HYPERSENSITIVITY 1& 2 BSc ALH.pptx

Hypersensitivity  Learning objectives At the end of the session, the students will be able to understand:  Definition and classification of hypersensitivity  Mechanism of Type I – IV hypersensitivity reactions 2   In...

Hypersensitivity  Learning objectives At the end of the session, the students will be able to understand:  Definition and classification of hypersensitivity  Mechanism of Type I – IV hypersensitivity reactions 2   Injurious consequences in the sensitised host, following subsequent contact with specific antigens. Definition 3  Type- I Type- II Type- III Type- IV 4 Type Anaphylact Cytotoxic Immune Delayed or Description ic Complex cell mediated Immune Humoral Humoral Humoral Cell response mediated Gell and altered Immediate Immediate Immediat Immediat Delayed or delayed e e Coombs Duration between 2min to 30 min 5-8 hrs 2-8 hrs 24 to 72 hrs Classification appearance of symptoms & antigen contact Antigen Soluble Cell Soluble Soluble or surface bound bound  5 Type- I Type- II Type- III Type- IV Effector Mast cell 1. ADCC Complement Macrophage activation Gell and mechanism degranulation 2. Complement activation and leads to phagocytosis mediated cytolysis inflammatory or cell cytotoxicity response Desensitiz ation to Easy, but short lasting Easy, but short lasting Easy, but short lasting Difficult but sustained Coombs the allergen Classification (Cont..) Typical  Anaphylaxi  Transfusion  Arthus  Tuberculin test manifestati s reactions reaction  Granuloma ons  Asthma  Rh  Serum formation in  Atopic incompatibility sickness tuberculosis, dermatitis  Hemolytic  Glomerulonep leprosy, etc anemia htiritis  Contact  Rheumatoid dermatitis arthritis  6  Occur immediately, within few minutes Immediate to few hours of antigen contact, as a Hypersensitivit result of abnormal exaggerated humoral response (antibody y Reactions mediated). Further classified into three types:  Type- I hypersensitivity reaction  Type- II hypersensitivity reaction  Type- III hypersensitivity reaction  7 Delayed  Occurs after few days of antigen contact, as a result of abnormal Hypersensitivit cell mediated immune response. y Reaction  Also called as type- IV hypersensitivity reaction.  8 TYPE I HYPERSENSITIVIT Y REACTION  9  Hallmark - Production of IgE by TYPE I sensitized B cells following a contact HYPERSENSITIVIT with an allergen which in turn induces Y REACTION mast cell degranulation.  These changes ultimately lead to:  Localized response (called atopy)  Systemic response (called anaphylaxis)  1 0 Allergen Examples types Food Nuts, egg, peas, sea food, Common beans, milk allergens Plants & Rye grass, rag weed, associated with pollens timothy grass type I hypersensitivity Proteins Foreign serum Vaccines reaction Drugs Penicillin, sulphonamides, local anesthetics and salicylates Insect bite Venom of Bee, Wasp, Ant, products Cockroach calyx and Dust mites Experiments to Demonstrate 1 1 Type I Reaction  Several experiments were conducted in the past to demonstrate type I hypersensitivity reactions - the most popular was P–K Reaction.  1 P–K Reaction 2  K Prausnitz and H Kustner (1921) - first to demonstrate that antibody in the serum responsible for the allergy.  Named it as P-K antibody or reaginic antibody.  Later - known as IgE (in 1960), after its discovery.  1 P–K Reaction 3 (Cont..)  Serum from an allergic person is injected intradermally into a nonallergic individual.  Later when the appropriate allergen is injected at the same site - wheal and flare reaction is developed at the site.  1 4  Wheal and flare response occurs in P–K three stages:  Appearance of an erythematous Reaction  area at the site of injury. Development of a flare (Cont..) (erythema) surrounding the site.  Wheal (swelling & congestion) forms at the site as fluid leaks under the skin from the surrounding capillaries. Mechanism of Type I Hypersensitivity 1 5 Sensitization Effector phase phase Both occurring with an interval of 2-3 weeks.  1 6 Mechanism of Type I Hypersensitivity (Cont..)  1 Sensitization 7 Phase  Sensitisation is most effective - allergen is introduced parenterally but may occur by any route, including ingestion or inhalation.  In susceptible individuals - very minute doses - sufficient to sensitise the host.  