MOD 4-PATHO-Hypersensitivity Reactions and Prototype Disorders PDF

PATHOLOGY 08/28/2024. MOD 4: HYPERSENSITIVITY REACTIONS AND PROTO...

PATHOLOGY 08/28/2024. MOD 4: HYPERSENSITIVITY REACTIONS AND PROTOTYPE DISORDERS Dr. Joanne Marie R. Pascual, MD Trans Group/s: 5B, 6B OUTLINE The immune system can be likened to the proverbial double-edged sword that although it normally serves as our defense against infections, a hyperactive immune I. Introduction system may cause diseases that can sometimes be fatal. II. Hypersensitivity III. Type I Hypersensitivity II. HYPERSENSITIVITY A. Common Antigens/Allergens Rather than being specific and distinct disease B. Phases of Type I Immune Reaction conditions, hypersensitivity reactions represent exaggerated or inappropriate immune responses to an C. Response Phases of the Immune Reaction antigen triggering a pathologic reaction. D. Symptoms It is an immunologically mediated mechanism of tissue E. Factors for Allergy Development Susceptibility injury. IV. Type II Hypersensitivity ○ These reactions can be elicited by exogenous environmental antigens both microbial or A. Mechanisms non-microbial in nature or endogenous B. Summary self-antigens. V. Type III (Immune Complex) Hypersensitivity Results from an imbalance between the effector mechanisms of immune responses and the control A. Antigens that Form Immune Complexes mechanisms that serves to limit those responses B. Major Forms of Immune Complex-Mediated The development of hypersensitivity diseases is often Hypersensitivity associated with inheritance of particular susceptibility C. Mechanism of Immune Complex-Mediated genes. Hypersensitivity D. Morphology HYPERSENSITIVITY REACTIONS E. Other Examples F. Summary Type I Immediate (IgE) Immunoglobulin VI. Type IV (Cell-Mediated) Hypersensitivity mediated Type II Antibody-mediated (IgG, IgM) hypersensitivity A. CD4+ Mediated Hypersensitivity / Type III Immune Complex (IgG, IgM) reactions Cytokine-Mediated Inflammation B. Inflammatory Reactions Stimulated by CD4 T-Cells Lymphoid C. Clinical Examples of CD4+ T-Cell Mediated Cell-Mediated (CD4+ / CD*+ Type IV cell-mediated or Inflammation T cells cell-mediated D. CD8+ Mediated Hypersensitivity E. Other Examples of Beneficial Protective Response Each type goes by another name that usually of T-Lymphocyte Mediated Hypersensitivity corresponds to the mechanisms underlying the reaction. Classification is of value to help distinguish the manner an immune response causes tissue injury and disease OBJECTIVES and accompanying pathological and clinical At the end of this video lecture, the learner should be able to: manifestations of each. Explain the pathophysiologic mechanism underlying Types I, II, and II - immunoglobulin-gated Type I hypersensitivity reactions hypersensitivity reactions Correlate the pathophysiology of Type I Hypersensitivity Type IV - lymphoid cell-mediated hypersensitivity reactions with the clinical manifestations of prototype diseases III. TYPE I HYPERSENSITIVITY Compare and contrast localized vs systemic Type I Also called IgE mediated hypersensitivity or hypersensitivity reactions Immediate type hypersensitivity ○ commonly called “allergy” PART 1 Disease examples: allergies, allergic rhinitis, bronchial I. INTRODUCTION 📖 asthma, and anaphylaxis Rapidly developing immunologic reaction occurring within minutes after the combination of an antigen with The immune system is vital for survival because our environment is dealing with potentially deadly microbes, antibody bound to mast cells in individuals previously and it is our immune system that protects us from infectious pathogens. 📖 sensitized to the antigen Mediated by IgE antibodies directed against specific antigens (allergens) Pathology - Mod 4 Hypersensitivity Reactions and Prototype Disorders 1 of 16 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  IgE mediated Immediate Class Switching means that B cells, which would normally produce IgM antibodies in an acute immune IgE - primary antibody Rapid, occurring within response, will instead make antigen-specific IgE involved minutes antibodies. These IgE antibodies then attach themselves to the surface of mast cells. A. COMMON ANTIGENS/ALLERGENS The mast cells now become sensitized to the antigen Allergens - antigens that elicit a type 1 hypersensitivity and are all geared up for the next encounter with the reaction same antigen. ○ Substances or