokines such as IL3, IL4, IL5, IL6;

27. Anaphylactoid reaction: Intravenous injection of peptone, trypsin and certain other substances provokes a clinical reaction resembling anaphylactic shock. This is termed ` anaphylactoid reaction` The clinical resemblance is due to the same chemical mediators participating in both reactions. The only difference is that anaphylactoid shock has no immunological basis

28. Atopy ( out of place or strangeness] The term ‘ atopy ` was introduced by coca[1923] Naturally occurring familial hypersensitivities of human beings, typified by hay fever and asthma. The antigens commonly involved in atopy are characteristically Inhalants (pollen, house dust) Ingestants (for example, eggs, milk).

29. Some of them are contact allergens, to which the skin and conjunctiva may be exposed. These atopens are generally not good antigens when injected parenterally but induce IgE antibodies Atopic sensitisation is developed spontaneously following natural contact with atopens . It is difficult to induce atopy artificially.

30. Predisposition to atopy is genetically determined probably linked to MHC genotypes. Atopy runs in families. What is inherited is tendency to produce IgE antibodies in unusually large quantities.

31. What causes the deaths? Laryngeal edema and acute bronchospasm >70% Circulatory collapse >25% other <5% - ?brain ?MI

32. In USA 30,000 emergency room visits each year 400 to 800 deaths/year IV penicillin accounts for 100 to 500 deaths per year Hymenoptera stings account for 40 to 100 deaths per year Risk factors: protracted course, betablockers, adrenal insufficiency

33. Clinical expression depends on: Degree of hypersensitivity Quantity, route, rate of antigen exposure Pattern of mediator release Target organ sensitivity and responsiveness

34. Management Adrenaline is to be administered 0.5 ml of a 1 in 1000 solution, subcutaneously or intramuscularly, the dose being repeated upto a total of 2 ml over 15 minutes

35. Controlling Hypersensitivity reaction (Type I) To avoid contact with known allergens Immunotherapy repeated injections of increasing doses of allergens (hyposensitization) Use of drugs that block release of allergic mediators by interfering with various biochemical steps in mast-cell activation and degranulation

36. TYPE II (CYTOTOXIC REACTION)

37. Cytotoxic reactions are defined as those reactions which cause injury to the cell by combining humoral antibodies with cell surface antigens; blood cells being affected more commonly.

38. Types of mechanisms 1. Cytotoxic antibodies to blood cells. This mechanism involves direct cytolysis of blood cells (red blood cells, leucocytes and platelets) by combining the cell surface antigen with IgG or IgM class antibodies. In the process, complement system is activated resulting in injury to the cell membrane. The cell surface is made susceptible to phagocytosis due to coating or opsonisation from serum factors or opsonins .

39. i) Autoimmune haemolytic anemia:- Red cell injury is brought about by auto-antibodies reacting with antigens present on red cell surface. ii) Transfusion reactions due to incompatible or mismatched blood transfusion iii) Haemolytic disease of the newborn :- Fetal red cells are destroyed by maternal isoantibodies crossing placenta.

40. 2. Cytotoxic antibodies to tissue components Cell injury may be brought about by auto-antibodies reacting, with some components of tissue cells in certain diseases, Example In myasthenia gravis, antibody to acetylcholine receptors of skeletal muscle is formed which blocks neuromuscular transmission at the motor end-plate resulting in muscle weakness

41. 3)Antibody-dependent cell-mediated cytotoxicity (ADCC). Cytotoxicity by this mechanism is mediated by leucocytes like monocytes, neutrophils, eosinophils & NK cells. The antibodies involved are mostly IgG The cellular injury occurs by lysis of antibody-coated target cells through Fc receptors on leucocytes. The examples of target cells killed by this mechanism are tumour cells, parasites etc.

42. IMMUNE COMPLEX DISEASES Type III

43. Arthus reaction Arthus [1903] observed that when rabbits were repeatedly injected subcutaneously with normal horse serum, the initial injections had no local effect later injections  intense local reaction consisting of edema , induration and hemorrhagic necrosis. This is known as the Arthus reaction and is a local manifestation of generalised hypersensitivity

44. The tissue damage is due to formation of antigen—antibody precipitates causing complement activation and release of inflammatory molecules. This leads to increased vascular permeability and infiltration of the site with neutrophils. Leucocyte—platelet thrombi are formed that reduce the blood supply and lead to tissue necrosis

45. Immune Complex mediated local inflammation in Arthus Reaction

46. Arthus reaction forms a pathogenic component of many clinical syndromes. Eg: intrapulmonary Arthus-like reaction to inhaled antigens, such as thermophilic actinomycetes from mouldy hay or grain causes Farmer`s lung and other types of hypersensitivity pneumonitis

47. Serum sickness As originally described by von Pirquet and Schick (1905) Appeared 7-12 days following a single injection of a high concentration of foreign serum such as the diphtheria antitoxin. Systemic form of Type lll hypersensitivity

48. The clinical syndrome consists of Fever Lymphadenopathy Splenomegaly Arthritis, Glomerulonephriris Endocarditis Vasculitis, Urticarial rashes, abdominal pain, nausea and vomiting.

49. Pathogenesis Formation of immune complexes (consisting of the foreign serum and antibody to it that reaches high enough titres by 7-12 days) Which get deposited on the endothelial lining of blood vessels in various parts of the body, causing inflammatory infiltration.

50. The plasma concentration of complement falls due to massive complement activation and fixation by the antigen antibody complexes. The disease is self limited

51. With continued rise in antibody production, the immune complexes become larger and more susceptible to phagocytosis and immune elimination. When all foreign antigen is thus eliminated and free antibody appears, the symptoms clear without any sequelae

52. The latent period of 7-12 days is required only for serum sickness following a single injection. With subsequent injections, the disease manifests earlier. Serum sickness differs from other types of hypersensitivity reaction in that a single injection can serve both as the sensitising dose and the shocking dose.

