Anaphylactic reaction Canonical concept of pathophysiology Internal factors e.g. predisposition Pathological condition External factors e.g. trauma “Updated”concept of pathophysiology Internal factors e.g. predisposition Pathological condition External factors e.g. trauma Immune system Immunity ̶ Innate ̶ Non-specific ̶ The first line of defense ̶ Universal tool (pathogen, tissue damage) ̶ Adaptive, acquired ̶ Specific ̶ The second line of defense ̶ Defense against non-self structures (pathogen, tumor cells) ̶ Only in vertebrates https://microbiologyinfo.com/difference-between-innate-and-adaptive-immunity/ Innate immunity Analytic functions Surveillance Damage e.g. trauma, necrosis Danger e.g. malign cells, pathogens Innate immunity Executive functions Analytic functions Surveillance Defense Healing Damage e.g. trauma, necrosis Danger e.g. malign cells, pathogens Innate immunity Executive functions Analytic functions Surveillance Defense Healing Damage e.g. trauma, necrosis Danger e.g. malign cells, pathogens Local inflammatory response Tissue macrophages Endothelial cells Pro-inflammatory cytokines Adhesion molecules Systemic inflammatory response Peripheral WBC infiltration Pathogen invasion/tissue damage Activation Targeting Local inflammatory response Tissue macrophages Endothelial cells Pro-inflammatory cytokines Adhesion molecules Systemic inflammatory response Peripheral WBC infiltration Pathogen invasion/tissue damage Activation Targeting Pro- inflammatory cytokines Proteolytic enzymes Reactive oxygen species Inflammation associated tissue damage may be worse than initial pathology Adaptive immunity Adapted from https://www.sciencedirect.com/topics/immunology-and-microbiology/adaptive-immune-system B cell response CD4+ T cell response CD8+ T cell response Type of immunity Humoral Cellular Cellular Precursor cell B lymphocyte CD4+ precursor CD8+ precursor Effector cell Plasma cell CD4+ helper CD8+ Cytotoxic T lymphocyte Receptors recognize antigenic epitopes presented as Linear and conformational epitopes on foreign antigens Antigenic peptides on class II molecules Antigenic peptides on class I molecules Mediator molecules Immunoglobulins (Igs) Cytokines Perforins, Granzymes, Cytokines Persistence of effectors Yes No No Anamnestic (memory) response Yes Yes Yes Classes of immunoglobulins Moura, Rita & Agua-Doce, Ana & Weinmann, Pamela & Graça, Luis & Fonseca, João. (2008). B cells: From the bench to the clinical practice. Acta reumatológica portuguesa. 33. 137-54. Immunopatological conditions ̶ Hypersensitivty ̶ Reaction against harmless antigen ̶ Antibody-mediated or cell-mediated ̶ Autoimmune diseases ̶ Reaction against autoantigen ̶ Immunodeficiency ̶ Deffect of immune system ̶ Genetically determined or acquired Hypersensitivity ̶ Immune response that is more damaging than helpful ̶ Gell and Coombs clasification ̶ Type I - immediate hypersensitivity ̶ Type II - is caused by specific antibody binding to cells or tissue antigens ̶ Type III - is mediated by immune complexes ̶ Type IV - is the only class of hypersensitive reactions triggered by antigen-specific T cells Type of hypersensitivity Immunopathologic mechanisms Mechanisms of tissue injury and disease Examples Type I reaction: Immediate hypersensitivity IgE antibody Mast cells and their mediators (vasoactive amines, lipid mediators, cytokines) Anaphylactic reaction Allergies Type II reaction: Antibody mediated IgM, IgG antibodies against cell surface or extracellular matrix antigens Opsonization and phagocytosis of cells Complement-and Fc receptor-mediated recruitment and activation of leukocytes (neutrophils, macrophages) Abnormalities in cellular functions, e.g., hormone receptor signaling Haemolitic anemias Transfusion reaction Erythroblastosis fetalis Graves`disease Myasthenia gravis Type III reaction: Immune complex mediated Immune complexes of circulating antigens and IgM or IgG antibodies Complement-and