proteins outside our bodies food, pollen, animal dander, medications ○ Can also be from things that one comes in contact with talc, latex, insect bites B. PHASES OF TYPE I IMMUNE REACTION 1. FIRST EXPOSURE/SENSITIZATION PHASE Mast Cell Sensitization. Dra Pascual’s Lecture Video The First Phase, or Sensitization Phase is usually asymptomatic. This means that during an individual’s very first encounter with the antigen, no allergic symptoms will be seen. First Phase/Sensitization (Asymptomatic). Dra. Pascual’s Lecture Video 2. SECOND PHASE/REEXPOSURE PHASE An antigen is introduced to a genetically susceptible individual The introduction of an antigen (ie. pollen) stimulates naive T lymphocytes to differentiate into Type 2 T Helper Lymphocytes (TH2 cells) TH2 cells play a pivotal role in Type I Hypersensitivity reactions because they produce cytokines that initiate the sensitization phase. CYTOKINES PRODUCED BY TH2 CELLS Interleukin 5 Involved in the development and (IL-5) activation of Eosinophils which are important effectors in Type I Second Phase/Reexposure. Dra. Pascual’s Lecture Video Hypersensitivity. Upon reexposure to the same antigen, the sensitized Interleukin 13 Enhances IgE production and acts on mast cells can now recognize and attach to the antigen (IL-13) epithelial cells to stimulate mucus This attachment triggers mast cells to degranulate and production/secretion. release vasoactive amines and other proinflammatory mediators that are responsible for immediate type Interleukin 4 Promotes the development of additional hypersensitivity reactions. (IL-4) TH2 cells and induces antibody class switching of B cells. VASOACTIVE AMINES AND PROINFLAMMATORY MEDIATORS HISTAMINE Potent vasoactive and spasmogenic agents. LEUKOTRIENE Cause Bronchial smooth muscle C4 AND D4 contraction. Difficulty of breathing Vasodilation PROSTAGLANDIN Intense bronchospasm D2 Increased mucus secretion Vasodilation Class Switching. Dra Pascual’s Lecture Video Pathology - Mod 4 🏠 Hypersensitivity Reactions and Prototype Disorders 2 of 16 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  As the caliber of the blood vessel increases, fluid flow In the delayed phase, the recruited leukocytes amplify also increases but since the blood vessel is also more and sustain the immune response even without permeable, more fluid is allowed to leak into the additional exposure to the triggering antigen. interstitium. Of the recruited leukocytes, eosinophils are the most ○ This causes edema or swelling and urticaria or important because they liberate specific proteolytic hives. enzymes and proteins like the eosinophilic cationic ○ The aforementioned symptoms (difficulty of protein and major basic protein that are toxic to epithelial breathing) coupled with an increased mucus cells. secretion are typical of an allergic reaction. ○ Activated eosinophils and basophils can also Drugs used to treat allergies typically target histamine directly activate mast cells to release more and these other mediators to alleviate the symptoms of mediators. an allergy. Cytokine mediators: TNF α, IL-1,5, GM-CSF, chemokines ○ Eosinophils cause tissue damage by releasing proteolytic enzymes and proteins. ○ Eosinophils + basophils directly activate mast cells. Eosinophil, Mast Cell, Basophil. Dra. Pascual’s Lecture Edema and Urticaria. Dra. Pascual’s Lecture Video Video C. RESPONSE PHASES OF THE IMMUNE REACTION In addition, eosinophils contain Charcot-Leyden crystals ○ These are sometimes released to the extracellular Rapid Delayed space that can be detected in the sputum of patients with asthma Within minutes after 2-12 hours after ○ Promote inflammation and enhanced Th2 re-exposure to antigen re-exposure to the antigen response Histamine Cytokines: Leukotrienes ○ TNF ○ IL-5 ○ eotaxin 1. RAPID PHASE Within minutes (5-30 min) after re-exposure to the same antigen. The effects of histamine and other mast cell mediators present during the rapid phase of immune reaction. In the rapid response phase, vasoactive amines like histamine are the key players. Leukotrienes Mediators: ○ Histamine → bronchial smooth muscle contraction Charcot-Leyden Crystals (sputum in Bronchial Asthma). Dra. ○ Leukotrienes → increased vascular permeability Pascual’s Lecture Video and dilatation ○ Prostaglandin D2 → increased mucous gland It is believed that the delayed phase reaction is a major secretion cause of symptoms in some