Hypersensitivity (HS) I, II, III, IV PDF

HYPERSENSITIVITY (HS) I, II, III, IV PM Dr Noraziah Mohamad Zin, Department of Biomedical Science, FSKB Block H, Level 5 Introduction Increased response to a/g results in tissue damage Def HS: ANY immunologic reaction where considerable tissue damage & someti...

HYPERSENSITIVITY (HS) I, II, III, IV PM Dr Noraziah Mohamad Zin, Department of Biomedical Science, FSKB Block H, Level 5 Introduction Increased response to a/g results in tissue damage Def HS: ANY immunologic reaction where considerable tissue damage & sometimes fatal results HS & protective immune reactions: differences and similarity..? – Cellular & molecular mechanisms are identical but HS cause immune-mediated damage to the host by (i) exaggerate reactions to foreign ag or inappropriate reactions to SELF-ag Anaphylaxis:damage occurs as a result of a protective response, but to a very particular type of HS HS reactions Re exposure Immunization? Caused by a wide range of a/g May effects different organ or tissue Originally classified according to the symptoms but now used Gell and Coombs (1960) which depended upon the underlying immunologic reactions (4 types of HS) HS types Type I/Immediate (anaphlylactic) HS – Associate with allergic responses – Allergens (a/g) stimulate the reaction are diversed but the outcome of exposure is similar – Genetic influence – Cellular interactions involved in a/g recognition – Immediate HS: within secs of a/g exposure – Early phase:30 min-local oedema, smooth muscle contraction, vasodilation and increased permeability of post-capillary venules. – By IgE-mediated mast cell (MC) degranulation – Later phase:4-12 hr, activation of basophils (BC), eosinophil - IgE-mediated reactions, stimulated by its binding (via Fc regions) to high affinity IgE-specific Fc receptors expressed on mast cell and basophils -Cross-linked by ag, IgE ab triggers the mast cells & basophils to release inflammatory mediators, lead to allergic r’x, incl rhinitis, asthma & anaphylxis - Rx are rapids, occurring within minute after challenge IgE FcR Sel mast atau Basofil anafilaksis dan alergi Alergi :pd individu ttu yg pradisposisi(?) /dlm ahli keluarga. Eg; pendedahan pd bulu kucing sbbkan hidung gatal, mata dan hidung berair Anafilaksis :boleh berlaku pd setiap individu sstu spesis, keadaan teruk dan merbahaya. Eg. pendedahan pd bulu kucing sbbkan kesan diatas DAN sesak nafas, renjatan  Characteristics of type I HS 1. Sensitization phase – IgE ab is produced in response to antigenic stimulus and binds to spscific receptors on MC & BC 2. Activation phase – re-exposure/challenge with ag triggers the MC & BC to respondby release their granules 3. Effector phase – Complex response occurs as a results of mediators Sensitization phase Individuals are genetically predisposed to certain allergies Not only re exposure but to ones that share common epotiopes with the ag Contact incl: skin, ingestion, injection & inhalation 50% generates IgE response to airborne, 20% develop clinical symptoms of hay fever IgE ab production is TH2 cell dependent Mast cells: found inaround blood vessels in connective tissue, in lining of gut & lung Activation phase Requires at least 2 receptors for Fc region of IgE molecules be bridged together in stable configuration How the crosslinking of IgE would be occurred?.......................................... Multivalent ag Physiologic consequences depend on the DOSE of ag & ROUTE OF ENTRY Effector phase How it is taking place? ………………………………………………………. Preformed mediators: histamine, heparin, proteases,IL-8 and other cytokines – Eg Histamine: formed in the cell by decarboxylation of amino acid histidine. When released, its bind rapidly to variety of cells via 2 major types of receptor H1 & H2 (diff. distribution & mediate diff effects…) Newly synthesized mediators:prostaglandins, throboxanes, leukotrienes  Mechanism of immediate type I HS (a) 1st exposure, allergen binds to B cells & presented as allergen fragment on the Surface of m/phages---activate Th cells which activate B cells (b) B cells---plasma cells--- IgE (c) IgE binds by Fc tail to basophils and mast (d) 2nd exposure,allergens bind to sensitized Mast cells, crosslingking IgE (e) Cross lingking stimulates degranulation of Histamine & others Late phase reaction of HS I… What is the mechanism? How it is occur? What are the components involved? Type II/Antibody-dependent cytotoxic HS Main Reaction Production of IgG & IgM that target cell surface a/g, bind to cell target via Fab regions (Bahagian Fab a/b bergabung dgn a/g dipermukaan sel dan sbbkan kerosakan mll fagositosis, tindakan komplemen yg diaktivasikan dan sitotoksisiti yg bergantung kpd a/b) Occur in response to a/g on transplanted cells. Host cells during autoimmune disorders or foreign a/g that bind to host Reaktan yg terlibat Kelas IgG dan kelas IgM dalam sirkulasi (a/b humoral) Epitop a/g di permukaan sel sasaran Sensitization phase Immunological response to cell surface