Allergen is processed by the antigen presenting cells and the antigenic peptides are presented to the CD4 helper T cells.  1 Sensitization 8 Phase (Cont..)  Activated TH cells are differentiated into TH2 cells which in turn secrete interleukin 4  induces the B cells to differentiate into IgE producing plasma cells and memory cells.  Secreted IgE migrate to the target sites, and coat on the surface of mast cells and basophils.  1 Sensitization 9 Phase (Cont..)  Fc region (the CH3 and CH4 domains) of IgE binds to high affinity Fc receptors (e.g. FcεR1) present on mast cell surface.  Such sensitized mast cells (coated with IgE) will be waiting for interaction with the subsequent antigenic challenge.  2 Effector Phase 0  When the same allergen is introduced subsequently (shocking dose) - directly encounters with the Fab region of IgE coated on mast cells.  IgE Cross linkage initiates degranulation-Allergen bound to IgE triggers the mast cells (and basophils) activation and degranulation.  Granules in turn release a number of pharmacologically active chemical mediators - lead to the various manifestations of type-1 reaction. Effector Phase 2 1 (Cont..)  The memory B cells further differentiate into plasma cells that supply the IgE.  Degranulation in two phases:  Primary mediators- The preformed chemical mediators which are already synthesized by mast cells, are immediately released.  Secondary mediators are those which the mast cells synthesize and release  2 Primary Action 2 Mediators Histamine, Heparin ↑Vascular and permeability Serotonin ↑Smooth-muscle contraction Mediators of Eosinophil Eosinophil type I chemotactic factor chemotaxis hypersensitivity (ECF-A) Neutrophil Neutrophil chemotactic factor chemotaxis (NCF-A) Proteases Bronchial mucus secretion;  2 Secondary Mediators Action 3 Platelet-activating Platelet aggregation and factor degranulation; Contraction of pulmonary smooth muscles Leukotrienes (slow ↑ Vascular permeability; Mediators of reactive substance of Contraction of pulmonary type I anaphylaxis, SRS-A) smooth muscles hypersensitivity Prostaglandins ↑Vasodilation; Contraction (Cont..) of pulmonary smooth muscles; Platelet aggregation Bradykinin ↑Vascular permeability; Smooth-muscle contraction Cytokines Systemic anaphylaxis; ↑ (IL-1 and TNF-α) Expression of cell adhesion  2 Effector Phase (Cont..) 4 Symptoms: Pharmacological Breathlessness, actions: hypotension and shock leading to death at times. Chemical mediators - ↑bronchial and other smooth muscle contraction, ↑increased vascular permeability and vasodilation. Manifestations 2 of Type I 5 Reaction  Grouped into:  Immediate, and  late. Immediate 2 6 Manifestations  Systemic anaphylaxis:  Acute medical emergency condition, characterized by severe dyspnoea, hypotension, and vascular collapse leading to death.  Occurs within minutes of exposure to allergen and unless treated promptly, may lead to fatality.  Epinephrine (adrenalin) is the drug of choice for systemic anaphylactic reactions. Immediate 2 Manifestations (Cont..) 7  Localized Anaphylaxis (Atopy):  The reaction is limited to a specific target tissue or organ, mostly the epithelial surfaces at the entry sites of allergen.  These allergies afflict more than 20% of people.  They almost always run in families (i.e. inherited) and are collectively called atopy. Immediate Manifestations (Cont..) 2 8 Localized Anaphylaxis (Atopy) (Cont..): Examples include: Allergic rhinitis (or hay fever) Asthma Food allergy Atopic dermatitis (allergic eczema) Drug allergy Late Manifestations  Immediate phase of type 1 reaction is followed, 4–6 hours later, by an inflammatory response.  This phase lasts for 1–2 days and leads to tissue damage. 29 Late Manifestations 3 0 (Cont..)  Mediators:  Released in acute induce recruitment of various inflammatory cells such as neutrophils, eosinophils, macrophages, and lymphocytes etc.  Among the infiltrates, eosinophils and neutrophils predominate; each accounting for 30% of the total inflammatory cells influx.  3 Late Manifestations 1 (Cont..)  Eosinophil influx:  Favoured by ECF (eosinophil chemotactic factor), IL-5 and GM-CSF.  Eosinophils express Fc receptors for IgG & IgE and thus bind directly to antibody- coated allergens.  