Hypersensitivity Reactions PDF

Hypersensitivity Reactions Immunologic Mechanisms of Tissue Damage (Immuopathology)  Immunopathology Exaggerated immune response may lead to different forms of tissue damage 1) An overactive immune response: produce more damage than it prevents e.g. hypersensitivity...

Hypersensitivity Reactions Immunologic Mechanisms of Tissue Damage (Immuopathology)  Immunopathology Exaggerated immune response may lead to different forms of tissue damage 1) An overactive immune response: produce more damage than it prevents e.g. hypersensitivity reactions and graft rejection 2) Failure of appropriate recognition: as in autoimmune diseases  Hypersensitivity Reaction Hypersensitivity or allergy * An immune response results in exaggerated reactions harmful to the host * There are four types of hypersensitivity reactions: Type I, Type II, Type III, Type IV * Types I, II and III which are antibody mediated * Type IV is cell mediated  Type I: Immediate hypersensitivity Occurs in atopic persons. Occurs in response to environmental antigens (e.g., allergens) or administered antigens (e.g., penicillin). Is mediated by IgE (reaginic) antibody bound to the surface of mast cells or basophils. May be localized or systemic.  Type I: Immediate hypersensitivity * An antigen reacts with cell fixed antibody (Ig E) 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  IgE in immediate hypersensitivity is produced in response to environmental antigens. binds by the Fc portion of IgE to mast cells or basophils. causes release of vasoactive and chemotactic factors from mast cells upon cross-linking of antigen on the surface. can also be measured for specific idiotypes  Pathogenic mechanisms * First exposure to allergen Allergen stimulates formation of antibody (Ig E type) Ig E 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  Pathogenic mechanisms * Three classes of mediators derived from mast cells: !) 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: smooth muscle contraction, mucous secretion and bronchial spasm, vasodilatation, vascular permeability and edema Products released by mast cells upon stimulation of surface IgE 1. Vasoactive mediators A. Histamine causes smooth muscle contraction in bronchioles and small blood vessels and increased permeability of capillaries B. Platelet-activating factor(PAF) activates platelets. C. Slow-reacting substance of anaphylaxis (SRS-A)consists of metabolite of arachidonic acid and includes the leukotrienes D. Prostaglandins and thromboxanes products of cyclooxygenase metabolism or arachidonic acid; cause erythema and vasopermeability. These metabolites are potent inducers of smooth muscle contractility, bronchoconstriction, and increased vascular permeability. 2. Chemotactic factors Eosinophil chemotactic factor of anaphylaxis (ECF-A) causes influx of eosinophils. Neutrophil chemotactic factor has a high molecular weight is chemotactic for neutrophils.  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 ant-tetanic serum anesthesia or insect venom * Clinical picture: Shock due to sudden decrease of blood pressure, respiratory distress due to bronchospasm, cyanosis, edema, urticaria * Treatment: corticosteroids injection, epinephrine, antihistamines  Atopy * Local form of type I hypersensitivity * Exposure to certain allergens that induce production of specific Ig E * Allergens : Inhalants: dust mice faeces, tree or pollens, mould spore. 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  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  Skin tests Skin test via intra dermal injection of allergens: if an individual is allergic to the substance injected, local mast cells de granulate producing a “wheel and flare” response within minutes  Management 1) Avoidance of specific allergen responsible for condition 2) Hyposensitization: Injection gradually increasing doses of extract of allergen - production of Ig G blocking antibody which binds allergen and prevent combination with Ig E - It may induce T cell tolerance 3) Drug Therapy: corticosteroids injection, epinephrine, antihistamines Type II: Cytotoxic or Cytolytic Reactions * An antibody (Ig G or Ig M) reacts with antigen on the cell surface * This antigen may be part of cell membrane or circulating antigen (or hapten) that attaches to cell membrane  Antibody to cell-surface antigen can cause reduction in cell-surface charges. can cause opsonic adherence via the Fc region of antibody to neutrophils, macrophages, and NK cells (the cells responsible for ADCC); enhances cell phagocytosis and promotes cell death. can activate complement to cause cell lysis.  Mechanism of Cytolysis * Cell lysis results due to : 1) Complement fixation to antigen antibody complex on cell surface The activated complement will lead to cell lysis 2) Phagocytosis is enhanced by the antibody (opsinin) bound to cell antigen leading to opsonization of the target cell  Mechanism of cytolysis 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 CD8  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 Myasthenia gravis antibody to muscle acetylcholine receptors : 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  Clinical Conditions 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 7-Goodpasture's syndrome antibody to glomerular and bronchial basement membrane  Type III Hypersensitivity Immune Complex Mediated Reaction Type III: Immune Complex Mediated Reaction *When antibodies (Ig G or Ig M) and antigen coexist immune complexes are formed *Immune complexes are removed by reticuloendoth. syst. *Some immune complexes escape phagocytosis *Immune complexes deposited in tissues on the basement membrane of blood vessels and cause tissue injury  involve soluble antigen that becomes bound antigen antibody complexes, which, especially in antigen excess, can cause a series of events that lead to pathologic expression, edema, neutrophil infiltrate, and lesions in blood vessels and kidney glomeruli.  