a/g. leading to IgM and IgG production which depends on the local milieu and type of cytokines secreted by CD4+ T cells Activated B cells – Differentiation to a/b secreting plasma – Memory B cells Effector phase a/g not removed from the body by the time a/g specific a/b are formed. IgG and/or IgM a/b, generated in the sensitization phase, play a role in complement activation, ADCC by natural killer and opsonin mediated phagocytosis When a/g on host cells, or transplanted donor cells. The a/g cannot be cleared for the system so pathological that ensues is the result of unregulated normal response (ADCC-Antibody dependent cell-mediated cytotoxicity) Effector phase..cont Role of complement – C5a – C3b Role of IgG – Interaction made destruction of host cells by phagocytoses or natural killer cells which express FcR on their surface, through which they interact with the Fc region of IgG bound to a/g. – Therefore, IgG facilitate both opsonin mediated phagocytosis and ADCC Clinical manifestation Transfusion (transplantation) r’x Hemolytic disease of the newborn (HDNB) Drug induced r’x Transfusion (transplantation) r’x Incompatible blood transfusions) – Bila seseorang menerima sel darah merah yg mengekspreskan a/g dan beliau ada a/b terhadapnya – Recipients of incompatible blood rapidly destroy the RBC in that blood because of existing IgM (isohemagglutinins) Blood gp. AB – good recipient, bad donor Blood gp. O - good donor, bad recipient Autoimmune haemolytic anaemias (RBC) and thrombocytopenia (platelets) Matched-but still mismatched Sometimes transfusions can occur even when blood is carefully matched. Some people, for example, lack IgA a/b of their own and thus do not acquire tolerance to this immunoglobulin. When such individuals receive transfusions, they are likely to produce a/b against IgA in the donated blood, and any subsequent transfusion will then evoke a transfusion reaction. Interestingly some patients exhibit such reactions on receiving their first transfusion, indicating a previous exposure to IgA. One possible explanation is that they have been sensitized by eating rare beef, the blood of which contains IgA  Haemolytic disease of the newborn Inherited Problem : Rh+ baby (Inherits from father) and Rh- mother 1st incompatible child is usually unaffected (mothers blood and baby not mix, separated by placenta) but the 2nd and later have risk of HDNB Rh (-) mother carries a 2nd Rh(+) infant, sensitization occur during birth of the first Rh(+) infant, when some fetal red cells leak back across the placenta in to maternal circulation, recognized by maternal immune system and produce a/b Mechanisme ofHS II Cell surface antigen IgG IgM Any cell Type III HS Normal condition=circulating immune complex>phagocytic cells>RBC with C3b receptors> liver cells>removed by phagocytic Kupffer cells If large quantities>deposited in tissues>trigger variety of systemic pathogenic events >HS III Requires IgG or IgM Soluble a/g binds to sps a/b and form large immune complex which activate complement deposited in small vessels, particularly those with filtering membranes such as kidneys & joints & cause localized destruction  Whether reactions are transient or ongoing, depends on whether a/g is cleared from the system Inflammation in the glomeruli of the kidneys, skin, joints choroid plexus and ciliary artery of eye. Formation Immune complexes initiated by exogenous ag (bact or viruses) or Arthus r’x (to large amounts of foreign protein) Endogenous ag (DNA)> target auto ab (SLE) Type III HS- mechanisms Mech-same regardless of which pattern of immune complex deposition is seen (systemic vs. local) Pathogenesis: tissue injury>fixation complement by immune complex.activation complement cascade & release biologically active fragments (anaphylotoxins C3a & C5b) > increased vascular permeability & realeased lysozomal enzymes MechanismeType III HS Clinical manifestation 1. Arthus reaction Horse serum Rabbit skin Rash , 5-6 h. 2. Serum sickness Horse serum Human body > 7 days Immunecomplex Clinical features - fever - lymph node, spleen - arthritis, vasculitis , nephritis 3. Autoimmune complex diseases 3.1 Rheumatoid arthritis Autoantibody( IgM ) + IgG IgM-IgG complex 3.2 Systemic lupus erythematosus( SLE ) Autoantibody + Nuclear antigen Immune complex Production of numerous autoantibodies a/b bind to soluble a/g, immune complexes form that become deposited and trapped in various tissues. The pathology observed depends on the site where the immune complexes deposit  4. Post streptococcal glomerulonephritis streptococcal infection antibody to toxin + toxin antibody-toxin complex glomerulonephritis glomerulus 5. Dengue hemorrhagic fever Dengue virus infection Antibody to dengue virus + dengue virus Vascular Antibody-dengue virus complex Vasculitis Skin rash 6. Hay fever - Farmer’s lung disease - Pigeon breeder disease Antibody Fungal spore Pneumonitis Organic material Pneumonitis Mechanisme that produces an Arthus reaction and hemorrhagic