Hypersensitivity

Through this presentation you will be able to learn detailed information about hypersensitivity reactions, its type and clinical manifestation of all types of hypersensitivity reactions and related diseases.

1. 18-05-2020 1 hypersensitivity PRESENTED BY : PRADDUM KUMAR NAMDEV BSc (Hons) ZOOLOGY 6 th sem. IGNTU AMARKANTAK MP

2. SYNOPSIS Hypersensitivity Types of hypersensitivity reaction Immediate hypersensitivity reaction Delayed hypersensitivity reaction Classification Type I hypersensitivity Type II hypersensitivity Type III hypersensitivity Type IV hypersensitivity Summary 18-05-2020 2

3. Hypersensitivity when immune system does not work properly or over activated, it causes deleterious effects resulting in significant tissue damage, serious disease and even death. Such unwanted, inappropriate and damaging immune response is termed as hypersensitivity . Although the word ‘hypersensitivity’ implies an increased response, the immune response in hypersensitivity reaction is not always heightened but may instead be an inappropriate response . Hypersensitivity reaction may develops in course of either cell mediated or humoral immune response 18-05-2020 3

4. Classification B y: Gell & coomb Hypersensitivity reactions are classified as Immediate or delayed type on the basis of time required by sensitized host to response to shocking dose of antigen. Hypersensitivity reactions can be distinguished by immune response and difference in effectors molecules generated in course of reactions. G.H Gell and R.R.A Coomb classified hypersensitivity reactions into four types. Type-I hypersensitivity reaction: IgE antibody mediated Type-II hypersensitivity reaction: Antibodies mediated Type-III hypersensitivity reaction: Antigen-antibody complex mediated Type-IV hypersensitivity reaction: Activated T-cell and cytokines mediated 18-05-2020 4

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6. Contd… ** Two additional types, Type-V and Type-VI hypersensitivity reaction are also proposed. Type-V hypersensitivity reaction: Antibody mediated Type-VI hypersensitivity reaction: Both antibody and cell mediated 18-05-2020 6

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8. Immediate hypersensitivity reactions Immediate hypersensitivity reaction is mediated by humoral antibody and manifests within minutes to few hours. The anaphylactic reaction initiated by antibody or Ag-Ab complex are referred as immediate hypersensitivity because it occurs within minutes or few hours after a sensitized host encounter with antigen Type-I, II and III hypersensitivity reaction are immediate. 18-05-2020 8

9. Delayed hypersensitivity reactions Delayed hypersensitivity reaction is mediated by sensitized CD4 T cells and manifests slowly usually after 24 hours or more. It is called delayed because symptoms appears days after exposure to antigen. In delayed hypersensitivity reaction, the effector molecules are various cytokines secreted by activated CD4 T cells themselves. Type-V hypersensitivity depends upon activation of T cells and occurs within cell mediated branch of immune response and termed as delayed type hypersensitivity reaction (DTH). 18-05-2020 9

10. Type I hypersensitivity reactions and clinical manifestations Type-I hypersensitivity reaction is an immediate type of reaction mediated by IgE . It is also known as anaphylactic reaction or allergy. It is induced by certain types of antigen called allergens such as pollen grains, dandruff, dusts, food components etc . Allergens induces humoral antibody response by the same mechanism as other soluble antigens in the generation of antibody secreting plasma cells and memory cells but the difference is that the plasma cell secretes IgE class of antibody. 18-05-2020 10

11. Contd … This IgE class of antibodies have high binding affinity to Fc receptor on the surface of tissue mast cells and blood basophils. Mast cells and basophils bound by IgE are said to be sensitized . A latter exposure to the same allergens cross links the membrane bound IgE on sensitized mast cell and basophils causing degranulation of these cells . Degranulation causes release of pharmacological active mediators which act on surrounding tissue causing vasodilation and smooth muscle contraction which may be either systemic or localized. This effect is also termed as Allergy. 18-05-2020 11

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13. MECHANISM OF TYPE I HYPERSENSITIVITY REACTIONS Development of allergy or anaphylactic reaction requires two dose of antigen. 1st dose is known as sensitizing dose and 2nd dose is known as shocking dose . 1. PRODUCTION OF IgE ANTIBODY When antigen (allergen) enters into host production of antibody begins. At first allergen is processed and presented by antigen presenting cells (APCs) to CD4 T cells. Activated CD4 t cells divides to form T helper cell and memory cell. T helper produces IL4. At the same time B cell bind to antigen in presence of APC and IL4 and gets activated. Activated B cells divide to form plasma cells and memory cells. Up to this step, mechanism is similar to that of normal humoral immune response. The difference between Type I hypersensitivity and normal immune response is that the plasma cell produces IgE antibody instead of Ig M or IgG. 18-05-2020 13