Causes release of toxic granules from eosinophils which contribute to the chronic inflammation of the bronchial mucosa that characterizes persistent asthma. Late Manifestations 3 (Cont..) 2  Neutrophil infiltration:  Induced by NCF (neutrophil chemotactic factor), and other cytokines such as IL-8.  Activated neutrophils release various mediators which further potentiates inflammatory tissue damage and thickening of basement membrane. Factors Influencing 3 3 Type I Hypersensitivity  Genetic makeup  Allergen dose  Dose of the allergen has a definite impact on the type of immune response produced.  TH1 vs TH2 response Detection of Type I Hypersensitivity 3 4  Skin Prick Test:  Small amounts of suspected potential allergens are introduced at different skin sites either by intradermal injection or by superficial scratching. Detection of Type I 3 Hypersensitivity 5 (Cont..)  Total Serum IgE Antibody:  Quantitative detection of total serum IgE - performed by various formats such as enzyme immunoassay or radiometric assay called radioimmunosorbent test (RIST, now not in use). Detection of Type I 3 6 Hypersensitivity (Cont..)  Allergen-specific IgE:  Detection of allergen-specific IgE is more specific than total IgE detection.  Various test formats are available.  Multiplex immunoblot assay  Fluoro-enzyme immunoassay (FEIA  Automated immunoassay system (Hytec 288 Plus system)  Anti-CCD absorbent IgE assay  RAST   Avoidance of contact with known allergens Treatment  Hyposensitization  Monoclonal anti-IgE 37  3 Drugs Mechanism of action 8 Antihistamine Block H1 receptors on target s cells; hence antagonise the effects of histamine released Epinephrine Stimulates cAMP production in (adrenaline) mast cells; thereby prevents mast cell degranulation Drugs used in Cortisone Blocks conversion of histidine type I to histamine and stimulates hypersensitivity cAMP levels in mast cells Theophylline Prolongs high cAMP levels in mast cells Cromolyn Blocks Ca2+ influx into mast sodium cells  3 9 TYPE II HYPERSENSITIVI TY REACTION TYPE II HYPERSENSITIVITY REACTION  Host injury is mediated by antibodies (IgG or rarely IgM) which interact with various types of antigens such as-  Host cell surface antigens  Extracellular matrix antigens  Exogenous antigens absorbed on host cells (e.g., a drug coating on RBC membrane). 40   Complement-dependent Reactions  Antibody-Dependent Cellular Mechanisms Cytotoxicity (ADCC)  Autoantibody Mediated (Antibody-dependent Cellular Dysfunction or ADCD) 41  4 2 Complement- dependent reactions   Transfusion reaction  Erythroblastosis fetalis (Rh Complement incompatibility) Mediated  Auto Immune hemolytic anemia, Type II agranulocytosis, or thrombocytopenia Reactions  Drug induced hemolytic anemia  Pemphigus vulgaris 43  4 4 Antibody- Dependent Cellular Cytotoxicity (ADCC)  4 5 Antibody-  ADCC is involved in destruction of the targets that are too large Dependent to be phagocytosed, e.g. Cellular parasites, tumors or graft rejection. Cytotoxicity  In certain instances (e.g., (ADCC) eosinophil-mediated killing of (Cont..) parasites) IgE antibodies are used.   Host produces certain autoantibodies which bind and Autoantibody disturb the normal function of Mediated human self-antigens. (Antibody-  Antibodies may be directed dependent against human receptors, resulting in: Cellular  Activation of receptor; e.g. Dysfunction or Grave’s disease ADCD)  Inhibition of receptor; e.g. Myasthenia gravis 46 Autoantibody Mediated (Antibody- 4 dependent 7 Cellular Dysfunction or ADCD) (Cont..) Other examples of ADCD:  Goodpasture syndrome (antibody produced against type IV collagen)  Pernicious anemia (antibody directed against intrinsic factor)  Rheumatic fever (antibody against streptococcal antigens cross reacting with heart)  Myocarditis in Chagas disease.  4 8 TYPE III HYPERSENSITIVIT Y REACTION TYPE III 4 HYPERSENSITIVITY 9 REACTION  Occurs as a result of excess formation of immune complexes (Ag-Ab complexes) which initiate an inflammatory response through activation of complement system leading to tissue injury.  Antigen involved- Immune complexes can involve exogenous antigens such as bacteria and viruses or endogenous antigens such as DNA. TYPE III 5 HYPERSENSITIVITY 0 REACTION (Cont..)  