areas. In severe cases, injection of horse protein leads to (b), (c), (d). Immune compelx also trigger platelet aggregatiopn that obstruct blood flow. Complements attract more neutrophils to the site & causes mast cells degranulation. Finallym platelet & complement trigger endothelial retraction (tissue death occurs) Type IV HS Delayed-type hypersensitivity (DTH), reactions take >24 h Mediated by antigen specific TH cells, not a/b Can only be transferred only by T cells. Sequence of Events in DTH T-cell dependent inflammatory response & not circulating Ab. Resting T lymphocytes need to be sensitized, i.e. to develop into memory T cells. DTH is induced by a 2nd immune response. The sequence of events in DTH involves numerous cell types and can vary in time course and histology. Sequence of Events in DTH-cont.. However, a summary of the model for the reaction is as follows. Upon encounter with the similar antigen, Langerhan's cells process the antigen and present it to local memory T cells, whether they are CD4+ or CD8+. These T cells in concert with activated Langerhan's cells secrete numerous cytokines that cause the early hallmarks of inflammation. Within 2 hours neutrophils begin to infiltrate the injection site. Currently, it is unknown if the T cells directly attract neutrophils and monocytes or if the vascular endothelium is responsible for recruitment of leukocytes, but the latter hypothesis seems more likely. The endothelial cells undergo changes as a result of TNF and IFN acting in concert. The endothelial cells remodel the basement membrane and allow the extravasation of plasma macromolecules, especially fibrinogen. The increase in fluid volume slows the blood flow and allows the lymphocytes to attach more readily to the endothelium. Additionally, endothelial cells are also capable of secreting chemokines which attract various types of cells into the site. Reaction develops slowly. Slow-developing inflammation mediated by immune cells (immunity) that continues  to level & period which damage tissue until clinical symptoms appear (hypersensitivity). Sensitized T cells react with cell bound or associated antigen and release lymphokines, causing mononuclear cell accumulation, tissue damage and inflammation, typically manifesting at least 24 hours after exposure to the antigen The phagocyte (monocyte/macrophage) is involved in all of these responses, sometimes as a host for the pathogen, but more often as an effector cell. The exact mechanism by which the macrophage is activated is still being debated but it is clear that a T cell is required to initiate the response. Which Th cell subset is involved in DTH? There are 2 types of Th cells: the Th1 and Th2 cells. The Th1 cell secretes IFN-, which activates macrophages and induces a CMI response. Th2 cells secrete cytokines such as IL-4, IL- 5 and IL-6, which activate B cells and induce humoral immunity or toleragenicity. Induction of the Th1 or Th2 phenotype is due to the APCs secreting IL-12 which suppresses Th1 cells  DTH patterns Induration, the hallmark of DTH DTH is not as an individual phenomenon but rather a group of related responses to Ag. In this respect DTH can be  various types. 4 Major types: the tuberculin reaction, Jones- Mote reaction, contact hypersensitivity and Granuloma hypersensitivity. Not mutually exclusive; overlapping features. Following Ag challenge, various hypersensitivity types can occur sequentially.  Tuberculin hypersensitivity/Mantoux test – Classical DTH reaction – In all species, this reaction is mediated by a mix of CD4+ and CD8+ T cells. Jones-Mote hypersensitivity – Also known as cutaneous basophil hypersensitivity – Jones-Mote hypersensitivity exclusively refers to DTH induced by injection of protein in adjuvant or protein Contact hypersensitivity – Three critical events must occur in generating a reaction: sensitization, trafficking and elicitation. – Exposure to hapten, usually through the skin but sometimes though inhalation or ingestion. Usually no symptoms of exposure are evident. – The hapten binds covalently to any cell-associated protein or extracellular protein. – conjugated to haptens. Granuloma hypersensitivity Chronic stimulation with persistent Ag Peak: at least a few weeks Clinical Picture A major example of skin type IV reaction is contact hypersensitivity. Examples; Nickel, chromium, rubber. Atopic eczema: type IV, or type I and type IV? Some indications that certain forms of chronic pulmonary diseases due to type Iv reaction. Examples: hard metal asthma, sarcoidosis. Whether in the gut type IV reaction plays an important role is not known. In Crohn’s disease granulomatous inflammatory reactions are frequently observed (type IV reaction?). Role of hypersensitivity type IV in food allergy is controversial. Some say Type IV reactions occur in approximately 95% of food hypersensitivity reactions. Transplant rejection and nickel skin allergies are common examples of Type IV reaction. Mekanisma HS taip IV