Hypersensitivity Reactions PDF

Hypersensitivity (HPS) Reactions Definition: Excessive immune responses that cause damage. It occurs in response to three different types of antigens: 1. Infectious agents - Influenza virus Cytokine storm - Chronic hepatitis Liver damage 2. Environmental subst...

Hypersensitivity (HPS) Reactions Definition: Excessive immune responses that cause damage. It occurs in response to three different types of antigens: 1. Infectious agents - Influenza virus Cytokine storm - Chronic hepatitis Liver damage 2. Environmental substances, e.g. allergy/ atopy such as asthma or rhinitis Dust stimulates IgE production 3. Self antigens, e.g. autoimmune disease Types of Hypersensitivity Reaction Coomb’s and Gell classification Classically four types are clinically recognized: 1. Immediate; Type-I: IgE-mediated 2. Antibody-Mediated; Type-II: IgG-mediated (Cytotoxic; Bound Antigen) 3. Immune Complex; Type-III: IgG-mediated 4. Delayed; Type IV: T cell-mediated Immediate Hypersensitivity (Type-I): Allergy Definition of Atopy: Immediate HPS reaction to environmental antigens, mediated by IgE: Atopy may be inherited/runs in families # Synonymous to High IgE (mostly due to allergy) Diseases: Anaphylaxis, angioedema, urticaria, rhinitis, asthma, dermatitis/eczema Two phases: Early and Late-Phases Allergen Triggering antigens of allergy Some are of low MW; present in environment Inhaled, Eaten, Administered as drugs: # Inhaled: Pollens, Fungal spores, Feces of House Dust Mite (HDM), HD, Grass # Ingested: Peanut, Fish, Egg, Milk # Administered: Drugs (e.g. Penicillins, Cephalosporines/cross react) & Venoms. Degranulating Cells 1. Mast cells (the major cell in allergy) - Resident in tissues - Express IgE receptor (FcER1) # Cross-Linking by allergens Release Mediators (degranulation): Early phase of allergy 2. Eosinophils: Circulating cells; migrate to areas of type-I reactions 3. Basophils: Circulating cells; become mast cells in tissues; functions unknown ? Non-Allergic Reactions - Complement Activation, e.g. during infections - Nervous system signals (e.g. temp.) Also activate the above mentioned cells Antibody IgE: B cells co-stimulated by IL-4 secreted by TH2 cells Switch to IgE production: # Bind FcER1 on mast cells (constantly) and eosinophils # High levels of IgE during: Parasitic infection, e.g. schistosomiasis Atopy # Tested for by: Prick test ELISA TH2 - TH2 activation inhibits IgG production and TCL (cytotoxic T cells): # TH1 express T-bet factor INF-Ɣ # TH2 express GATA3 factor IL-4,5,13 (T-bet/TH1 VS GATA3/TH2) - Determinants of TH1 or TH2 activation: 1. Treg cells: Prevent TH1 and TH2 activation (peripheral Tolerance) by TGF-beta & IL-10, as occurs in non-allergic individuals (vs allergic individuals) cont./… Cont./… activation of TH2 vs TH1 2. APCs play role in determining the type cells stimulation, e.g. mucosal antigens stimulate TLR-2 which favors TH2 response. # If APCs produce IL12 (as in intracellular organism) TH1 cells stimulated - Also, Positive feedback by secretion of IL-4 from mast cells after Ag cross-linking of FcER1 to increase IgE production and more TH2 (polarization) cont./… Cont./… activation of TH2 vs TH1 - IL-4 inhibits also release of INF-Ɣ by TH1 - IL-5, IL-13 and eotaxin: Maintain TH2 cells response, eosinophil migration, and switching off macrophages Predisposing Factors - Allergy is common in developed countries # Peanut allergy is increasing 1. Atopy Trait # Exaggerated IgE response # Run in families (high IgE levels) # Have different allergies (i.e. risk of allergy is inherited, NOT the specific allergy) # Several genes involved (polymorphism), e.g. IL-4 and FcER1 genes (FcER1 from mother contributes more than from father) 2. Hygiene Hypothesis Allergy is influenced by: 1. Cleaner houses 2. Growing in farms decreases allergy 3. Allergy is rare where TB is common Mycobacteria prevent TH2 polarized response: 1. M.B. survive in macrophages and elicit TH1/INF-Ɣ response (suppress TH2) 2. M.B. favor T-reg production (major cells in non-allergic individuals for environmental allergens- Suppressor) Mediators of Early Phase Mast cells produce immediately (in Anaphylaxis) 1. Prostaglandins: Cyclooxygenase pathway 2. Leukotrienes: Lipoxygenase pathway # Vasodilators # Increase vascular permeability - Fall in B.P. # Leukotrienes increase nasal secretion (in rhinitis/asthma); S.M. contraction in lungs 3. Histamine: From skin mast cells (not lung) # Contributes to swelling and fluid shift Mediators of Late Phase 1. Eosinophils: Peroxidase, eosinophil major basic protein, cationic protein: Damage to bronchial tissue Chronic inflammation S.M. hypertrophy, mucous secretion 2. TH2 cells IL-4 secretion/chemokines leading to chronic allergic inflammation. Treatment - Tailored according to severity of condition - Identifying and avoiding allergens - Drugs - Desensitization Drugs Beta2-Adrenergic agonists (e.g. salbutamol): # Prevents S.M. contraction in asthma Epinephrine (adrenaline): In anaphylaxis Anti-Histamine: Helpful in allergy of mm, skin, and nose, and not in asthma; slow in anaphyl. Leukotriene receptor antagonist: Montelukast Corticosteroids: Prevent immediate HPS & late phase; given inhaled or topically mainly Desensitization (Immunotherapy) Most useful in a single allergen Can prevent anaphylaxis Sc. increasing doses injected, e.g. venom # 90% successful Mechanisms: 1. TH1 stimulation Blocking IgG (prevents allergen attachment to IgE) 2. T-reg cells inhibit TH2 polarized response Latex Allergy Skin Prick Test Peanut Allergy