BMS Immunology Hypersensitivity Spring 2023 Student Copy PDF

HYPERSENSITIVITY REACTIONS NATHAN M. PHAM, OMS-IV MARIAN UNIVERSITY COLLEGE OF OSTEOPATHIC MEDICINE [email protected] OBJECTIVES  Diagram the pathophysiology of each Hypersensitivity reaction  Identify and explain for each Hypersensitivity reaction the:  Immune component  Antigen...

HYPERSENSITIVITY REACTIONS NATHAN M. PHAM, OMS-IV MARIAN UNIVERSITY COLLEGE OF OSTEOPATHIC MEDICINE [email protected] OBJECTIVES  Diagram the pathophysiology of each Hypersensitivity reaction  Identify and explain for each Hypersensitivity reaction the:  Immune component  Antigen type  Mechanism  Timing  Related disorders  Recognize and correlate disorders to the appropriate Hypersensitivity reaction WHAT IS A HYPERSENSITIVITY? NORMAL ROLE OF THE IMMUNE SYSTEM Recognition of infection Amplification of First line of defense and Clearance of infection response Local immune defense Normal flora, skin, Complement, Phagocytes, Macrophage B cells, Specific mucosal surfaces, local Antimicrobial peptides, activation, Cytokines, antibodies, CD4 and CD8 chemical factors phagocytes - neutrophils, DCs migrate towards T T cells, T cell dependent macrophages, dendritic and B lymphocytes to activation of cells (DCs) initiate a specific immune macrophages, Cytotoxic T response cells Innate immunity Adaptive immunity  THE (TRUE) NATURE OF THE IMMUNE SYSTEM  Both friend and foe  It all has to do with recognition:  Self antigens → autoimmunity  Oversensitivity to innocuous and/or otherwise harmless antigens → Hypersensitivity HYPERSENSITIVITY & ALLERGIES FUNDAMENTALS 1. All hypersensitivities are the consequence of an adaptive immune response 2. There must be an initial stimulus - aka an inciting antigen Allergen/Innocuous antigen Adaptative Immune Response (Development of Memory) Subsequent re-exposure to allergen/antigen Overreaction of the Immune System (Hypersensitivity) GELL AND COOMBS CLASSIFICATION OF HYPERSENSITIVITY Type I Type II Type III Type IV IgE-mediated IgG or IgM-mediated Cell-mediated or Immune complex mediated Anaphylaxis Cytotoxicity Delayed-type A C I D GET OUT YOUR PAPERS!  For each Hypersensitivity: I. Immune Component? I. Antigen? I. Mechanism? I. Time? I. Disorders? TYPE I HYPERSENSITIVITY (ANAPHYLAXIS)  Antigens are usually soluble – ex: peanuts, pollen, animal dander, etc.  Pathogenesis: Initial exposure: innocuous antigen recognized as foreign Immune response leads to IgE generation by plasma cells Subsequent exposure: IgE binds to Mast Cells via FcE-Receptor Activation of Mast Cells and Histamine release Inflammation and Anaphylaxis TYPE I HYPERSENSITIVITY – ANAPHYLAXIS  Histamine mediated  ↑ Vascular permeability, vasodilation, swelling/inflammation, bronchoconstriction  Systemic response – within an hour of exposure  An acute, potentially life-threatening hypersensitivity reaction  Sudden respiratory signs and symptoms – shortness of breath, wheezing, cough, stridor, hypoxemia  Sudden drop in blood pressure CAUSES OF ANAPHYLAXIS COMMON DISORDERS AND RESPONSE Syndrome Response Allergic rhinitis Irritation of nasal mucosa (red, watery, itchy eyes) (hay fever) Allergic asthma Bronchial constriction, airway inflammation Wheal and flare Local edema, local vasodilation Food allergy Vomiting, pruritus, diarrhea, urticaria Anaphylaxis Edema, vasodilation, shock TYPE 1 HYPERSENSITIVITY MANAGEMENT  Depends on the condition  Antihistamines (oral or intranasal)  Corticosteroids (oral, inhaled)  Mast cell stabilizers (Cromolyn)  Epinephrine  Allergen Immunotherapy (Desensitization)  Subcutaneous (“allergy shots” – multi-allergen)  Sublingual (limited - monotherapy) TYPE II HYPERSENSITIVITY (CYTOTOXICITY)  Antigens are usually cell-surface antigens – ex: Rh and ABO antigens on RBCs  Pathogenesis: Initial exposure: innocuous antigen recognized as foreign Immune response leads to IgG or IgM generation by plasma cells Subsequent exposure: IgG/IgM binds cell surface antigen Antibody-Dependent Cellular Cytotoxicity and Complement activation Inflammation TYPE II HYPERSENSITIVITY – HEMOLYTIC DISEASE  Acute Hemolytic Transfusion