Hypersensitivity reactions. Immune responses which are damaging rather than helpful to the host.

Transcription

1 Hypersensitivity reactions. Immune responses which are damaging rather than helpful to the host. 1

2 Hypersensitivity reaction depends on: 1) chemical nature of allergen 2) route involved in sensitization ie inhalation, ingestion, injection 3) physiological state of individual / genetic potential 2

3 Hypersensitivity reactions can occur in response to three different types of antigen: Infectious agents the resultant disease is a type of hypersensitivity. Environmental substances Hypersensitivity can occur in response to harmless environmental antigens-one example of this is allergy. For example, in hay fever, grass pollens themselves are incapable of causing damage; it is the immune response to the pollen that causes harm. Self antigens. hypersensitivity cause autoimmune disease 3

4 TYPES OF TRIGGERS FOR HYPERSENSITIVITY: 1-Hypersensitivity to Infectious Agents Not all infections are capable of causing hypersensitivity reactions. For example, although the common cold elicits a strong immune response, this never appears to cause harm. Other respiratory viruses, for example, influenza can cause hypersensitivity Influenza virus damages epithelial cells in the respiratory tract, but can sometimes elicit an exaggerated immune responses, which is far more damaging than the virus itself. Influenza can trigger high levels of cytokine secretion-sometimes referred to as a cytokine storm. The cytokines attract leukocytes to the lungs and trigger vascular changes leading to hypotension and coagulation. In severe influenza inflammatory cytokines also spill out into the systemic circulation, causing ill effects in remote parts of the body, for example, the brain This is analogous to the cytokine response seen in septic shock, which also leads to a type of cytokine storm. Hepatitis B virus infection can result in chronic hepatitis in some individuals The response depends on the infecting dose of virus and the immune response genes of the individual. Another very different example of an infection causing hypersensitivity is immune complex disease caused by streptococci. 4

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6 2-Hypersensitivity to Environmental Substances For environmental substances to trigger hypersensitivity reactions, they must be fairly small in order to gain access to the immune system. Dusts trigger off a range of responses because they are able to enter the lower extremities of the respiratory tract, an area that is rich in adaptive immune response cells. These dusts can mimic parasites and may stimulate an antibody response. If the dominant antibody is immunoglobulin E (IgE), they may subsequently trigger immediate hypersensitivity, which is manifest as allergies such as asthma or rhinitis. If the dust stimulates IgG antibodies, it may trigger off a different kind of hypersensitivity, for example, farmer's lung (associated with intense or repeated exposure to inhaled biologic dusts) Smaller molecules sometimes diffuse into the skin, and these may act as haptens, triggering a delayed hypersensitivity reaction. This is the basis of contact dermatitis caused by nickel, 6

7 Drugs administered orally, by injection, or onto the surface of the body can elicit hypersensitivity reactions mediated by : IgE or IgG antibodies or by T cells. Immunologically mediated hypersensitivity reactions to drugs are very common and even very tiny doses of drug can trigger life-threatening reactions. These are all classified as idiosyncratic (distinctive) adverse drug reactions...this is not an allergy!! Allergy should not be referred to any hypersensitivity reaction to exogenous substances. Allergy mean any altered reaction to external substances. Allergen:the antigens that give rise to immediate hypersensitivity Atopy:the genetic predisposition (tendency) to synthesize inappropriate levels of IgE specific for external allergens (immediate hypersensitivity reaction to environmental antigens, mediated by IgE) 7

8 3-Hypersensitivity to Self Antigens A degree of immune response to self antigens is normal and is present in most people. When these become exaggerated or when tolerance to other antigens breaks down, hypersensitivity reactions can occur This is autoimmune disease. 8

9 Hypersensitivity reactions originally divided into 2 categories: immediate and delayed In 1968 Coombs & Gell defined the 4 types used today based on the mechanisms involved and time taken for the reaction. Type I: classical immediate hypersensitivity Type II: cytotoxic hypersensitivity Type III: immune-complex mediated hypersensitivity Type IV: cell mediated or delayed hypersensitivity 9