Fc receptor-mediated recruitment and activation of leukocytes Vasculitis Revmatoid arthritis Post-streptococ glomerulonephritis Type IV reaction: T cell mediated 1. CD4+ T cells (delayed-type hypersensitivity) 2. CD8+ CTLs (T cell-mediated cytolysis) 1. Macrophage activation, cytokine-mediated inflammation 2. Direct target cell killing, cytokine-mediated inflammation Tuberculosis Syphilis Contact dermatitis Atopy vs. allergy vs. anaphylaxis - Atopy (Greek ατοπία - placelessness) is an inborn predisposition for exaggerated IgE mediated immune reaction to harmless environmental antigens (allergens). - Allergy is a clinical manifestation of inappropriate IgE immune response to allergens. Allergy occurs after sensitisation, is rapid and predictable. ̶ Anaphylaxis is an acute systemic (multi-system) and severe Type I Hypersensitivity allergic reaction in humans and other mammals. The term comes from the Greek words ανα ana (against) and φύλαξις phylaxis (protection). Atopy vs. allergy vs. anaphylaxis - Atopy (Greek ατοπία - placelessness) is an inborn predisposition for exaggerated IgE mediated immune reaction to harmless environmental antigens (allergens). - Allergy is a clinical manifestation of inappropriate IgE immune response to allergens. Allergy occurs after sensitisation, allergy is rapid and predictable. ̶ Anaphylaxis is an acute systemic (multi-system) and severe Type I Hypersensitivity allergic reaction in humans and other mammals. The term comes from the Greek words ανα ana (against) and φύλαξις phylaxis (protection). ̶ exposure to an antigen ̶ activation of TH2 cells specific for the antigen ̶ production of IgE antibody ̶ binding of the antibody to Fce receptors of mast cells ̶ triggering of the mast cells by re-exposure to the antigen, resulting in the release of mediators from the mast cells and the subsequent pathologic reaction Immediate hypersensitivity: Type I reaction Immediate hypersensitivity: Type I reaction The clinical and pathologic manifestations ➢ Immediate reaction ➢ Degranulation of mast cells and eventually basophils ➢ Late-phase reaction ➢ Inflammation mediated leukocytes infiltrating from periphery (neutrophils, macrophages, lymphocytes, eosinophils, basophils) Mast cell ̶ In perivascular space of all subcutaneous/submucosal tissues, ̶ Including conjunctiva, upper/lower respiratory tracts, and gut ➢ Activation of mast cells by binding of multivalent antigens to the IgE – FcεRI complex ➢ Response of mast cells to activation ̶ Degranulation - secretion of the preformed mediators by a regulated process of exocytosis, ̶ Production and secretion of arachidonic acid derivates (leukotuirens and prostaglandins,etc.), ̶ Production and secretion of cytokines and chemokines Mediators derived from Mast Cells ̶ Biogenic amines ̶ histamine ̶ Granule proteins and proteoglycans (Enzymes) ̶ Serine proteases ̶ Lipid mediators ̶ Prostaglandins, leukotrienes ̶ Cytokines ̶ IL-1, IL-3, IL-4, IL-5, IL-6, GM-CSF, TGF-β, TNF-α Mast cell activation Mast cell degranulation Biological effect of mediators Biological effect of histamine ̶ H1- receptors • Constriction of smooth muscle • Increased vascular permeability • Irritation of sensitive nerves • Vasodilation • Prostaglandin genration ̶ H2-receptors • Stimulation of HCl secretion • Positive chronotropic and ionotropic effect • Release of histamine from mast cells and basophils ̶ H3-receptors (nerve cells). • Regulatory function – after activation – decrease of histamine and other mediators production in CNS ̶ H4-receptory (eosinophils, bone marrow, lung) • Regulation of immune system Tissue Effects of Histamine ➢ Cardiovascular  Decreased blood pressure  Increased heart rate  Edema (separation of endothelial cells & increased permeability) ➢ Respiratory  Bronchoconstriction ➢ Gastrointestinal  Smooth muscle contraction and diarrhea ➢ Skin  Urticaria Tissue Effects of Histamine ➢ Cardiovascular  Decreased blood