Session 19 - Type I and II Hypersensitivity Reactions (1).pptx

Type I and II Hypersensitivit y Reactions PBC 9700 Session 19 Randal K. Gregg, PhD Learning Objectives 1) Identify antigens, genetic predispositions, cytokines, antibody isotype and effector mechanisms of type I and II hypersensitivity reactions. 2) Recognize diseases associated with type I and II h...

Type I and II Hypersensitivit y Reactions PBC 9700 Session 19 Randal K. Gregg, PhD Learning Objectives 1) Identify antigens, genetic predispositions, cytokines, antibody isotype and effector mechanisms of type I and II hypersensitivity reactions. 2) Recognize diseases associated with type I and II hypersensitivity reactions. 3) Recall the mechanisms of action of antihistamines, leukotriene modifying agents and allergy injections. 2 Hypersensitivities Immune responses that can cause tissue damage or cellular dysfunction Hyper means excessive and sensitivity equates to the capacity to generate an immune response against an Ag 20% of the human population generate a hypersensitivity response to an Ag termed an allergen 3 Types of Ags of hypersensitivity ENVIRONMENTAL Ags Large amount or continuous presence of noninfectious Ags in the environment that can bind to and promote a specific immune response leading to the symptoms of allergy MICROBIAL Ags Persistent or chronic infections provide a continual source of Ag Immune complexes (Ag-Ig) can form and deposit in tissues leading to inflammation and damage Inability to clear the Ag also can generate granulomas SELF-Ags Immune cells escape central tolerance to create a self-reactive pool of cells Continual presence of self-Ag and failures of peripheral tolerance provide opportunities for cell activation and tissue damage 4 Overview of the types of hypersensitivity reactions Some disease conditions may involve more than just one type of hypersensitivity 5 Type I and II hypersensitivity 6 TYPE I HYPERSENSITIVITY 7 Type I hypersensitivity IMMEDIATE HYPERSENSITIVITY Immunology history – 1873 Placed pollen grains in the nose of patients and generated rhinitis Rapid response to soluble microbial or environmental allergens Took pollen extract and injected (I.D.) into the same patients = wheal and flare responses occurred Generalized clinical presentation: o Depends upon the site of encounter and dispersal of the allergen o SKIN = itching (pruritus), urticaria (hives), erythema (flare) o RESPIRATORY = bronchoconstriction, hypersecretion of mucus, edema o GI TRACT = vomiting, cramping, diarrhea o CARDIOVASCULAR = vasodilation, circulatory collapse Charles Blackley 8 Common allergens of type I reactions 9 Hypersensitivity factor driving type I reactions P-K sensitization reaction (in 1921) o Heinz Küstner (he is allergic to fish) injected (I.D.) his serum into his colleagues’ skin, Otto Prausnitz (who is not allergic to fish) o Prausnitz then ate fish o He developed a wheal and flare lesion at the site of the injection o Something contained within the serum of Küstner transferred a local allergic response to Prausnitz 1967 – Kimishige Ishizaka purified IgE from the serum of patients with hay fever caused by ragweed exposure Genetic predisposition for type I reactions 1) Certain MHC class II haplotypes associated with “Th2” cytokines and allergic responses (atopy) o o o Upon allergen epitopes binding to the MHC class II molecule – DC are influenced to produce IL-4 and IL-13 for Th2 differentiation IL-4 Activated Basophils also provide a source of IL-4 for Th2 differentiation (+ IL-10) Recall that the source of Th2 cytokines for IgE class switching is the TFH cells 2) Mast cells express Fc R with increased affinity for IgE 3) The Fc R remain on the mast cell surface significantly longer in patients with allergies compared to nonallergic individuals (i.e. reduced FcR turnover) TFH cell IgE half-life bound to Fc R is months compared to days when IgE is in serum Germinal Center B cell Plasma cell 11 Step 1 = Sensitization First exposure CD4+ T cells differentiate into IL-4 producing Th2 cells (and IL-4 producing TFH cells) GC B cells generate plasma cells producing allergen-specific IgE o Nonallergic = produce a different Ig isotype to the allergen if responding Plasma cells