10 TYPES OF HYPERSENSITIVITY REACTION 10

11 Each type of hypersensitivity reaction produces characteristic clinical disease whether the trigger is an environmental, infectious, or self antigen. For example, in type III hypersensitivity, the clinical result is similar whether the antigen is streptococcus, a drug, or an autoantigen, such as DNA. Hypersensitivity reactions are reliant on the adaptive immune system. Previous exposure to antigen is required to prime the adaptive immune response to produce IgE (type I), IgG (types II and III), or T cells (type IV). Because previous exposure is required, As hypersensitivity reactions do not take place when an individual is first exposed to antigen. In each type of hypersensitivity reaction, the damage is caused by different aspects of the adaptive and innate systems. 11

12 Type I hypersensitivity (immediate hypersensitivity ) Mediated through the degranulation of mast cells and eosinophils. The effects are felt within minutes of exposure. This type of hypersensitivity is sometimes referred to as immediate hypersensitivity and is also known as allergy. Type II hypersensitivity (Bound Antigen) Caused by IgG reacting with antigen present on the surface of cells. The bound Ig then interacts with complement or with Fc receptor on macrophages. These innate mechanisms then damage the target cells using processes that may take several hours, as in the case of drug-induced hemolysis. Type III (immune complex ) IgG is also responsible for type III hypersensitivity. In this case, immune complexes of antigen and antibody form and either cause damage at the site of production or circulate and cause damage elsewhere. Immune complexes take some time to form and to initiate tissue damage Poststreptococcal glomerulonephritis is a good example of immune complex disease. Type IV (delayed hypersensitivity) The slowest form of hypersensitivity is that mediated by T cells (type IV hypersensitivity). This can take 2 to 3 days to develop and is referred to as delayed hypersensitivity. 12

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14 DIAGNOSIS AND TREATMENT OF HYPERSENSITIVITY There are major differences in how the types of hypersensitivity reaction are diagnosed and treated. For example, although skin tests are used to diagnose both type I and type IV hypersensitivity, the exact type of testing depends on the type of disease suspected. Treatment for each type of hypersensitivity is also very different. A criticism of the Coombs and Gell classification system many diseases are caused by an overlap of different types of hypersensitivity. However, some knowledge of the classification system makes it easier to understand how the different disorders come about and how they can be effectively diagnosed and treated. 14

15 TYPES OF HYPERSENSITIVITY The four types of hypersensitivity are: 1. Type I Hypersensitivity- IgE mediated 2. Type II Hypersensitivity- Antibody mediated 3. Type III Hypersensitivity- immune complex 4. Type IV Hypersensitivity- cell mediated The first three are mediated by antibody, the fourth by T cells. 15

16 Immediate Hypersensitivity (Type I): Allergy A hypersensitivity due to excessive production of IgE. Reactions between allergens and IgE bound to mast cells and basophils cause a greatly heightened inflammatory response. es/multimedia/uploads/immunology/ type1.swf 16

17 Type I: Immediate hypersensitivity Occur within 10-30min and resolve quickly Common among population in developed nations Mediated by serum IgE Systemic and regional tissue dysfunction * An antigen reacts with cell fixed antibody (Ig E) Genetic predisposition leading to release of soluble molecules An antigen (allergen) soluble molecules (mediators) * Soluble molecules cause the manifestation of disease * Systemic life threatening; anaphylactic shock * Local atopic allergies; bronchial asthma, hay fever and food allergies 17

18 Type- I Hypersensitivity: Production of IgE in Response to an Allergen 18

19 Allergen : Pathogenic mechanisms pollen dust mite Insects * First exposure to allergen Allergen stimulates formation of antibody (Ig E type) IgE fixes, by its Fc portion to mast cells and basophiles * Second exposure to the same allergen It bridges between Ig E molecules fixed to mast cells leading to activation and degranulation of mast cells and release of mediators 19 etc selectively activate CD4+Th2 cells and B cells Allergen and its production IgE: mainly produced by mucosal B cells in the lamina prapria special affinity to the same cell IL-4 is essential to switch B cells to IgE production High affinity receptor of the IgE on mast cell and basophil Eosinophil

