Types of Hypersensitivity Excessive immune response in a sensitized individual leading to tissue damage. Types of Hypersensitivity: Types I,II,III------>Immediate, Abs. Type IV ------>Delayed, T cells.

Cooms and Gell (in the early 1960s) Type I, II, III: Cooms and Gell (in the early 1960s) Type I, II, III: Ab mediated Type IV: T cell mediated TYPE I :IgE-mediated Reactions Immediate hypersensitivity TYPE II: ANTIBODY-MEDIATED CYTOTOXIC Reactions TYPE III: IMMUNE COMPLEX REACTIONS TYPE IV: T-CELL-MEDIATED, DELAYED-TYPE HYPERSENSITIVITY (DTH)

1. Basic concepts Hypersensitivity reactions are harmful antigen-specific immune responses , occur when an individual who has been primed by an innocuous antigen subsequently encounters the same antigen , produce tissue injury and dysfuntion. Allergen：the antigens that give rise to immediate hypersensitivity Atopy：the genetic predisposition to synthesize inappropriate levels of IgE specific for external allergens Types of hypersensitivity：I、II、III、IV

2. Type I hypersensitivity 1)、Characteristics 2)、Components and cells 3)、The process and mechanism 4)、Commen diseases of type I Hypersensitivity 5)、Therapy for type I Hypersensitivity

Type I Hypersensitivity Known as: Immediate hypersensitivity Anaphylaxis IgE-associated immune responses Immunreaktionen der Haut

1) Characteristics Occur and resolve quickly Mediated by serum IgE Systemic and regional tissue dysfuntion Genetic predisposition

pollen、dust mite、insects etc 2) Components and cells in Type I hypersensitivity Allergen ： pollen、dust mite、insects etc selectively activate CD4+Th2 cells and B cells Allergin（IgE）and its production IgE： mainly produced by mucosal B cells IL-4 is essential to switch B cells to IgE production Only Ab that can bind mast cells. Cross linking of IgE Fc receptors leads to Mast cell degranulation. High affinity receptor of the IgE on mast cell and basophil Eosinophil

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 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

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

Type-I Hypersensitivity: Animation II Allergen Interaction with IgE on the Surface of Mast Cells triggers the Release of Inflammatory Mediators

Summary of Mast cell activation IgE Fc Receptor Mast cells Histamine granule release activated phospholipase A2 arachidonic acid cyclo-oxygenase pathway lipoxygenase pathway histamine,proteolytic enzymes, heparin, chemotactic factors prostaglandins leukotrienes Preformed Mediators Newly Synthesized

Physiological Effects of mast cell mediators Chemo-attractants Attract neutrophils, eosinophils, monocytes and basophils NCF ECF LTB4 Y Y IgE Fc Receptor Activators Mast cells Histamine PAF Tryptase Kininogenase vasodilatation & vascular permeability Histamine and other mediators Microthrombi Activation of C Kinins-->vasodilatation spasmogens Bronchial smooth muscle contraction, mucosal oedema, mucus secretion Histamine Prostaglandins Leukotrienes

Type I Hypersensitivity Reaction

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

Type I Hypersensitivity: Systemic or Localized Systemic (Anaphylaxis shock) Symptoms include: labored breathing, drop in blood pressure, smooth muscle contraction, bronchiole constriction (suffocation) Localized Examples: Hay fever (allergic rhinitis), asthma (allergic or intrinsic), food allergies, atopic dermatitis (eczema)

Bee venom has Mellitin which can directly trigger mast cells Anaphylaxis to bee venom Bee venom has Mellitin which can directly trigger mast cells

IgE binds to the FceRI on mast cell and basophil Mechanism of type I hypersensitivity Primary Generation Allergen Individual IgE Adhesion Secondary IgE binds to the FceRI on mast cell and basophil Allergen binds to the IgE on primed target cell Crosslikage of FceRI Degranulate and release the biological mediators Preformed granule mediators New generated mediators Histamine Bradykinin Leukotrienes PAF Prostaglandin D2 Dilate capillaries,increase permeability, increase mucus secretion, contract smooth muscle Systemic anaphylaxis Skin Respiratory tract Degist tract

Non-steroidal anti-inflammatories Treatment for Type I Pharmacotherapy Drugs. Non-steroidal anti-inflammatories Antihistamines block histamine receptors. Steroids Theophylline OR epinephrine - prolongs or increases cAMP levels in mast cells which inhibits degranulation.

