hypersensitivity reactions

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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 reactions – originally divided into 2 categories: immediate and delayed In 1968 Coombs & Gell defined the 4 types used today:

Hypersensitivity reactions – originally divided into 2 categories: immediate and delayed In 1968 Coombs & Gell defined the 4 types used today Type I : classical immediate hypersensitivity Type II : cytotoxic hypersensitivity Type III : immune-complex mediated hypersensitivity Type IV :cell mediated or delayed hypersensitivity

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 basophils * 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


Mechanism: Allergen Plasma cell B m Th cell B cell TCR CD4 IL-4 MHC-I I IgE mast cell Sensitized Fc  R mast cell Degranulation Allergen Smooth muscle cell, Small blood vessel, Mucous gland, Blood platelets, Sensory nerve endings, Eosinophil .

Pathogenic mechanisms:

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: smooth muscle contraction, mucous secretion and bronchial spasm, vasodilatation, vascular permeability and edema

Principal mediators involved in type I hypersensitivity:

Principal mediators involved in type I hypersensitivity Mediator Activities Primary 1. Histamine: Increased vascular permeability ; Smooth muscle contraction. 2. Serotonin: Increased vascular permeability; Smooth muscle contraction. 3. Eosinophil chemotactic factor: (ECF-A) Eosinophil chemotaxis 4. Neutrophil chemotactic factor: (NCF-A) Neutrophil chemotaxis 5. Proteases: Degradation of blood-vessel basement membrane ; Generation of complement split product s .

Principal mediators involved in type I hypersensitivity:

Principal mediators involved in type I hypersensitivity Mediator Activities Secondary 1. Platelet-activating Platelet aggregation and Factor:(PAF) degranulation . Contraction of pulmonary smooth muscles. 2. Leukotrienes : Increased vascular permeability; ( SRS-A) Contraction of pulmonary smooth muscles . 3. Prostaglandins: Vasdilation ; Contraction of pulmonary smooth muscles . Platelet aggregation. 4. Brady Kinin : Increased vascular permeability; Smooth-muscles contraction.


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 spore. Ingestants : milk, egg, fish, chocolate Contactants : wool, nylon, animal fur Drugs : penicillin, salicylates , anesthesthetics , 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- Radioimmunosorbent test ( RIST) 4) Determination of specific Ig E levels to the different allergens- Radioallergosorbent test (RAST)

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Skin test

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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

Mechanism of type II:

Mechanism of type II Cytotoxic action (ADCC) Target cell NK Cell-surface Ag Fc IgG 1 . Target cell Complement mediated lysis Antibody C 2 . Phagocyte 3. CR

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 : Graves’s disease - 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:

Type III Hypersensitivity IMMUNE COMPLEX DISEASE Localized reactions ( Arthus Reaction )- I/C deposits in tissue near site of Ag entry Systemic reactions ( Serum Sickness )- I/C forms & circulate in blood, deposits in various organs.

The Arthus reaction :

The Arthus reaction Maurice Arthus found that injection of soluble antigen intradermally into hyperimmunized rabbits with high levels of precipitating antibody produced an erythematous and edematous reaction reaching a peak at 3-8 hours which then usually resolved. The lesion was characterized by an intense infiltration with neutrophils & Anaphylatoxin production.

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Arthus Reakn

Pathogenic mechanism:

Pathogenic mechanism I/C activate Complement system Split products-C3a, C4a,C5a are anaphylatoxins Cause localized Mast Cell degranulation vascular permeability-influx of fluid C3a, C4a, C5b67-Chemotactic for Neutophils Neutrophils attempt to phagocytose C3b coated I/C. Release of proteolytic enzymes-neutral proteinases and collagenase , kinin -forming enzymes, polycationic proteins and reactive oxygen and nitrogen intermediates

Pathogenic mechanism:

Pathogenic mechanism Complement activation leads to aggregation of Platelets release of clotting factors Formation of Microthrombi - Necrosis Eg of Local Type III I/C disease Farmer’s lung- prolong exposure to spores of thermophilic actinomycetes growing in hay.