Reaction:  Symptoms (typically within 24hrs):  Fever, chills, itching, urticaria, dyspnea, hemoglobinuria, hypotension  Dangerously low blood pressure → shock → multi-organ failure and death TYPE II HYPERSENSITIVITY – HEMOLYTIC DISEASE  Hemolytic Disease of the Newborn:  ABO incompatibility  Rh factor incompatibility  Recipe: Rh-negative mother + Rh-positive father = Rh-positive baby  Treatment:  RhoGAM®  Anti-Rh IgG TYPE III HYPERSENSITIVITY (IMMUNE COMPLEX)  Antigens are usually soluble – ex: anti-venom, self-DNA  Pathogenesis: Initial exposure: innocuous antigen recognized as foreign Immune response leads to IgG generation by plasma cells Subsequent exposure: IgG binds to soluble antigen forming free-floating Immune Complexes Immune complexes deposit in various tissue and activates Complement Inflammation TYPE III HYPERSENSITIVITY: COMPLEMENT  Complement Activation  Production of anaphylatoxins C3a and C5a  Mast cell degranulation → histamine  Neutrophil migration and degranulation  Release of lysosomal enzymes  Extracellular destruction of immune complexes  Damage to surrounding tissues  TYPE III HYPERSENSITIVITY – SERUM SICKNESS  Serum Sickness:  Cardinal features: rash, fever, polyarthralgias or polyarthritis  Timing: 1-2 weeks after first exposure  Significant quantities of antibody are needed to generate complexes and symptoms  Agents:  Microbial anti-toxins (ex: equine anti-diphtheria or anti-rabies)  Venom anti-toxins (ex: equine, rabbit, ovine anti-snake venom)  Higher doses = more likely to result in serum sickness TYPE III HYPERSENSITIVITY – SLE  Systemic Lupus Erythematosus (SLE):  Chronic autoimmune disease of unknown cause that can affect virtually any organ of the body  Major features: fatigue, fever, myalgia, arthritis/arthralgias, mucocutaneous involvement…and everything else (heart, lungs, GI, neuro, what have you!)  Type III hypersensitivity underlies most of the pathophysiology  Antigen: self-DNA  Antibody: IgG  End result: systemic reaction to immune complex deposition  Treatment: complex and tailored to individual’s disease condition  TYPE IV HYPERSENSITIVITY (DELAYED-TYPE)  Antigens are usually soluble – ex: poison ivy, metals, dyes/fragrances, tuberculin  Can be cell surface as well - granulomatous hypersensitivity  Pathogenesis: Initial exposure: innocuous antigen recognized as foreign Immune response leads to generation of TH1 type response Subsequent exposure: memory TH1 cells recognize antigen Activation of TH1 pathway – cytokines + CD8+ and MØ activation Inflammation TYPE IV HYPERSENSITIVITY: TH1 RESPONSE  Cell-mediated  We classically think of the Th1 effector T-cell response when considering intracellular pathogens  MØ activation helps clear infection  Mechanism:  Sensitization: sensitization of Th1 helper T-cells to release cytokines  Elicitation: activation of cytotoxic T-cells and macrophages TYPE IV HYPERSENSITIVITY – PPD  PPD – Tuberculin:  Antigen: soluble tuberculin – protein extract from M. tuberculosis  Tests for prior exposure to TB  If prior exposure:  Activation of memory helper T-cells  Production of activating/inflammatory cytokines (IFN-𝞬, TNF-𝛼)  Activation of resident macrophages and recruitment of additional immune cells  Reaction at injection site 1-3 days later  High rate of false positives  TYPE IV HYPERSENSITIVITY – CONTACT DERMATITIS  Contact dermatitis:  Antigen: soluble haptens (ex: metals, chemicals, plants)  Haptens: low molecular weight chemicals that are NOT immunogenic by themselves  Penetrates skin and results in inflammatory reaction  Presentation: eczematous skin reaction at contact site within 24-48 hours  THANK YOU! Questions? Email: [email protected] SUMMARY & REVIEW Type I Type II Type III Type IV Immune component IgE IgG or IgM IgG T cells Antigen Soluble Cell surface Soluble Soluble or cell surface Mechanism Mast cell Cytotoxicity Immune Cell-mediated activation: complexes Anaphylaxis Time < 60 mins 1-24 hours 1-2 weeks 24-48 hours Allergic Hemolytic Serum Contact Disorders asthma, transfusion sickness, dermatitis, allergic rhinitis reaction Systemic Lupus Tuberculin Erythematosus reaction