Pharmacy 310: Immune Disorders: Allergy & Hypersensitivity vs. Autoimmune Disease PDF

Pharmacy 310 Immune Disorders: Allergy & Hypersensitivity versus Autoimmune Disease Dr. Michael R. Doschak Professor Faculty of Pharmacy & Pharmaceutical Sciences University of Alberta Email: mdoschak@ualb...

Pharmacy 310 Immune Disorders: Allergy & Hypersensitivity versus Autoimmune Disease Dr. Michael R. Doschak Professor Faculty of Pharmacy & Pharmaceutical Sciences University of Alberta Email: [email protected]  Allergy & Hypersensitivity Immune system over-reaction, often to harmless environmental antigens Termed “Allergic” or “Hypersensitivity” reactions Allergy [Gr: Altered reactivity] Afflicts 10-40% in developed countries Can result in Anaphylaxis (rapidly progressing, life-threatening allergic reaction) Figure 10-1 part 1 of 2 Figure 10-1 part 2 of 2  Four Types of Hypersensitivity Reactions Grouped according to the effector mechanisms that produce the reaction Types I, II, and III mediated by Antibody effector molecules Type IV caused by cytotoxic products of effector T-cells Figure 10-2 part 1 of 2 Figure 10-2 part 2 of 2  Type I Hypersensitivity (Anaphylactic) Commonly caused by inhaled particulate Antigen (eg, plant pollens, dried dust mite or pet proteins) Ag binds to specific IgE on granulocyte cells expressing Fcε (epsilon) receptors [primarily on mast cells, eosinophils, basophils] Causes degranulation of the cell and the release of “pre-packaged” inflammatory mediators Later stage mediators are also synthesized by the cells after activation Molecules Released by Mast Cells (Red: Immediate “pre-packaged” reactants) Figure 10-5 part 1 of 2 Molecules Released by Mast Cells (Red: Immediate “pre-packaged” reactants) Figure 10-5 part 2 of 2 (White: Synthesized after mast cell activation)  Mast Cells synthesize Prostaglandins and Leukotrienes from Arachidonic Acid (produced by oxidation of cell membrane fatty acids) Figure 10-7 part 1 of 2 Tissue Specific Effects of Degranulation Figure 10-18  The Eosinophil Response The Eosinophil response is highly toxic to parasites, but potentially damaging to host tissues as well Eosinophils mostly reside in loose connective tissues underlying epithelial and mucosal surfaces (notably for the respiratory, gastrointestinal and urogenital tracts), with only a small minority found in peripheral blood Eosinophils will regulate expression of Fcε (epsilon) and Complement receptors after stimulation by an inflammatory environment  The Eosinophil Response Figure 10-8 Picture of a Langerhans cell Blood smear with partly (skin-resident macrophage) degranulated eosinophils (arrows) histiocytosis Molecules Released by Eosinophils Figure 10-9 part 1 of 2 (Red: Immediate “pre-packaged” reactants) Molecules Released by Eosinophils Figure 10-9 part 2 of 2 (White: Synthesized after Eosinophil activation) Basophil granules are similar (but not identical) to Mast cells. Common stem-cell precursor with Eosinophil. Will secrete IL-4 Figure 10-11 and IL-13 to initiate TH2 lymphocyte activation (Aby secretion) The site (route) of allergen exposure will dictate the type of allergic response Figure 10-12 Sensitization to Inhaled Allergen Figure 10-15 part 1 of 2  Figure 10-15 part 2 of 2 IL-4 central to IgE isotype production  Immediate vs. Late-phase allergic reactions IgE-mediated allergic reactions consist of an immediate response followed by a late-phase response Seen in the lungs with allergic asthma, in the nasal mucosa with allergic rhinitis (hay fever), and in the intestinal mucosa with ingested food allergens Allergens that activate mast cells in the skin cause raised itchy swellings (or wheals) known as an urticarial rash or hives Forms the basis for allergen skin-prick testing  Allergic Asthma Figure 10-22 part 1 of 2  Allergic Asthma Figure 10-22 part 2 of 2 Time Course of an Asthmatic Response Figure 10-17 FEV: Forced Expiratory Volume (breathing capacity)  Allergic Rhinitis Figure 10-21 part 1 of 2  Allergic Rhinitis Figure 10-21 part 2 of 2 Local Allergens – Skin “Wheal & Flare” Figure 10-24 part 1 of 2 Allergen-induced Release of Histamine Figure 10-24 part 2 of 