Removal of immune complexes  Under normal circumstances, the immunocomplexes are rapidly cleared by activation of complement system.  Immunocomplexes coated with complements are either directly phagocytosed by macrophages/ monocytes or are bound to RBCs and carried to liver and spleen where they are phagocytosed.   Antibody excess or antigen- Soluble vs antibody equivalence, immune Insoluble complexes formed are large & insoluble; which tend to localize Immune near the site of antigen administration to produce a Complexes localized type III reaction. 51 Soluble vs  If antigen is in excess (particularly monovalent Insoluble antigens), small soluble complexes are formed which tend Immune to travel through blood and get Complexes deposited in various sites producing a generalized type III (Cont..) reaction. 52 Mechanism  Classical Complement Activation of Tissue  Platelet Activation Injury  Activation of Hageman Factor 53 Classical 5 4 Complement Activation  Ag-Ab-immune complexes stimulate the classical pathway of complement; the products of which mediate the tissue injury in type III reaction.  Anaphylatoxin  Chemoattractant  Role of neutrophils- Neutrophils fail to phagocytose large immune complexes Platelet Activation Immunocomplexes bind to the Fc receptors on platelets leading to their activation. Platelet aggregation (leads to microthrombi formation) and vasoactive amines released from activated platelets. Cause tissue ischemia leading to further tissue damage. 55 Activation  Activation of Hageman factor of leads to activation of kinin which in turn causes causes Hageman vasodilatation and edema. Factor 56 Types of Type III  Localized Hypersensitivit  Generalized y Reaction 57 Localized 5 8 or Arthus  Defined as localized area of tissue necrosis due to vasculitis resulting Reaction from acute immune complex deposition at the site of inoculation of antigen.  The reaction is produced experimentally (N.M. Arthus,1903) by injecting an antigen into the skin of a previously immunized animal, e.g. rabbit. Localized  Circulating antibodies bind with the antigen in the dermis or Arthus and form immune complexes  fix the complement  Reaction localised immune complex mediated inflammatory (Cont..) response. 59  6 Arthus reaction 0  In skin- i) following insect bites or ii) during allergic desensitization treatment wherein repeated injections of the same antigen is given for long periods.  In lungs, following inhalation of bacteria, fungi, spores or proteins may produce intrapulmonary lesions. Examples include conditions causing extrinsic allergic alveolitis such as-  Farmer’s lung  Bird-Fancier’s disease  6 1  Formation of small sized soluble Ag-Ab Generalized complexes- following entry of a large dose of antigen in to the body. or Systemic  Deposition of the immune complexes Type III in various tissues, thus initiating an inflammatory reaction in various sites Reactions throughout the body such as:  Blood vessels (vasculitis)  Glomerular basement membrane (glomerulonephritis),  Synovial membrane (arthritis).  6 2 Mechanism of systemic type III hypersensitivity reaction  6 3 CONNECTIVE TISSUE DISORDERS: RESULT DUE TO AUTOANTIBODIES FORMING IMMUNE COMPLEXES WITH SELF-ANTIGENS  SLE (SYSTEMIC LUPUS ERYTHEMATOSUS): ANTI- Diseases DNA AB  RHEUMATOID ARTHRITIS: AB AGAINST HUMAN associated with IMMUNOGLOBULIN  PAN (POLYARTERITIS NODOSA) generalized type Parasitic diseases: Resulting from immune III complex deposition  Nephrotic syndrome in Plasmodium malariae hypersensitivity  Katayama fever in schistosomiasis reactions  African trypanosomiasis Bacterial diseases: Resulting from immune complex deposition  Streptococcus pyogenes: Post-streptococcal glomerulonephritis  Mycobacterium leprae (Lepra reaction type 2)  6 4 Viral diseases: With immune Diseases complex deposition associated with  Hepatitis B (arthritis) generalized type  Hepatitis C (arthritis) III  Infectious mononucleosis (Epstein- Barr virus) hypersensitivity  Dengue (arthritis) reactions Others: (Cont..)  