Desensitization (hyposensitization) also known as allergy shots. Treatment for Type I Immunotherapy Desensitization (hyposensitization) also known as allergy shots. Repeated injections of allergen to reduce the IgE on Mast cells and produce IgG.

Type II Hypersensitivity Cytotoxic or Cytolytic Reactions 1. Characteristic features 2. Mechanism of Type II Hypersensitivity 3. Common diseases of Type II Hypersensitivity

+ 1. Characteristic features Primed IgG or IgM Antigen or hapten on membrane Injury and dysfunction of target cells

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 * 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

Type II Hypersensitivity Antibody-Complement Dependent Mediated Lysis Animation: IgG or IgM reacts with epitopes on the host cell membrane and activates the classical complement pathway. Membrane attack complex (MAC) then causes lysis of the cell. Immunreaktionen der Haut

A. Opsonic phagocytosis Allergen Stimulate Antibody Cell A. Opsonic phagocytosis Combined opsonic activities D. ADCC of NK C. Effect of complement Cell injury ways of type II hypersensitivity

Type II Hypersensitivity Antibody-Complement Dependent Mediated Lysis Example: Autoimmune Hemolytic Anemia

Type II Hypersensitivity Antibody Dependent Cell Mediated Cytotoxicity Animation: Antibodies react with epitopes on the host cell membrane and NK cells bind to the Fc of the antibodies. The NK cells then lyse the cell with pore-forming perforins and cytotoxic granzymes

Drug-Induced Reactions: Adherence to Blood Components blood cell adsorbed drug or antigen drug metabolite antibody to drug complement lysis

Change the function ofTarget cell 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

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

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

Examples of drug-induced type II hypersensitivity Red cells: Penicillin, chloropromazine, phenacetin Granulocytes: Quinidine, amidopyridine Platelets: sulphonamides, thiazides

TYPE III HYPERSENSITIVITY Antigen antibody immune complexes. IgG mediated 1. Characteristics 2. Mechanism of type III hepersensitivity 3. Common disease of type III hepersensitivity

Free Ag + Primed Ab Larger immune complex 1、characteristics Free Ag + Primed Ab Larger immune complex Deposit in tissue or blood vessel wall   Inflammation

Types of immune complex disease cause antigen site of deposition persistent infection bacterial, viral, parasitic, etc. infected organ, kidney inhaled antigens mold, plant or animal antigen lung injected material serum kidney, skin, arteries, joint autoimmunity self antigen kidney, joint, arteries, skin

2、Mechanism of type III hypersensitivity Formation of the intermediate immune complex Deposition of the intermediate immune complex Tissue injury by the immune complex

Large amount of antigen and antibodies form complexes in blood. If not eliminated can deposit in capillaries or joints and trigger inflammation. PMNs and macrophages bind to immune complexes via FcR and phagocytize the complexes. BUT If unable to phagocytize the immune complexes can cause inflammation via C’ activation ---> C3a C4a, C5a and "frustrated phagocytes".

"Frustrated Phagocytes" If neutrophils and macrophages are unable to phagocytize the immune complexes these cells will degranulate in the area of immune complex deposition and trigger inflammation. Unable to eat -------try to digest outside cell. Complexing of antigen plus antibody facilitates phagocytosis and clearing of antigen Large amounts of these complexes can lead to tissue damage

Immune processes involved: “Immune complex disease” Soluble Ag/IgG or IgM high titers of each required Immune processes involved: classical complement pathway phagocytic cells

Immune complexes not cleared Activation of Complement C3a & C5a Inflammation Mast cells

Type III hypersensitivity mechanism

Type III hypersensitivity mechanism

Type II Hypersensitivity Antibody-Mediated Cell Disfunction Example: Myasthenia Gravis Immunreaktionen der Haut

TYPE III Immune Complex Disease Localized disease Deposited in joints causing local inflammation = arthritis. Deposited in kidneys = glomerulonephritis.

Arthus Reaction

Serum sickness Serum sickness from large amounts of antigen such as injection of foreign serum. Serum sickness is usually transient immune complex disease with removal of antigen source. Occurs when antigen enters bloodstream, circulating immune complexes form Symptoms include: Fever Weakness Rashes And many others

Complement initiates mast cell degranulation Neutrophils are chemotactically attracted to the site Neutrophils release lytic enzyme after failed attempts to endocytose the immune complex