14. 2. SENSETIZATION Fc region of IgE antibody has receptor on the surface of tissue mast cells and blood basophils. So the IgE antibody binds to FcRI of mast cells and basophils . This binding of IgE to mast cell and basophil is known as Sensitization and the mast cells and basophils are said to be sensitized. 18-05-2020 14

15. 3. SHOCKING DOSE OF ANTIGEN When the same antigen (allergen) enter into same host for second time in life, antigen cross linked with Fab region of IgE molecules on the surface of mast cell or basophils. 4 .DEGRANULATION OF MAST CELLS The cross-linking of antigen (allergen) to IgE antibody causes degradation of mast cell and basophils releasing various pharmacological active chemicals such as histamine, heparin, serotonin, cytokines, leucotriene, prostaglandin etc . 18-05-2020 15

16. 5. ANAPHYLATIC REACTIONS These active chemical mediators acts on surrounding tissue producing various symptoms of allergy such as vasodylation, smooth muscle contraction, mucus production, sneezing, etc . The allergic reaction may be localized or systemic depending upon types of allergen. 18-05-2020 16

17. Clinical menifestaions of type I hypersensitivity Clinical symptoms ranges from life threatening conditions such as systemic anaphylaxis and severe asthma to localized reaction such as hey fever and eczema. 1. Systemic anaphylaxis: It is a shock like and often fatal state, which is usually initiated by allergen directly into blood stream or absorbed from gut or skin. The symptoms are; Labored breathing Drop in blood pressure Smooth muscle contraction Bronchiole constriction Suffocation 18-05-2020 17

18. 2. Localized hypersensitivity: It is limited to specific target tissue or organs, often involving epithelial surface at the site of allergen entry. The tendency to manifests hypersensitivity reaction is inherited and is called atopy. Atopic allergy includes wide range of IgE mediated disorders such as : Hey fever (allergic rhinitis) Asthma (allergic or intrinsic) Food allergy Atopic dermatitis (eczema) 18-05-2020 18

19. Type II hypersensitivity: mechanism and examples Type II hypersensitivity reaction involves antibody mediated destruction of cells. It is also known as cytotoxic reaction. In this hypersensitivity reaction, specific antibody (IgG or IgM) bound to cell surface antigen and destroy the cell. If the cell is microorganism, killing of cell is beneficial to host. However in Type II hypersensitivity, the cells are own RBC. The killing of cell can occurs by one of the three mechanisms. They are- Complement mediated cell lysis Antibody dependent cell mediated cytotoxicity (ADCC) Opsonization 18-05-2020 19

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21. Example of type II hypersensitivity 1. ABO blood transfusion ABO blood transfusion reaction is an example of type II hypersensitivity reaction. Human RBCs contains A and/or B antigen as major antigen on the surface of RBC. Other minor antigens such as Rh, Kell, Duffy etc. are also present. Antibodies to ABO antigen are called isohemagglutinin and are usually of IgM class whereas antibodies to other minor antigen are of IgG class. An individual with blood group A recognizes B antigen like epitope (blood group B) as foreign and produces isohemagglutinin (antibodies). The same individual does not produce antibodies to A antigen as it is similar to self antigen, so that state of tolerance exists . 18-05-2020 21

22. Contd… If individual with blood group A is transfused with blood containing B antigen then transfusion reaction occurs in which anti-B isohemagglutinin ( antibodies) binds with B- blood cells and mediate destruction of transfused RBC by complement activation. Since lysis of RBC occurs in intravascular space, free hemoglobin appears in urine. Hemoglobin may be converted into billirubin which is highly toxic to tissues. For treatment of this hypersensitivity reaction, transfusion should be stopped immediately. Furthermore patients should be given diuretic to eliminate hemoglobin in urine. 18-05-2020 22

23. Contd… Blood transfusion reaction occurs immediately in case of mismatched ABO antigen. In this case transfused RBCs are lysed by complement. In case of minor antigen (Rh) mismatched, delayed reaction occurs and in this case transfused RBCs are lysed by opsonization (IgG antibody) and no free hemoglobin appears in urine. 18-05-2020 23