traffick to the tissue of exposure and produce IgE IgE captured by mast cell Fc R The IgE remains on the surface of the mast cells for a long duration o Nonallergic = IgE/Fc R turnover is much greater 12 Step 2 = Exposure and Degranulation Second exposure Allergen binds to the IgE (displayed by Fc R) on mast cells Multiple Fc R/IgE engagements “crosslink” the receptor signaling Triggers mast cell activation Mast cell degranulates Preformed molecules are released for a rapid reaction (min to hrs) 13 Degranulation releasing preformed Primary mediators mediators Histamine  Triggers nerve bundles to promote itch signal  Induces smooth muscle release of NO vasodilation and shrinks endothelia for vascular permeability  Constriction of smooth muscles Bronchioles wheezing o Intestines cramps and diarrhea IL-1, IL-6, TNF-  adhesion molecules on endothelial cells  vascular permeability Exotaxin (CCL11) or Eosinophil chemotactic factor of anaphylaxis-A (ECF-A) o These mediators are rapidly released and active for a few min as they are inactivated; for persistent activity must continue to stimulate the mast cells for synthesis and release o Recruites eosinophils Tryptase and chymase o Activate matrix metalloproteinases (MMP) to remodel ECM o Tryptase can promote pruritus (itching) 14 Degranulation releasing preformed mediators Primary mediators Heparin o Binds to plasma factor XII inducing a conformational change into an active form o Active factor XII cleaves prekallikrein plasma kallikrein o Plasma kallikrein activates more factor XII o Plasma kallikrein levels increase and proteolytically liberate bradykinin from high molecular weight kininogen o Bradykinin binds to B2 receptors to promote:  Vasodilation  vascular permeability  Recruitment of neutrophils  Fluid efflux 15 Mediators synthesized after activation Secondary mediators Derived from arachidonic acid using cyclooxygenase (COX) and lipoxygenase (LOX) pathways 16 Mediators synthesized after activation Secondary mediators COX pathway Prostaglandins o vascular permeability o Constriction of smooth muscles (bronchoconstriction) o Recruit neutrophils Thromboxanes o Aggregate platelets – regulates influx of cells and fluids into tissue LOX pathway Leukotrienes o 1,000-fold more potent than histamine o vascular permeability o Constriction of smooth muscles (bronchoconstriction) o mucus secretion (lungs) 17 Mediators synthesized after activation Secondary mediators Cytokines / Chemokines VEGF (vascular endothelial growth factor)  Recruits monocytes/macrophages  vascular permeability IL-5  IL-4 and IL-13  Recruits and activates eosinophils Promotes Th2 responses for IgE production IL-8 and IL-17 o Recruits and activates neutrophils 18 Clinical effects of mast cell activation depends upon site of degranulation 19 IgE-mediated allergic reactions Syndrome Allergens Route of entry Response Allergic rhinitis (hay fever) Pollens Danders Dust mite feces Inhalation Nasal mucosa edema Nasal mucosa irritation Asthma Pollens Danders Dust mite feces Inhalation Bronchial constriction Increased mucus production Airway inflammation Food allergy Tree nuts Peanuts Shellfish / Fish Milk Eggs Oral Urticaria (hives) Insect bites Allergy testing Intradermal or subcutaneous Systemic anaphylaxis Drugs Serum Venom Peanuts Intravenous (direct or absorption) Vomiting Diarrhea Pruritus (itching) Urticaria (hives) Anaphylaxis Local increase in blood flow Increased vascular permeability Edema Increased vascular permeability Tracheal occlusion Circulatory collapse (and death) 20 Pathophysiology of systemic anaphylaxis Systemic anaphylaxis = systemic hypersensitivity reaction that is rapid in onset and characterized by potentially life threatening airway, breathing and/or circulatory problems – usually associated with skin and mucosal changes o Presentation ranges from urticaria (hives) to shock-like symptoms o Most often driven by IgE but some examples of IgG anaphylaxis as well o Little information available due to few human studies; most based on animal models IgE-mediated activation of mast cells and complement activation (C3a, C4a, C5a) associated with anaphylaxis Levels of C3a, C4a, C5a are correlated with the severity of anaphylaxis Severity could be