Hyperacute graft rejection  Subacute bacterial endocarditis  Serum sickness   Seen following serum therapy i.e. administration of foreign serum e.g., horse anti-tetanus serum, to treat tetanus cases. seen in the past Serum  Horse serum proteins being foreign  induce antibody formation in the host, leading to formation of large number of Sickness  immune complexes Typically, after 7-8 days, the individuals begin to show various manifestations which are collectively called as serum sickness. 65  6 6 TYPE IV HYPERSENSITIVIT Y REACTION   Type IV hypersensitivity reactions differ from other types in various ways-  Delayed type (occurs after 48- 72 hours of antigen exposure) TYPE IV HYPERSENSITIVIT  Cell mediated-Characteristic cells called TDTH cells (delayed Y REACTION type of hypersensitivity T cells) are the principal mediators.  Tissue injury occurs predominantly due to activated macrophages. 67  6 8 Mechanism  Sensitization phase  Effector phase of Type IV Reactions  6 9 Sensitization phase and Effector phase Role of DTH: Protective vs Tissue 7 0 Damage Response  Protective response  Under normal circumstances, the pathogens are usually cleared with little tissue damage; mediated by the enhanced microbicidal potency of activated macrophages.  Role of  Tissue damage response DTH:  When the intracellular microbes escape the Protective macrophage killing mechanisms  enhanced vs Tissue phagocytic activity and release of various lytic Damage enzymes by the activated macrophages in an attempt to Response kill the pathogen leads to non specific tissue destruction. (Cont..) 71  7 Intracellular pathogens inducing DTH 2 Intracellular Intracellular fungi bacteria  Pneumocystis jirovecii  Mycobacterium  Candida albicans leprae  Histoplasma capsulatum  M. tuberculosis  Cryptococcus neoformans  Listeria Examples of monocytogenes  Brucella abortus delayed-type Intracellular Skin test to demonstrate hypersensitivity viruses  Herpes simplex DTH  Tuberculin test (Mantoux (DTH) virus test)  Variola (smallpox)  Lepromin test  Measles virus  Montenegro test (leishmaniasis)  Frei test—done in LGV Contact dermatitis Following exposure to contact antigens:  7 3 Other examples of DTH Noninfectious  Crohn’s disease conditions  Chronic transplant  Diabetes mellitus rejection  Graft-versus-host Examples of type 1  Multiple sclerosis disease delayed-type  Peripheral hypersensitivity neuropathies  Hashimoto’s (DTH) (Cont..) thyroiditis Granuloma Other example formation seen in Lepra reaction type I Tuberculosis, sarcoidosis, schistosomiasis and other trematode infections Pathology of DTH 7 Reaction (Granuloma 4 Formation)  Initial TH cell infiltrate is progressively replaced by macrophages in 2 to 3 weeks. Macrophages transform into two type of cells  Large, flat, and eosinophilic; denoted as epithelioid cells.  Epithelioid cells occasionally fuse (induced by IFN-γ) to form multinucleated giant cells. Pathology of DTH 7 Reaction (Granuloma Formation) (Cont..) 5  Granuloma consists of an inner zone of epithelioid cells, typically surrounded by a collar of lymphocytes and a peripheral rim of fibroblasts and connective tissue.   Tuberculin test is the prototype of delayed hypersensitivity.  In sensitized individuals, (i.e. who possess sensitized TDTH cells due Tuberculin to prior contact with M.tuberculosis); when a preparation of tuberculin antigen Test (an extract of M.tuberculosis) is injected intradermally.  Local reaction develops after 48- 72 hours consisting of induration surrounded by erythema. 76  7 7 Contact Many antigens such as nickel,  poison oak, etc act by producing Dermatitis  DTH response. Most of these substances are haptens; they complex with skin proteins, which act as carrier to make the haptens immunogenic.  7 8  This hapten-skin protein Contact complex is internalized by skin APCs (e.g., Langerhans cells), Dermatitis then presented to TH cells to induce a TDH reaction. (Cont..)  Activated macrophages release lytic enzymes which result in skin lesions (e.g. redness and pustule seen following contact with poison oak) Questions:  Q1. Type I hypersensitivity is mediated by which of the following immunoglobulins: a. IgA b. IgG c. IgM d. IgE 79 Questions:  Q2. Type of hypersensitivity reaction in myasthenia gravis is: a. Type I b. Type II c. Type III d. Type IV 80 Questions:  Q3. Example of antibody-dependent cellular dysfunction or ADCD: a. Graves’ disease b. Hemolytic anemia c. Pemphigus vulgaris d. Transfusion reaction 81