24. 2.Hemolytic disease of new born (Erythroblastosis fetalis) 18-05-2020 24

25. Contd… Hemolytic disease of newborn develops when maternal IgG antibodies specific for fetal blood group crosses placenta and destroy fetal RBCs. The consequences of such transfer of antibody can be minor, serious or lethal to fetus. Serious hemolytic diseases of new born develops when Rh –ve mother conceive Rh +ve fetus, which causes erythroblastosis fetalis. During pregnancy fetal RBCs are separated from mother’s circulation by a layer of cell in placenta called trophoblast. During her 1st pregnancy with Rh+ve fetus, mother circulation is not exposed to enough fetal RBC to activate Rh specific B cells for antibody production. 18-05-2020 25

26. Contd… At the time of delivery, large amount of fetal umbilical cord blood enter to mother’s circulation. These fetal blood activates mother Rh specific B cells resulting in production of plasma cell and memory cell. The plasma cell produce IgM antibodies which binds and destroy fetal RBCs from mother’s circulation but the memory cell remains which threat any subsequent pregnancy with Rh+ve fetus . Activation of memory cells in subsequent pregnancy with Rh+ve fetus causes production of IgG antibodies which can cross placenta and destroy fetal RBCs. 18-05-2020 26

27. Contd… Mild to severe anemia develops in fetus and sometime fetal. The conversion of hemoglobin to billirubin produces additional threat to new born because billirubin may accumulate in brain and damage it . This hemolytic disease of new born can be prevented by injecting preformed antibodies against Rh antigen to mother at around 28 weeks of pregnancy and within 24-48 hours of 1st The antibodies marketed as Rhogam. These antibodies bind to RBCs of fetus in mother circulation and clear before B cell activation. 18-05-2020 27

28. 3. Drug induces hemolytic anemia Certain drugs such as penicillin, cephalosporin and streptomycin can absorb non-specifically to protein on surface of RBC forming complex similar to hepten-carrier complex . In some patients these complex induce formation of antibodies, which binds to drugs on RBC and induce complement mediated lysis of RBC and thus produce progressive anemia . This drug induced hemolytic anemia is an example of Type II hypersensitivity reaction. 18-05-2020 28

29. TYPE III HYPERSENSITIVITY REACTION: factor causing immune complex formation, mechanism & types The reaction of antibody with antigen generates immune complex. In most of the cases, these immune complexes are removed from blood circulation. Some immune complexes are removed by phagocytic action of phagocytic cells in blood. Most other immune complexes are first carried by blood to spleen where they are destroyed by macrophages. Complement system is also needed for removal of immune complexes from blood to spleen . In some cases large amount of immune complexes are formed and deposited on various body parts and leads to tissue damage resulting in Type III hypersensitivity reaction. 18-05-2020 29

30. Contd… If immune complexes are not removed from blood, they accumulate on wall of blood vessels and on tissue where filtration of blood and plasma occurs such as glomerular membrane, synovial membrane of joints etc . Type III hypersensitivity reaction is characterized by deposition of immune complexes on various tissues such as wall of blood vessels, glomerular basement membrane of kidney, synovial membrane of joints and choroid plexus of brain . Deposition of immune complexes initiates reaction resulting in damage of surrounding tissue and cause inflammation. 18-05-2020 30

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32. Factors that causes deposition of immune complex and increase susceptibility to type III hypersensitivity reaction: 1. P ersistent infection In persistent infection such as Malaria, large number of immune complexes are formed and deposited in tissues . 2.complement defeciency Complement removes immune complexes from blood, but when complement system is deficient, large amount of immune complexes circulates in blood and deposits in tissues. 18-05-2020 32

33. 3. Autoimmunity : In autoimmune disease, large amount of immune complexes are formed and deposited in tissues . 4. Genetic defects: In certain genetic defects, small and soluble immune complexes are formed that can not be phagocytized. 18-05-2020 33

34. Mechanism of hypersensitivity reaction Type III hypersensitivity reaction develops when immune complex activates C3a and C5a components of complement system . C3a and C5a are lymph toxin (anaphylotoxin) that causes localized mast cell degranulation . Degranulation of mast cell releases histamine which increases vascular permeability of blood capillaries. This facilitates deposition of immune complexes on wall of blood vessel . C5a, C3a and C5b67 also acts as chemotatic factors for neutrophils, So it attracts neutrophils at the site of immune complex deposition . C3b acts as opsonin by binding with immune complex. Neutrophil binds to C3b coated immune complex by means of type I complement receptor which is specific for C3b. 18-05-2020 34