due to higher numbers of tissue mast cells and serum IgE as well as more robust degranulation of mast cells in animals following anaphylaxis by agonist anti-IgE Most common systemic anaphylaxis is to penicillin Mutation of gene (c-kit) of mast cells promotes higher proliferation upon activation in some patients that develop anaphylaxis First line therapy = epinephrine (induce vasoconstriction to prevent tissue/airway edema, hypotension and shock; activate beta-1 adrenergic receptors to increase heart rate and cardiac contractibility; activate beta-2 adrenergic receptors to dilate airways and block further primary/secondary mediator release 21 Mediators implicated in anaphylaxis Epinephrine acts much more rapid than antihistamines (10 min vs 1-3 h IM injection); epinephrine acts as a vasoconstrictor to prevent edema, hypotension and shock CysLTs = cysteinyl leukotrienes PAF = platelet activating factor 1,500 fatalities due to anaphylaxis in the US annually 22 Syndrome Therapy Mechanism Anaphylaxis Primary (fast-acting) Epinephrine Stimulates cAMP production (PKA) in mast cells (prevents mast cell degranulation) Secondary Antihistamines (Benadryl™, Claritin™, Tagamet™) Blocks histamine receptors IV Corticosteroids Cortisone Reduce inflammation Blocks histidinehistamine conversion and stimulates mast cell cAMP production Corticosteroids Reduce inflammation Antihistamines Blocks histamine receptors Leukotriene modifiers Leukotriene receptor antagonist (blocks LTD4 and LTE4 receptors) Desensitization Administration of low doses of allergen every 1015 min to slowly trigger mast cells (unknown?) Hyposensitization (allergy shots) Administration of low doses of allergen over months to induce IgG responses, desensitize mast cells and induce Treg cells Most Allergic Diseases Allergic Rhinitis Prophylactic 23 Syndrome Asthma Asthma Attack (fast-acting) Prophylactic (continuous treatments) Therapy Mechanism Inhaled Beta Agonists (Albuterol, Levalbuterol) Bronchodilator Oral Corticosteroids (Prednisone) Reduce inflammation Inhaled Corticosteroids (Fluticasone propionate, Budesonide) Reduce inflammation Leukotriene modifier (Montelukast or Singulair™) Leukotriene receptor antagonist (blocks LTD4 and LTE4 receptors) Theophylline Inhibits action of phosphodiesterase (cleaves cAMP 5’-AMP; prolongs cAMP levels in mast cells) Cromolyn Sodium Blocks Ca2+ influx into mast cells (prevents mast cell degranulation) Omalizumab (Xolair) Anti-IgE antibody (IgG1) binds to Fc portion of IgE to block from binding to Fc R 24 TYPE II HYPERSENSITIVITY 25 Type II hypersensitivity CYTOTOXIC HYPERSENSITIVITY Response to cell surface antigen (either self-Ag or microbial Ag) Disease associated with three outcomes: 1) Antibodies (IgM, IgG) are generated and bind to the cell surface Ag o Surface bound Ig triggers inflammation and leads to tissue damage (true “cytotoxic hypersensitivity”) 2) Antibodies bind to cell surface receptors and block signaling through the receptors (antagonistic antibodies) 3) Antibodies bind to cell surface receptors and induce signaling through the receptor (agonistic antibodies) 26 Cytotoxic hypersensitivity MECHANISMS OF TISSUE DAMAGE IgM (or IgG) binds to cell surface Ags C1 (C1q-C1r-C1s) binds to the Ig Classical pathway of complement is activated C3a, C5a produced to recruit neutrophils, macrophages, and monocytes Neutrophils and macrophages use Fc R to bind to IgG; use CR to bind to C3b The cells cannot engulf the tissue cells expressing the Ag = frustrated phagocytosis Neutrophils expel contents of all granules into environment; Macrophages release lysosomal digestive enzymes, ROS, RNS into environment o Otherwise, opsonization can occur and phagocytosed cells (i.e. blood cells) are eliminated usually associated with blood disorders Membrane attack complex forms (C5b-C9) leading to cell lysis Inflammation results in tissue damage and destruction 27 Disease related to complement activation and frustrated phagocytosis ANTI-GBM DISEASE Formerly known as Goodpasture’s syndrome 3-5% of glomerulonephritis cases (males 20-40y most common) 80% carry HLA-DRB1*1501 or HLA-DRB1*04 alleles ~70% of cases also suffer from pulmonary hemorrhage as well as renal disease Initial symptoms (days-weeks) = fatigue, weakness, anemia, nausea, vomiting Lung symptoms = shortness of breath, chest pain, coughing up blood, dry cough Renal symptoms = darkened urine (hematuria), proteinuria, hypertension, edema in legs Mechanism of disease IgG generated against NC1 (non-collagenous) domain of type IV collagen ( 3 chain) in the glomerular basement membrane of the kidney o IgG cross-reactive with same epitope of the collagen in the alveolar basement membrane 28 Anti-GBM IgG binds to the GBM Ag Capillary lumen Urinary space E = endothelium F = endothelial fenestrae P2 = epithelial foot processes 29 Bound anti-GBM IgG activates complement Capillary lumen C2a C4b Urinary space C1q (r, s) C3 convertase 30 C3b deposits in the GBM tissue Capillary lumen Urinary space C3b 31 C3a and C5a recruits neutrophils Capillary lumen Urinary space C3a, C5a 32 Neutrophils and macrophages recruited and activated Fc Receptor Complement Receptor 33 Frustrated phagocytosis Nucleases Proteases Lipases NO H2O2 ROS 34 Recruitment and degranulation of mast cells Histamine Proteases Chemokines C3a, C5a 35 MAC can lyse epithelial and endothelial cells 36 ABO blood group incompatibility RBC Abs Present Ags Present Complement-mediated lysis primarily mechanism of RBC lysis 37 Antagonistic antibody-mediated cell dysfunction IgG binds to cell surface Ag IgG impairs or blocks cell functioning associated with the protein target No direct cell injury or inflammation occurs Myasthenia Gravis – Ig binds to acetylcholine (Ach) receptor and prevents ACh binding and signaling for muscle movement to occur Myasthenia Gravis Eye muscles o Drooping of one or both eyelids o Double vision Face and throat muscles o Difficulty speaking after talking for some time o Difficulty swallowing and chewing o Limited facial expressions Morning Neck and limb muscles o Weakness in arms, legs, neck, fingers, etc o Weakness in chest muscles Evening 38 Agonistic antibody-mediated cell dysfunction IgG binds to cell surface Ag IgG stimulates cell functioning associated with the protein target (if receptor no ligand required; no regulation occurs No direct cell injury or inflammation occurs Graves’ Disease (hyperthyroidism) Eyes o Eyeballs protruding from their sockets o Double vision o Pain and photophobia o Blindness due to pressure on optic nerve Enlarged thyroid (goiter) General o o o o o Anxiety and irritability Heat sensitivity and sweating Fatigue Rapid irregular heartbeat Thick, red skin on shins or top of feet 39 Graves’ disease pathogenesis Driven by a Th2 response (IL-4-driven IgG4 production) Agonistic anti-TSHR (thyroid stimulating hormone receptor) IgG binds to the TSHR leading to: o T3 and T4 (hyperthyroidism) o TSH (TSH binds to TSHR T3/4 release negatively regulate TSH levels Anti-TSHR IgG binds to TSHR+ preadipocytes and fibroblasts behind the eye eye muscle hyperplasia and increased connective tissue levels (glycosamines) resulting in ophthalmopathy 40 Type II hypersensitivity therapies ANTI-GBM DISEASE Plasmapharesis + immunosuppressants (Glucocorticoids, Cyclophosphamide, Rituximab) MYASTENIA GRAVIS Cholinesterase inhibitors – cholinesterase is an enzyme that regulates levels of Ach by breaking it down; inhibitor prevents Ach loss and improves muscle contraction and strength Corticosteroids – reduce Ig production Immunosuppressants (Cyclosporine, Tacrolimus, Methotrexate, etc) + Albumin as replacement fluid Daily 4 L exchange for 2-3 wks GRAVES’ DISEASE Anti-thyroid agents – interfere with use of iodine to produce thyroid hormones (Methimazole) Radioactive iodine – taken up by thyroid and radiation destroys overactive thyroid cells over time Beta blockers – blocks thyroid hormone effects (Propranolol, Atenolol, Metoprolol) Thyroidectomy Ophthalmopathy – corticosteroids (reduce swelling), orbital surgery (create space for the eye to move back), intravenous Ig (IVIG) Functions of IVIG Saturates FcR inhibit FcR-mediated phagocytosis Saturates FcRn clearance of IgG Fc RIIB on phagocytes (inhibitory FcR which signals to inhibit phagocytosis) Contains anti-V region Ig to neutralize autoantibodies Contains anti-BAFF Ig that blocks B cell survival (FDC provides survival using BAFF) Ag presentation (T cell responses) 41