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21 Type- I Hypersensitivity: Allergen Interaction with IgE on the Surface of Mast Cells Triggers the Release of Inflammatory Mediators 21

22 MECHANISM OF ACTION BASIC ELEMENTS ARE: 1. MEDIATOR = IgE 2. PRIMARY CELLULAR COMPONENT = MAST CELL AND BASOPHILS 3. AMPLIFIER = PLATELETS, NEUTROPHILS AND EIOSINOPHILS 22

23 MECHANISM OF ACTION 23

24 MECHANISM OF ACTION STEP 1: EXPOSURE OF ANTIGEN TO ANTIGEN PRESENTING CELL STEP 2: RECOGNITION BY T- HELPER CELLS ACTIVATION OF B-CELLS INTO PLASMA AND MEMORY CELLS SECRETION OF ANTIBODIES (IgE) 24

25 STEP 3: IgE BINDS TO HIGH AFFINITY RECEPTORS (FC EPSILON-RI FceRI ) ON THE SURFACE OF MAST CELLS STEP 4: SUBSEQUENT EXPOSURE OF ANTIGEN STEP 5: ANTIGEN BINDS WITH IgE ON THE SURFACE OF MAST CELLS RELEASE OF PRIMARY INFLAMMATORY METABOLTES ACTIVATION OF SECONDARY METABOLITES 25

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28 Effect stage: Immediate/early phase response: Mediated by histamine Start within seconds Last several hours Late-phase response : Mediated by new-synthesized lipid mediators Take up 8-12hours to develop Last several days 28

29 Pathogenic mechanisms * Three classes of mediators derived from mast cells: 1) Preformed mediators stored in granules (histamine) 2) Newly sensitized mediators: leukotrienes, prostaglandins, platelets activating factor 3) Cytokines produced by activated mast cells, basophils e.g. TNF, IL3, IL-4, IL-5 IL-13, chemokines These mediators cause: increase smooth muscle contraction, mucous secretion and bronchial spasm, vasodilatation, increase vascular permeability 29 and edema

30 MECHANISM OF ACTION MOLECULE HISTAMINE SEROTONIN ECF-A NCF-A PROTEASES LEUKOTRIENES PROSTAGLANDINS BRADYKININ CYTOKINES PRIMARY MEDIATORS EFFECTS VASCULAR PERMEABILITY, SMOOTH MUSCLE CONTRACTION VASCULAR PERMEABILITY, SMOOTH MUSCLE CONTRACTION EOSINOPHIL CHEMOTAXIS NEUTROPHIL CHEMOTAXIS MUCUS SECRETION, CONNECTIVE TISSUE DEGRADATION SECONDARY MEDIATORS VASCULAR PERMEABILITY, SMOOTH MUSCLE CONTRACTION VASCULAR PERMEABILITY, SMOOTH MUSCLE CONTRACTION AND PLATELET ACTIVATION VASCULAR PERMEABILITY, SMOOTH MUSCLE CONTRACTION NUMEROUS EFFECTS INC. ACTIVATION OF VASCULAR ENDOTHELIUM, EOSINOPHIL RECRUITMENT AND ACTIVATION 30

31 SPECIAL NOTES The reactions, mediated by agents without IgEallergen interaction, are not hypersensitivity reactions although they produce the same symptoms. 31

32 Common disease of type I hypersensitivity 1. Systemic anaphylaxis: a very dangerous syndrome 1) Anaphylactic drug allergy :penicillin 2) Anaphylactic serum allergy 2. Respiratory allergic diseases : 1) Allergic asthma:acute response, chronic response 2) Allergic rhinitis 3. Gastrointestinal allergic diseases : The lack of SIgA protein hydrolase Undigested protein Allergen 4. Skin allergy: 32