2 Ragweed Saline Histamine Food Allergies Causing Intestinal and Systemic Effects Figure 10-25 part 1 of 2 Figure 10-25 part 2 of 2  Allergic Reaction Treatment (3 current strategies) Prevention: Avoid contact with allergen (food, mites, pets, seasonal pollen) Pharmacological: – Block effector pathways (e.g., histamine receptor blockers) – Suppress leukocyte function (corticosteroids) – Prevent degranulation (Cromolyn sodium) – Treat anaphylactic reactions (Epinephrine [a.k.a. Adrenaline] – acts as potent vasoconstrictor to counter life-threatening systemic vasodilation)  Allergic Reaction Treatment (3 current strategies) Immunological: Prevent the production of allergen-specific IgE – Desensitization procedure, to shift away from IgE towards IgG4 isotype – Series of allergen injections, with initial dose very small, and gradually increased – or, Vaccination with discrete allergen-derived peptides to promote TH1 responses, or anti-idiotype Aby vaccine Example of Acute Management of Anaphylaxis (Information reference ONLY!) Australian Medicines Handbook, 2007 Courtesy King Pharma Canada Ltd.  Type II Hypersensitivity (Cytotoxic) Caused by small molecules that covalently bond to surface of human cells Produce modified structures recognized as foreign by the immune system Results in cell destruction through IgG Aby formation and Complement protein activation, and phagocytosis Antibiotic penicillin can induce Type II Figure 10-26 Figure 10-27 part 2 of 2 Figure 10-28 part 2 of 2  Type III Hypersensitivity (Immune Complex) Due to small, insoluble immune complexes of Ag and specific Aby Immune complexes become deposited on walls of blood vessels (kidneys), or lung alveoli Activate Complement on tissue surface, and ensuing inflammatory response damages tissue Immune Complex Stoichiometry Figure 10-29  Type III Hypersensitivity Can result after Intravenous administration of therapeutic proteins/Aby from other species (termed “Serum sickness”) Will manifest from 4 to 10 days after exposure Results in fever, lymphadenopathy, arthralgia, cutaneous eruptions (urticarial rash), gastrointestinal disturbances (vomiting, diarrhoea), proteinuria, decreased serum complement levels Serum Sickness Figure 10-32 Type III Urticarial Rash Polycyclic wheal-like swelling with central clearing (similar to hives) that overlap each other Can be located on the trunk, extremities, face, lateral borders of the hands and feet Oral edema without mucosal involvement  Type III Arthus Reaction Localized area of erythema and hard swelling (induration) from immune complex formation after sub-cutaneous Ag injection (notably diphtheria & tetanus vaccines) Named after Nicolas Arthus who detailed the reaction in 1903 (repeated horse serum injections in rabbits) Can also occur from sub-cutaneous exposure to fungi in mold, proteins in feathers & furs Figure 10-30 part 1 of 2 Figure 10-30 part 2 of 2 Type III Hypersensitivity Results in vasculitis  Route of Immunogen Exposure Dictates the Resulting Type III Disease Figure 10-31 part 1 of 2  Type II & III Hypersensitivity Treatment Strategies Discontinue and avoid known drugs that ellicit hypersensitivity (penicillins, scavenging Aby therapy) For blood products, careful cross-matching of ABO and Rhesus antigens Mild cases (urticaria): antihistamines Anaphylaxis: epinephrine, oxygen supplementation, airway management, ECG (heart) monitoring, i.v. fluids (and/or dialysis) [fluid/electrolyte disturbances, cardiac arrhythmia] Type IV Hypersensitivity (Delayed Type and Contact Type) Caused by the products of Ag-specific effector T- cells Mostly by CD4 TH1 (Eg, inflammatory reaction around the site of an insect bite or sting A minority of reactions caused by cytotoxic CD8 T-cells (Eg, contact with small, reactive, lipid soluble molecules [urushiol, a.k.a. penta-deca- catechol in poison ivy]) Also involved with Chronic Transplant Rejection (organ and/or bone marrow cells) and Autoimmune Disease Figure 10-33 Figure 10-34 Figure 10-35  Leaf Poison Ivy Vine Flower (Wikipedia.org)  Poison Ivy Figure 10-36 (Urushiol) Results in Bullous (fluid filled) lesions  Type IV Hypersensitivity Treatment