Type 1 hypersensitivity disorders, such as allergic asthma 2. DELAYED PHASE ○ Therefore, treatment of these disorders require the Happens 2-12 hours after re-exposure to the antigen. use of broad-spectrum anti-inflammatory drugs, Cytokines like the tumor necrosis factor (TNF), such as steroids, rather than antihistamine drugs, Interleukin 5 (IL-5) and chemokines, such as eotaxin, which are of benefit only in the immediate reaction set the stage for the delayed phase. as occurs in allergic rhinitis. These cytokines, particularly Interleukin 5 (IL-5), which is also called the most potent eosinophil-activating cytokine, recruit more eosinophils and other leukocytes like basophil to the site of antigen deposition. Pathology - Mod 4 🏠 Hypersensitivity Reactions and Prototype Disorders 3 of 16 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited. D. SYMPTOMS 2. ENVIRONMENTAL FACTORS Immediate hypersensitivity may occur as a systemic or Environmental Pollutants localized reaction ○ Exposure to such is an important predisposing factor for allergy development. 1. LOCAL Viral Infections Exemplified by atopic allergies ○ Viral infections of the airways are triggers for Affected individuals tend to develop local type I bronchial asthma response to common inhaled allergens Non-atopic Factors Local reactions are diverse and vary depending on the ○ 20-30% of cases of immediate hypersensitivity portal of entry of the allergen. reactions are non atopic in nature They may take the form of: ○ Triggered by non-antigenic stimuli (e.g. temperature ○ localized cutaneous rash or blisters (skin allergy or extremes and exercise) hives) ○ DO NOT involve Th2 cells or IgE ○ Nasal and conjunctival discharge (allergic rhinitis or conjunctivitis) 3. “HYGIENE HYPOTHESIS” ○ Hay fever Sometimes living in a too clean environment can also be ○ Bronchial asthma bad. This is the idea of the “Hygiene Hypothesis”. ○ Allergic gastroenteritis (food allergy) The observation that the incidence of many allergic diseases has increased in high income countries has led 2. SYSTEMIC to the idea that living in a too clean environment and the Follows parenteral or oral administration of an lack of early childhood exposure to infectious agents, allergen (e.g. Penicillin, peanuts) gut flora, and parasites increases the susceptibility to More severe allergic diseases by modulating the development of the The systemic form of Type I Hypersensitivity most often immune system. follows injection of an antigen into a sensitized This means that the allergic immune response mediated individual. This could be in a form of: by Th2 lymphocytes develop more than the immunologic ○ Bee sting system normally used to fight infections which is ○ Medication mediated by Th1 lymphocytes. ○ Nuts (highly antigenic substance) Within minutes after exposure to the allergen, itching, hives, and skin erythema appear. Followed shortly by a striking contraction of pulmonary bronchioles and respiratory distress. Vomiting, abdominal cramps, diarrhea, and laryngeal obstruction may follow. Vascular permeability and dilation, and the narrowing of the airways can become so severe that blood pressure drops and there is a marked decrease of oxygen delivery to vital organs basically putting a person into shock within an hour from the onset of symptoms. ○ This severe, systemic, life threatening reaction is called Anaphylaxis. ○ it is considered as a medical emergency ○ once you see severe allergic symptoms, it’s time for an epinephrine (adrenaline) shot and head to the emergency room Hygiene Hypothesis. Dr. Pascual’s Lecture Video, Moodle E. FACTORS FOR ALLERGY DEVELOPMENT Key Events in Type I Hypersensitivity Reactions SUSCEPTIBILITY (Allergies) Atopy Environmental Factors Th2 cells ”Hygiene Hypothesis 1. ATOPY Production of IgE antibodies “Not ALL individuals have allergies” ○ Susceptibility to immediate hypersensitivity Triggering of mast cells reactions is genetically determined. A propensity to develop immediate hypersensitivity The clinical features that are seen in Type I reactions Hypersensitivity ranging from localized allergies to Atopic individuals tend to have a higher serum IgE systemic form anaphylaxis result from the release of levels and more IL-4 - producing Th2 cells than does mast cell mediators as well as the eosinophil-rich the general population inflammation that occur in the rapid and the late phase A positive family