33 Anaphylaxis * Systemic form of Type I hypersensitivity * Exposure to allergen to which a person is previously sensitized * Allergens: Drugs: penicillin Serum injection : anti-diphtheritic or anti-tetanic serum anesthesia or insect venom * Clinical picture: Shock due to sudden decrease of blood pressure, respiratory distress due to bronhospasm, cyanosis, edema, urticaria * Treatment: corticosteroids injection, epinephrine, antihistamines 33

34 Atopy * Local form of type I hypersensitivity * Exposure to certain allergens that induce production of specific Ig E * Allergens : Inhalants: dust mite faeces, tree or pollens, mould spor. Ingestants: milk, egg, fish, choclate Contactants: wool, nylon, animal fur Drugs: penicillin, salicylates, anesthesia insect venom * There is a strong familial predisposition to atopic allergy * The predisposition is genetically determined 34

35 Respiratory allergic diseases: Asthma & Rhinitis In Asthma -inhaled allergens stimulate mast cells in the nasal mucosa. -then vasodilation and edema in the nose, causing nasal stuffiness and sneezing. -in the lungs, leukotrienes cause smooth muscle contraction, which has the most dramatic effects on airflow reduction In allergic rhinitis - Leukotrienes increase mucus secretion, which causes the discharge that is characteristic of allergic rhinitis. 35

36 Methods of diagnosis 1) History taking for determining the allergen involved 2) Skin tests: Intradermal injection of battery of different allergens A wheal and flare (erythema) develop at the site of allergen to which the person is allergic 3) Determination of total serum Ig E level 4) Determination of specific Ig E levels to the different allergens 36

37 Management 1) Avoidance of specific allergen responsible for condition 2) Hyposensitization: Injection gradually increasing doses of extract of allergen - production of IgG blocking antibody which binds allergen and prevent combination with IgE - It may induce T cell tolerance Desensitization induces IgG antivenom antibodies. 3) Drug Therapy: corticosteroids injection, epinephrine, antihistamines 37

38 TREATMENT 1. ANTIHISTAMINES 2. Corticosteroids 3. Chromolyn sodium 4. leukotriene receptor blockers 5. use of IgG antibodies Drug treatment for allergy. 38

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40 THE CYTOTOXIC HYPERSENSITIVITY TYPE 2 HYPERSENSITIVITY A hypersensitivity resulting from antibodies mistakenly reacting with normal self antigens on body cells. Binding of the antibodies to these normal cells results in immune destruction 40

41 Type II: Cytotoxic or Cytolytic Reactions Primed IgG or IgM + Antigen or hapten on membrane Injury and dysfunction of target cells 41

42 Surface antigen on target cells Target cells: Normal tissue cell, changed or modified self tissue cells Antigen: Blood group antigen, Common antigen, Drug antigen, Self-antigen modified by physical factors or infection Antigen-antibody complex Antibody, complement and modified self-cell Activate complement Opsonic phogacytosis Mf NK T Stimulating or blocking effect Lyse target cells Destroy target cells Antibody depended cellular cytotoxicity (ADCC) Promote /surpress the target cell funcion 42

43 cytotoxic type_ii_hypersensitivity_.html 43

44 MEDIATORS IgG OR IgM IN THIS CASE 1. MADE AGAINST SELF ANTIGENS 2. ATTACH TO THE SURFACES OF CELLS HAVING SELF EPITOPS SELF ANTIGEN=Any constituent of the body's own tissues capable of stimulating autoimmunity FACTORS FOR RELEASE OF MEDIATORS 1. FAILURE IN IMMUNE TOLERANCE 2. ENTERANCE OF FOREIGN ANTIGEN RESEMBLING SOME MOLECULE ON THE SURFACE OF HOST CELLS 'IMMUNE TOLERANCE' is the process by which the immune system does not attack an antigen THESE FACTORS LEAD TO: 1. OPSONIZATION 2. MAC LYSIS 3. ADCC 44