Strategies Avoid contact with known agents that ellicit hypersensitivity (nickel, plants) Monitor for local infection risk Corticosteroids, cyclosporins and immunotherapy  Introduction to Autoimmune Diseases A related set of chronic diseases caused by adaptive immune responses that become misdirected at healthy cells and tissues More than 100 types of Autoimmune Disease have been clinically described  Autoimmune Disease Results from Aby and effector T-cells that attack healthy cells and tissues, as though they were infected with a pathogen Termed an “autoimmune response” – Remains throughout lifetime of patient – Usually increases in severity and may contribute to cause of death  Autoimmune Disease Classified by causative effector mechanism – which correspond to the type II, type III and type IV hypersensitivities No known autoimmune disease is mediated by IgE (the cause of type I hypersensitivity)  Autoimmune Disease Type II disease caused by Aby against cell surface or matrix antigen Type III disease caused by Immune Complexes Type IV disease caused by T-cell mediated cytotoxicity  Autoimmune Hemolytic Anemia Type II autoimmune disease frequently target erythrocytes (red blood cells, RBC) In autoimmune hemolytic anemia, IgG and IgM Aby bind to antigens on the RBC surface, where they activate Complement by the Classical Pathway RBC coated with Aby and opsonins (notably C3b) are cleared from the circulation (by Fc and/or C’ receptors on phagocytic cells in the spleen), or undergo lysis after formation of the MAC  Association of Infections with Autoimmune Disease Autoimmune Disease can be an adverse side-effect of an immune response to infection – Evidence of infection associated with almost every autoimmune disease! Experiments inducing autoimmune disease with injected extracts of cellular antigens need to be mixed with microbial products to induce response Rheumatic Fever involves inflammation of heart, joint, and kidney tissues (2-3 weeks following throat infection with certain strains of Streptococcus pyogenes Association of Infections with Autoimmune Disease  Lyme Disease Defined as an infection caused by Borrelia bacteria transmitted by tick bites, from rodents to humans Can be prevented by early, single course of doxycycline antibiotic Characteristic “bullseye” rash (erythema migrans; sometimes just patchy round shape), surrounding skin site of bite Can manifest as chronic neurological symptoms / fatigue with ongoing infection, or predispose to developing an autoimmune arthritis (termed Lyme Arthritis) Lyme disease different to “Tick Paralysis” (muscle weakness and respiratory difficulty 2-7 days after tick bite), thought to be caused by Neurotoxin from tick salivary gland Tick paralysis depends on duration of tick residence, and will resolve over time  Lyme Disease (Bullseye Rash) https://www.ualberta.ca/news-and-events/newsarticles/2017/july/3-surprising-facts-about-lyme-disease CDC: Centers for Disease Control & Prevention http://www.cdc.gov/ticks/index.html Canadian Lyme Disease Foundation http://canlyme.com/ HLA as the Dominant Genetic Factor in Autoimmune Disease Susceptibility to autoimmune disease is familial, and varies between ethnic groups Almost every autoimmune disease has an HLA gene association – notably with the “polymorphic” and “highly polymorphic” class I (A, B, C) and class II (DQ, DR) MHC isotypes Particular alleles of polymorphic HLA genes are combined in HLA haplotypes at higher frequency with particular disease Phenomenon of preferential allele association is called linkage disequilibrium Figure 3-23  Summary: Autoimmune Disease Type II disease caused by Aby against cell surface or matrix antigen Type III disease caused by Immune Complexes Type IV disease caused by T-cell mediated cytotoxicity  Resource Materials Parham P: The Immune System, 2nd Edn., Garland Science, New York, 2005. Australian Medicines Handbook, 2007 AMH Pty Ltd, Rundle Mall, Adelaide S.A., 5000 © Copyrighted material contained herein is reproduced under ss. 29-29.4 of the Canadian Copyright Act. This document is available for your individual use; further distribution may infringe copyright.