Consequences of antigen antibody complex formation Platelet aggregation, leading to formation of microthrombi and release of vasoactive amines Activation of complement and release of anaphylatoxins (causing histamine release) and chemotactic factors (for neutrophils) Clotting factor XII activation, leading to fibrin, plasmin, and kinin formation  Mechanism Of Tissue Injury Immune complexes trigger inflammatory processes: activate release 1) Immune complexes the complement anaphylatoxins C3a, C5a stimulate release degranulation of basophiles and mast cells histamine Histamine vascular permeability and help deposition of immune complexes 2) Neutrophils are attracted to the site by immune complexes and release lysosomal enzymes which damage tissues and intensify the inflammat. Pro. 3) Platelets are aggregated with two consequences a- release of histamine b- form of microthrombi which lead to ischemia Clinical conditions of Type III Hypersensitivity Diseases produced by immune complexes are those in which antigens persists without being eliminated as: Reason include a- Repeated exposure to extrinsic antigen b- injection of large amounts of antigens c- Persistent infections d- Autoimmunity to self components  Examples of type III hypersensitivity reactions 1. Arthus reaction immunization of rabbits with horse serum (classic prototype of type III reaction) 2. Farmer's lung antibody to inhaled aspergillus mold 3. Cheesemaker's lung antibody to fungi 4. Pigeon fancier's disease antibody to pigeon dander 5. Serum sickness antibody to foreign‌ immunoglobulin injection 6. Rheumatoid arthritis rheumatoid factor (IgM) against the Fc portion of self-IgG  1- Arthus Reaction * This is a local immune complex deposition phenomenon result from repeated injections of the same antigen e.g. diabetic patients receiving insulin subcutaneously edema * Local reactions in the form of erythema necrosis deposited * Immune complexes in small blood vessels vasculitis leading to microthrombi formation vascular occlusion necrosis  2- Serum Sickness * A systemic immune complex phenomenon * Injection of large doses of foreign serum * Antigen is slowly cleared from circulation * Immune complexes are deposited in various sites fever urticaria * 10 days after injection arthralgia lymphadenopathy splenomegaly glomerulonephritis e.g. treatment with corticosteroids  2- Serum Sickness it is also occur after treatment with penicillin antidiphtheritic serum sulphonamides Type III Hypersensitivity Clinical Conditions 3- Post-streptococcal glomerulonephritis glomerulitis associated with infective endocarditis 4- Hypersensitive pneumonitis (farmer lung) immune complexes depositition in lung after repeated inhalation of dust , mould spores 5- Endogenous antigen antibody complexes involved in autoimmune diseases e.g. SLE, rheumatoid arthritis  Type IV Cell Mediated Delayed Type Hypersensitivity  Type IV Is differentiated from immediate-type hypersensitivity reactions (types I, II, and III). Is an example of cell-mediated immunity types I, II, and III are mediated by antibody and are examples of humoral immunity. Sequence of events in a type IV reaction 1. An appropriate antigen (tuberculin, purified protein derivative of Mycobacterium tuberculosis, tumor cell, transplanted cell, virally transformed cell) is processed by macrophages; epitopes of antigen are expressed on the macrophage surface via class II HLAs; macrophages produce IL-1. 2. TH cells react to antigen epitope and class II antigens via TCR and CD4, respectively. 3. TH cells are also stimulated by IL-1 from macrophages. 4. TH cells produce IL-2, and IL-2 receptors become fully activated and release lymphokines, having an effect on T cells and macrophages.  Type IV: Cell Mediated Delayed Type Hypersensitivity DTH triggering DTH reactions by TH1 * T-cells cause tissue injury by or directly killing target cells by CD8 * TH1 and CD8 T cells secrete cytokines (IFN-γ and TNF) attract lymphocytes * Cytokines activate macrophages induce inflammation * Tissue damage results from products of activated macrophages  Tuberculin –Type Hypersensitivity * When PPD is injected intradermally in sensitized person * Local indurated area appears injection site (48-72 hs) * Indurations due to accumulation Of: macrophages and lymphocytes * Similar reactions observed in diseases e.g. brucellosis, lepromin test in leprosy, Frei’s test in lymphogranuloma venereum  Granulomatous lesions * In chronic diseases : T.B., Leprosy, schistosomiases * Intracellular organisms resist destruction by macrophag. * Persistent antigen in tissues stimulate local DTH reaction * Continuous release of cytokines leads to accumulation of macrophages which give rise to epitheloidal and giant cell granuloma  Contact Dermatitis * Contact of skin with chemical substances or drugs e.g. poison, hair dyes, cosmetics, soaps, neomycin and nickle salts (nickle jewellery) * These substances enter skin in small molecules * They are haptens that attached to body proteins, form immunogenic substances * DTH reaction to these immunogenic subst. lead to: eczyma inflammtory reaction of skin in rash vesicular eruption Type IV Hypersensitivity Clinical Conditions 4) Auto immune diseases and graft rejection are due to in part to delayed hypersensitivity reactions 5) Insulin dependant diabetes mellitus T-cells invade the pancreatic islets and specifically destroy insulin secreting beta cells Thanks