35. Contd… The neutrophils attempt to phagocytose the immune complex but phagocytosis is not possible because immune complexes are deposited on basement membrane, so the neutrophil releases lytic enzymes to destroy immune complex. The lytic enzymes cause tissue damage surrounding of immune complex deposits, resulting hypersensitivity reaction. Furthermore complement proteins can also contribute to tissue destruction. 18-05-2020 35

36. Types of hypersensitivity reaction 1. localozed type III hypersensitivity reaction Acute Arthus reaction is an example of localized Type III hypersensitivity reaction . When antigen is injected or enters intradermally or subcutaneously, they bind with antibody to form localized immune complexes which mediate acute Arthus reaction within 4 to 8 hours . As the reaction develops, localized tissue damage and vascular damage results in accumulation of fluids (edema) and RBCs (erythema) at the site of antigen entry . The severity of reaction can vary from mild swelling and redness to tissue necrosis. 18-05-2020 36

37. 2. Generalized type III hypersensitivity reaction Serum sickness is an example of generalized Type III hypersensitivity reaction . When large amount of antigen enter blood stream and bind to antibody, circulating immune complexes forms. If antigens are in significantly excess compared to antibody, the immune complexes formed are smaller and soluble which are not phagocytosed by phagocytic cells leading to Type III hypersensitivity reaction . The manifestation of serum sickness depends on the quantity of immune complex as well as overall site of deposition. The site may vary but accumulation of complexes occurs at site of blood filtration . Generalized Type III hypersensitivity reaction at different site results in different diseases such as Glomerulonephritis (Kideny), vacuities (arteries), Arthritis (synovial joints). 18-05-2020 37

38. Type IV hypersensitivity reaction or Delayed type hypersensitivity (DTH) Type IV hypersensitivity reaction is also known as delayed type hypersensitivity (DTH ). When some subpopulation of activated T helper cells encounters certain antigen, they secrete cytokines that induce a localized inflammatory reaction called delayed type hypersensitivity (DTH). The reaction is characterized by influxes of non-specific inflammatory cells particularly macrophages . DTH occurs slowly and reaches a peak level within 48-72 hours after 2nd encounter of antigen . In DTH tissue damage is mediated by Th cells and macrophages but not by antibodies . Although DTH causes some tissue damage, it is very important defense mechanism against intracellular microorganisms such as Mycobacterium tuberculosis, Mycobacterium leprae, Brucella spp, etc. 18-05-2020 38

39. DTH occurs in two phases 1. Sensitization of DTH DTH begins with initial sensitization by primary contact with antigen. At first antigen is processed and presented by antigen presenting cells (APCs) to CD4+T cell . CD4 +T cells are activated to form TH cells . During this TH cells are clonally expanded by binding with MHC-II molecule carrying antigen by appropriate APCs. Varieties of APCs have been shown to be involved in activation of DTH response including langerhans cell and macrophages . CD4+ T cell are the primary cell activated during sensitizing phase of DTH response. However in some cases CD8 + cells are also found to induce DTH response. 18-05-2020 39

40. 2. Effector phase of DTH A subsequent or second time exposure to antigen induces the effector phage . In this phase, TH1 cell secretes varieties of cytokines that recruits and activates macrophages and other non-specific inflammatory cells to the site of antigen injection . Macrophages are the principle effector of DTH response. The activated macrophages exhibit increased level of phagocytosis and increased ability to kill the antigen (microorganisms) by various cytotoxic lytic enzymes . Activated macrophages releases lytic enzymes that damage surrounding tissues and intracellular bacteria . The influx and activation of macrophages in DTH is important in host defense against intracellular bacteria and parasite, where circulating antibodies cannot reach them. 18-05-2020 40

41. Contd… Increased phagocytic activity and build up lytic enzyme from macrophages in the area of infection leads to non-specific destruction of tissues and intracellular pathogens . Generally pathogens are killed rapidly with little tissue damage. However in some case, especially if the antigen is not easily cleared, a pro-long DTH response can itself become destructive to host as intensive and chronic inflammation develops into a visible granulomatous reaction . A granuloma develops when continuous activation of macrophages induces the epitheloid shape and some time fusion of macrophages to form multinucleated giant cells. These giant cells displace normal cells forming palpable nodules and release high concentration of lytic enzymes which destroy surrounding tissues leading to necrosis 18-05-2020 41

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43. Examples of type IV hypersensitivity reaction Tuberculin skin test (Mantoux test) Lepromin test Brucellergin test 18-05-2020 43

44. Summary 18-05-2020 44

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