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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 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 are antibody mediated * Type IV is cell mediated

Type I: Immediate hypersensitivity:

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

Pathogenic mechanisms:

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 cellsleading to activation and degranulation of mast cells and release of mediators

Pathogenic mechanisms:

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


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 bronhospasm , 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 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

Methods of diagnosis:

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

Management :

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:

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

Mechanism of Cytolysis:

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:

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

Clinical Conditions:

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 disea 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:

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

Type III Hypersensitivity Immune Complex Mediated Reaction:

Type III Hypersensitivity Immune Complex Mediated Reaction

Type III: 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

Mechanism Of Tissue Injury:

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:

Clinical conditions of Type III Hypersensitivity Diseases produced by immune complexes are those in which antigens persists without being eliminated as: a- Repeated exposure to extrinsic antigen b- injection of large amounts of antigens c- Persistent infections d- Autoimmunity to self components

1- Arthus Reaction:

1- Arthus Reaction * This is a local immune complex deposition phenomenon 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 :

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 antidiphtheritic serum e.g. treatment with penicillin sulphonamides

Type III Hypersensitivity Clinical Conditions:

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

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Type IV Cell Mediated Delayed Type Hypersensitivity

Type IV: Cell Mediated Delayed Type Hypersensitivity:

Type IV: Cell Mediated Delayed Type Hypersensitivity 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:

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:

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 Dermatitis * Contact of skin with chemical substances or drugs e.g. poison, hair dyes, cosmetics, soaps, neomycin * 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:

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

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