Local or systemic immune complex diseases Soluble antigen Body Antibody Immune complex Small molecular soluble Immune complex intermediate molecular soluble Immune complex Large molecular insoluble Immune complex Deposit on the basement of capillaries Eliminate by phogacytosis Combine and activate complement system Basophils and mast cells Platelets C3a,C5a,C3b Infiltration of neutrophils Blood Clotting Mechanisms Release of vasoactive amine Phagocytose complex Release of vasoactive amine Aggregation of platlets Release the enzymes in lysosome Increase vascular permeability Increase vascular permeability Thrombus Edema Tissue injury Bleeding Edema Local or systemic immune complex diseases

common disease of type III hypersensitivity 1. Local immune complex disease Arthus reaction ：Experimental local reaction, Necrotic vasculitis vasculitis, Ulcer Human local reaction: insulin-dependent diabetes mellitus (IDDM) 2. Acute systemic immune complex disease    serum sickness  Anti-serum Ab+Ag systemic tissue injury ,fever, arthritis, skin rash Pinicillin、Sulfanilamide Acute immune complex glomerulonephritis : Streptococcus infection 3. Chronic immune complex disease SLE Rheumatoid arthritis ：RF+IgG Deposit on synovial membrane

5. Type IV hypersensitivity 1、characteristics of type IV hepersensitivity 2、 mechanism of type IV hepersensitivity 3、common diseases of type IV hepersensitivity

1. Characteristics Interaction of primed T cells and associated antigen Infiltration of Mononuclear Cells, Inflammatory response

2. Mechanism of type IV hypersensitivity Formation of effector and memory T cells Inflammation and cytotoxicity caused by effector T cells 1) Inflammation and tissue injury mediated by CD4+Th1 Release chemokines and cytokines Immune injury mainly caused by infiltration of mononuclear cells and lymphocytes 2) Cytotoxicity of CD8+CTL

Delayed type hypersensitivity Th1 cells and macrophages DTH response is from: Th1 cells release cytokines to activate macrophages causing inflammation and tissue damage. Continued macrophage activation can cause chronic inflammation resulting in tissue lesions, scarring, and granuloma formation. Delayed is relative because DTH response arise 24-72 hours after exposure rather than within minutes.

Stages of Type IV DTH Sensitization stage Memory Th1 cells against DTH antigens are generated by dendritic cells during the sensitization stage. These Th1 cells can activate macrophages and trigger inflammatory response.

Stages of Type IV DTH Effector stage Secondary contact yields what we call DTH. Th1 memory cells are activated and produce cytokines. IFN-g, TNF-a, and TNF-b which cause tissue destruction, inflammation. IL-2 that activates T cells and CTLs. Chemokines- for macrophage recruitment. IL-3, GM-CSF for increased monocyte/macrophage

Stages of Type IV DTH Effector stage Secondary exposure to antigen Inflamed area becomes red and fluid filled can form lesion. From tissue damage there is activation of clotting cascades and tissue repair. Continued exposure to antigen can cause chronic inflammation and result in granuloma formation.

Inflammation characterized by infiltration of Mf , monocyte, monocyte and Mf Proliferation of T cell Exudation and edema Cytotoxicity Cytokines IL-2 TNF-b INF-g TF MCF MIF MAF SRF Induce Antigen T cell (CD4+,CD8+) Release CD4+ T cell Secondary contact Primed T cell CD8+ T cell Directly kill target cells Inflammation characterized by infiltration of Mf , monocyte, And tissue injury Mechanism of type IV hypersensitivity

Figure 16.1 The DTH reaction

3. Common disease of type IV hypersensitivity 1) Infectious delayed type hypersensitivity OT( Old Tuberculin ) test 2) Contact dermatitis : Paint, drug red rash, papula, water blister, dermatitis 3) Acute rejection of allogenic transplantation and immune response in local tumor mass Same disease (SLE), multiple immune injury ,hypersensitivity involved Same drug (penicillin), several types of hypersensitivity

Tuberculin-type Hypersensitivity Tuberculosis Patient PPD(Ag derived from M.tuberculosis) Erythema & Induration Used as a diagnostic Test Not accurate.

Type IV DTH Contact dermatitis The response to poison oak is a classic Type IV. Small molecules act as haptens and complex with skin proteins to be taken up by APCs and presented to Th1 cells to get sensitization. During secondary exposure Th1 memory cells become activated to cause DTH.

Four types of Hypersensitivity Reactions Type II Type I Ag Target cell Y Y Y Y IgG IgE Target cell Fc receptor Fc recep- tor Killer cell Mast cells Y Ab Histamine Complement Type III Type IV Ag Ag Complement Y Y Th Th cell Endothelial cells Ab Macrophage Y Y Cytokines Neutrophils Activated Macrophage

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