Serum Sickness:

Serum Sickness Clinical features 7 days post exposure to foreign sera Fever Weakness Generalized vasculitis with edema & erythema -Rash Lymphadenopathy Arthritis Glomerulonephritis .

Serum Sickness:

Serum Sickness Large amount of Ag enter blood stream binds to Antibodies forming I/C. Antigen excess-small soluble I/C forms- not easily phagocytose by Macrophages. Circulating I/C deposits in places where plasma filtration takes place. Basement membrane of blood vessel- Vasculitis Glomerular BM- Glomerulonephritis Synovial membrane- Arthritis

Generalized I/C disease:

Generalized I/C disease Autoimmune disease SLE Rheumatoid Athertis Drug Penicillin Sulphonamides Infectious disease Post Streptococcal glomerulonephrits Hepatitis B Malaria

TYPE IV hypersensitivity:

TYPE IV hypersensitivity Delayed type Hypersensitivity or Cell Mediated Hypersensitivty Develops after 48-72 hrs of second exposure to antigen in a sensitized individual. Some subpopulations of activated T H cells encounter certain types of antigens, they secrete cytokines that induce a localized inflammatory reaction- delayed-type hypersensitivity (DTH). The reaction is characterized by large influxes of nonspecific inflammatory cells, macrophages.

PHASES of DTH response:

PHASES of DTH response Sensitization phase Activation of T H cells by APC- Langerhans cells & Macrophages Proliferation T H 1 subtype occurs. Effector phase T H 1 secrete cytokines – INF gamma, IL2, TNF β Recruitment & activation of Macrophages


DTH The heightened phagocytic activity and the buildup of lytic enzymes from macrophages in the area of infection lead to nonspecific destruction of cells and thus of the intracellular pathogen .


DTH A prolonged DTH response leads to destructive inflammatory response with development of granulomatous reaction. A granuloma develops by continuous activation of macrophages. Giant cells displace the normal tissue cells, forms palpable nodules, and release high concentrations of lytic enzymes, which destroy surrounding tissue.


CONTACT DERMATITIS Contact-dermatitis reactions to formaldehyde, trinitrophenol , nickel, turpentine, and active agents in various cosmetics and hair dyes, poison oak, and poison ivy are mediated by TH1 cells. Most of these substance are haptens that can complex with skin proteins.

Contact Dermatitis:

Contact Dermatitis

Contact dermatitis:

Contact dermatitis Approximately 48–72 h after the second exposure, the secreted cytokines cause macrophages to accumulate at the site. Activation of these macrophages and release of lytic enzymes result in the redness and pustule

Gell and Coombs classification of hypersensitivity reaction:

Gell and Coombs classification of hypersensitivity reaction Type Description Time Mechanism, Typical manifestation Type I IgE -mediated 2-3min Ag induce cross-linkage Systemic anaphylaxis hypersensitivity of IgE bound to mast cells Localized anaphylaxis: or basophils with release -Hay fever, Asthma, of vasoactive mediators Hives, Food Allergy Eczema. Type II Ab -mediated 5-8h Ab directed against cell- Blood-transfusion cytotoxic surface Ags mediates cell reactions. hypersensitivity destruction via C activation Erythroblastosis fetalis Autoimmune hemolytic anemia.

Gell and Coombs classification of hypersensitivity reaction:

Gell and Coombs classification of hypersensitivity reaction Type Description Time Mechanism Typical Manifestations TypeIII Immune complex 2-8h Ag- Ab complexes Localized Arthus -mediated deposited in various reaction hypersensitivity tissues induce C acti - Generalized reactions: vation and an ensuing Serum sickness, inflammatory response Glomerulonephritis Rheumatoid arthritis SLE Delayed reactions Type IV cell-mediated 24-72h Sensitized T DTH cells Contact dermatitis, hypersensitivity release cytokines that Tubercular lesions, activation M  or Tc , Graft rejection. which mediate direct cellular damage.


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