53. Syndrome is currently more commonly seen following injections of penicillin or other antibiotics. Immune complexes occur in many diseases including bacterial, viral and parasitic infections Disseminated malignancies Autoimmune conditions.

54. The nephritis and arthritis seen in these conditions may be caused by deposition of immune complexes.  

55. Type IV reactions : Delayed Hypersensitivity

56. They constitute one aspect of cell mediated immunity Provoked by specific antigens Evolve slowly and consist of a mixed cellular reactions involving lymphocytes and macrophages in particular

57. Reaction is not induced by circulating antibodies but by sensitized T cells which on contact with specific antigen ,release lymphokines that cause biological effects on leucocytes, macrophages and tissue cells.

58. Delayed hypersensitivity can be transferred by lymphocytes or other transfer factors not by serum Two types Tuberculin type Contact dermatitis type

59. Tuberculin type Archetype of delayed hypersensitivity is the tuberculin reaction When small dose of tuberculin is injected intradermally in an individual sensitised to tuberculoprotein by prior infection or immunisation An indurated inflammatory reaction occurs at the site within 48-72 hours

60. If unsensitised no response Its different from the skin test for Type 1 hypersensitivity : longer interval of appearance its morphology and histology Seen in many infections especially its subacute and pathogen intracellular Also seen in allograft reaction and many autoimmune disease

61. Cutaneous basophil hypersensitivity Produced by intradermal injection of some protein antigen Resembles tuberculin response It can be passively transferred by serum so its not delayed hypersensitivity Formerly known as Jones Mote reaction. Characterised by prominent basophil infiltration Significance unknown

62. Contact dermatitis type Results from skin contact with variety of chemicals , drugs , metals Sensitization is liable when contact is with an inflamed area of skin and when chemical is applied in an oily base Substances involved themselves not antigenic but may acquire antigenicity in combination with skin proteins Sensitization may require percutaneous absorbtion.

63. Most of substances are fat soluble, so passage along sebaceous gland may be method of entry of allergens Langherhan cells of skin capture locally applied haptens , along with modified tissue protein and migrate to draining lymphnode where they present the processed antigens along with MHC molecules to Tcells The sensitised Tcells travel to the skin site, where on contacting the antigen release various lymphokines Th1 cells secrete IFN-r and IL-2 which activate macrophages and lymphocytes.

64. Th2 cells release IL4,IL5, GM-CSF and other factors that lead to an influx of eosinophills and tissue damage. Activated Tc cells mediate killing of target cells Lesions of contact dermatitis varies from papule to macule to vesicle, that breakdown, leaving behind raw weeping areas typical of acute eczematous disease

65. Patch test Allergen is applied to the skin under an adherent dressing. Sensitivity is indicated by itching appearing in 4-5 hours Local reaction may vary from erythema to vesicle or blister formation after 24-48 hours.

66. Shwartzman reaction Its not an immune reaction,it has superficial resemblance with hypersensitivity Alteration in factors affecting intravascular coagulation

67. Shwartzman 1928 observed that if a culture trait of S.Typhi is injected intradermally in a rabbit followed by same filtrate intravenously, a hemorrhagic necrotic lesion develops at the site of intradermal inj

68. Injections need not be of same or even related endotoxins. Culture suspension or filtrates of variety of bacteria will sensitize the skin intravenous injection by an equally wide variety of cultures and infiltrates

69. Initial or preparatory dose is an endotoxin Intravenous or provoctive injection can be a variety of substances (bacterial endotoxins,antigen antibody complex etc ) Initial inj can cause accumulation of leucocytes which condition the site by release of lysosomal enzymes damaging capillary walls.

70. If both inj are given IV the animal die 12-24 hours after 2 nd inj Autopsy shows bilateral cortical necrosis of the kidney and patchy hemorrhagic necrosis in liver , spleen, other organs

71. An essentially similar phenomenon was described by sanarelli in experimental cholera The reaction is called Sanarelli - Shwartzman reaction or generalised shwartzman reaction

72. Similar kind of mechanisms are seen in:- Purpuric rashes of meningococcal septicaemia Acute hemorragic adrenal necrosis (Waterhouse-Frederichsen)

73. Massive activation of compliment by the alternative pathway, associated with release of thromboxane A2 and prostaglandin may lead to DIC The mechanism may be execessive release of cytokines such as TNF and IL 1&6 by macrophages and endothelial cells in response to contact with large number of lipopolysacchride endotoxin

74. Staphylococcus aureus can induce TNF secretion by macrophages and peptidoglycan mediated platelet aggregation, leading to DIC Staphylococcal enterotoxins can act as super antigen activating whole families of Tcells irrespective of their antigen specificity and causing massive release of cytokines ,leading to toxic shock syndrome These conditions has similar pathogenic mechanism and resemble those in immune inflammation

75. Conclusion Hypersensitive reactions can be as mild as rashes to severe life threatening condition A thorough history of the patient is mandatory before undergoing any medical treatment to avoid an emergency. Drugs for anaphylactic reactions should always be kept ready in the vicinity. Good presence of mind and prompt reaction of the practitioner can bring a patient back to life…..

76. References Text book of micobiology-Ananthanarayan 2 nd edition Text book of introductory immunology- Nandini Shetty Microbiology5th Edition Lansing M. Prescott Abbas , Lichtman Basic Immunology 2nd Edition Kuby immunology- Richard Goldsby Robinsons book of pathology – 7 th edition