45 45 OPSONIZATION MECHANISM The attachment of microbes and other foreign cells to phagocytes by antibody molecules such as IgG and complement proteins such as C3b. Also called enhanced attachment or immune adherence. THE OPSONIZATION IS OF THE HOST CELL PHAGOCYTES STICK TO MEMBRANES OF HOST CELL VIA IgG, C3B, C4B PHAGOCYTES DISCHARGE THEIR LYSOSOMES RESULT: LYSIS OF HOST CELL

46 MAC LYSIS MECHANISM A protein complex produced during the complement pathways. C5b6789 (MAC or membrane attack complex) puts pores into lipid bilayer membranes of human cells to which antibodies have bound. This results in cell lysis. IgG / IgM BINDS WITH EPITOPS ON CELL SURFACES ACTIVATE CLASSICAL PATHWAY OF COMPLEMENT SYSTEM MAC CAUSES LYSIS OF CELL 46

47 ADCC Antibody depended cellular cytotoxicity MECHANISM The process of NK cells binding to the Fc portion of antibodies that have bound to epitopes of cells recognized as nonself such as infected cells and tumor cells. Once bound to the Fc portion of the antibody, the NK cell will then lyse that cell with perforins. IgG / IgM BINDS WITH EPITOPS ON CELL SURFACES NK CELLS ATTACH TO THE Fc PORTION OF IgG/IgM edu/courses/bio141/le cguide/unit5/hypersen sitivity/type2/adcctii.ht ml RELEASE OF PERFORINS AND GRANZYMES BY NK APOPTOSIS es/bio141/lecguide/unit5/hyperse nsitivity/type2/adccapop.html 47

48 Mechanism of Cytolysis * Cell lysis results due to : 1) Phagocytosis is enhanced by the antibody (opsinin) bound to cell antigen leading to opsonization of the target cell 2) Complement fixation to antigen antibody complex on cell surface The activated complement will lead to cell lysis 3) Antibody depended cellular cytotoxicity (ADCC): - Antibody coated cells e.g. tumour cells, graft cells or infected cells can be killed by cells possess Fc receptors - The process different from phagocytosis and independent of complement - Cells most active in ADCC are: NK, macrophages, neutrophils and eosinophils 48

49 cytotoxic type_ii_hypersensitivity_.html 49 Antigen or hapten on cell Antibody (IgG, IgM) Activate complement Opsonic phagocytosis NK, phagocyte Stimulate / block Lyse target cell Destroy target cell ADCC Target cell injury Change the function oftarget cell Mechanism of Type II hypersensitivity

50 Clinical Conditions 1) Transfusion reaction due to ABO incompatibility 2) Rh-incompatability (Haemolytic disease of the newborn) 3) Autoimmune diseases The mechanism of tissue damage is cytotoxic reactions e.g. SLE, autoimmune haemolytic anaemia, idiopathic thrombocytopenic purpura, myasthenia gravis, nephrotoxic nephritis, Hashimoto s thyroiditis 4) A non-cytotoxic Type II hypersensitivity is Graves s disease It is a form of thyroditits in which antibodies are produced against TSH surface receptor This lead to mimic the effect of TSH and stimulate cells to over- produce thyroid hormones 5- Graft rejection cytotoxic reactions: In hyperacute rejection the recipient already has performed antibody against the graft 6- Drug reaction: Penicillin may attach as haptens to RBCs and induce antibodies which are cytotoxic for the cell-drug complex leading to haemolysis Quinine may attach to platelets and the antibodies cause platelets destruction and thrombocytopenic purpura 50

51 Type II Hypersensitivity: Drug-Induced Hemolysis Anaphylactic drug allergy : penicillin 51

52 DIAGNOSTIC TESTS 1. DETECTION OF CIRCULATING ANTIBODY AGAINST THE TISSUES INVOLVED 2. THE PRESENCE OF ANTIBODY AND COMPLEMENT IN THE LESION (BIOPSY) BY IMMUNOFLUORESCENT STAINING TREATMENT ANTI-INFLAMMATORY DRUGS IMMUNOSUPPRESSANT DRUGS 52