pressure  Increased heart rate  Edema (separation of endothelial cells & increased permeability) ➢ Respiratory  Bronchoconstriction ➢ Gastrointestinal  Smooth muscle contraction and diarrhea ➢ Skin  Urticaria Leukotriens Effects of other mediators LTC4, LTD4, LTE4, LTB4 ̶ Potent bronchoconstrictors ̶ Increased vascular permeability ̶ Slower onset than histamine ̶ Effects last longer than histamine PG D2 ̶ Vasodilation ̶ Bronchospasm ̶ Increased capillary permeability Prostaglandins ̶ Vasodilation ̶ Increased capillary permeability ̶ Bronchoconstriction ̶ Stimulates vascular endothelium to release vasoactive factors (Prostacyclin, NO) ̶ Causes platelets to aggregate and release inflammatory products ̶ PAF causes profound wheal-and-flare response, smooth muscle contraction & increase capillary permeability Kinins Platelet-Activating Factor Clinical manifestation ̶ Localized reaction ✓Asthma bronchiale ✓Nasal allergy ✓Atopic dermatitis ✓Food allergy ̶ Systemic (anaphylactic reaction) ✓Generalized, life-threatening, shock Immediate hypersensitivity: Type I reaction Clinical picture and manifestation ̶ Symptoms depend on: • Sensibilization level of patient • Place of allergen entry • Allergen type ̶ Mucous membrane, derm ✓Erythema, exanthema, pruritus, edema ̶ Respiratory system ✓ Acute rhinitis, nasal obstruction, sneezing, irritation to cough, breething problems ̶ GIT ✓vomitus, colic, diarrhoea Clinical picture and manifestation ̶ Cardiovascular system: ✓Palpitation, tachycardia, hypotension, arrhytmia ̶ Urogenital system: ✓Picture of renal colic ̶ General symptoms: ✓Cognition disorders, spasms Anaphylaxis vs. anaphylactoid reaction ̶ Anaphylaxis ̶ Systemic reaction of multiple organ systems to antigen-induced IgE-mediated immunulogic mediator release in previously sensitized individual ̶ Anaphylactiod reaction ̶ Non-IgE mediated ̶ Anaphylatoxins-mediated ̶ No sensitization needed, may occur after first contact with anaphylatoxin ̶ Clinical manifestation and treatment similar to anaphylactic reaction Anaphylatoxins (Histamine liberators) ̶ Nonimmunologic histamine release or complement activation ̶ Bee sting venom ̶ Iodinated contrast ̶ Some drugs ▪ Antibiotics (Vancomycin) ▪ Muscle relaxants (atracurium, mivacurium) ▪ Opioids (morphine, meperidine, codeine) ▪ Thiobarbiturates Complement ̶ “activation follows both immunologic (Ab-mediated, i.e., classic pathway) and nonimmunologic (alternative) pathways to include a series of multimolecular, selfassembling proteins that liberate biologically active complement fragments of C3 & C5” ̶ C3a & C5a “anaphylatoxins” ̶ Release histamine, contract smooth muscle, increase capillary permeability and stimulate interleukin synthesis ̶ C5a interacts with specific high-affinity receptors on white blood cells & platelets initiating leukocyte chemotaxis, aggregation & activation ̶ Aggregated leukocytes embolize to various organs, producing microvascular occlusion & liberation of inflammatory mediators such as arachadonic acid metabolites, O2 free radicals & lysosomal enzymes Treatment of Type I reaction ̶ Adrenaline i.v. Stimulation of cAMP production due to binding to b-receptors in mast cells (cAMP inhibits histamine release from mast cells) ̶ Corticosteroids i.v. Inhibition of leucotrien synthesis Inhibition of inflammatory cells infilration in place of allergy reaction Inhibition in cytokine production ̶ Antihistaminics Inhibition of H1 and H2 receptors in terminal cells Summary ̶ 4 types of hypersensitivities ̶ 3 involve antibodies ̶ Anaphylaxis mediated by IgE ̶ Anaphylactoid is Ab independent Summary ̶ Anaphylaxis ̶ Bronchospasm ̶ Vasodilation, increased capillary permeability ̶ Associated with profound CV collapse ̶ Urticaria Summary ̶ Mediators ̶ Histamine ̶ Leukotrienes & Prostaglandins ̶ Kinins ̶ Platelet-activating Factor ̶ Complement Simons FER. 9. Anaphylaxis. Journal of Allergy and Clinical Immunology. 2008;121:S402–S407.