history of allergy is found in 50% of of this hyperactive immune reaction. atopic individuals Pathology - Mod 4 🏠 Hypersensitivity Reactions and Prototype Disorders 4 of 16 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  PART 2 The activation of complement via the Classical Pathway generates C3b and C4b, which are IV. TYPE II HYPERSENSITIVITY potent opsonins that make the antigenic cell Type II Hypersensitivity is also called extra delicious for phagocytosis and its Antibody-mediated Hypersensitivity because this subsequent destruction inside the phagocytes. type is mediated by antibodies directed towards antigens present on the surface of cells and other tissue components. Some authors also refer to this type of Professor’s Notes: hypersensitivity as antibody-mediated cytotoxic In mechanism 2A, phagocytosis is not the only means hypersensitivity because this reaction is governed by by which cells are destroyed. an antibody-mediated destruction of healthy cells. Compared to Type I Hypersensitivity wherein IgE 1.2 Antibody-Dependent Cellular Toxicity (ADCC) antibodies are the key players, the antibody key players in Type II Hypersensitivity are in the form of either IgG or IgM. The antibodies may be specific for exogenous antigens such as chemical or microbial proteins, or for normal cells or tissue antigens so-called autoantibodies that bind to a cell surface or tissue matrix. Professor’s Notes: Antibody-Dependent Cellular Toxicity (ADCC). These antigens, whether endogenous or exogenous Dra. Pascual’s Lecture Video, Moodle are present on the surface of cells. To a lesser extent antibody-mediated destruction of cells may also occur by another method called Antibody-Dependent Cellular Toxicity (ADCC) A. MECHANISMS Cells that are coated with IgG antibodies are directly There are three (3) sub-mechanisms by which the killed by effector cells, mainly the natural killer cells and antibody dependent hypersensitivity causes tissue injury macrophages. or disease: Basically, cell lysis proceeds even without phagocytosis. Clinically antibody-mediated cell destruction and Opsonization & Phagocytosis; Antibody phagocytosis occur in the following disease examples: IIa Dependent IIa Cellular Cytotoxicity (ADCC) 1 Hemolytic Transfusion Reactions Complement and Fc receptor-mediated IIb inflammation 2 Autoimmune Hemolytic Anemia (AIHA) IIIb Antibody-mediated cellular dysfunction 3 Erythroblastosis Fetalis 1. IIa. OPSONIZATION & PHAGOCYTOSIS/ 4 Autoimmune Thrombocytopenic Purpura (AITP) ANTIBODY-DEPENDENT CELLULAR CYTOTOXICITY (ADCC) 1.2.1 Transfusion Reactions In opsonization and phagocytosis, the basic mechanism of cell destruction involves opsonization of the involved antigenic cell, rendering it palatable for phagocytosis and its eventual destruction. Opsonization and Phagocytosis. Dra. Pascual’s Lecture Video, Moodle 1.1 Opsonization It can occur in 2 ways: Example of a Transfusion Reaction. Cells with antigens adsorbed on their surface are Dra. Pascual’s Lecture Video, Moodle opsonized by either IgG or IgM antibodies that are 1 then recognized and phagocytosed by Involves transfusion of incompatible blood corresponding phagocytes. ○ Type A blood (donor) to a Type B recipient would cause a reaction wherein the incompatible donor’s Through the activation of complement by the blood would be opsonized by the pre-formed 2 deposition of IgM and IgG antibodies on antigenic (Anti-A) antibodies in the recipient, causing RBC cells. hemolysis. Pathology - Mod 4 🏠 Hypersensitivity Reactions and Prototype Disorders 5 of 16 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited. 1.2.2 Erythroblastosis Fetalis 1.2.3 Autoimmune Hemolytic Anemia and Autoimmune Thrombocytopenic Purpura (AIHA, AITP) ANTIBODY-MEDIATED CELL DESTRUCTION (AIHA, AITP) Autoimmune Hemolytic Autoimmune Hemolytic Anemia (AIHA) Anemia (AITP) Antibodies against red cell Antibodies against platelet membrane proteins membrane proteins RBC Hemolysis Thrombocytopenia Other disorders characterized by antibody-mediated cell destruction ○ Individuals produce antibodies to their own blood cells For Autoimmune Hemolytic Anemia (AIHA): Erythroblastosis Fetalis. Dra. Pascual’s Lecture Video, ○ Antibodies are produced against red cell membrane Moodle proteins ○ Results in red cell destruction ○ Patient presents with hemolytic anemia ERYTHROBLASTOSIS FETALIS For Autoimmune Hemolytic Anemia (AITP): ○ Antibodies are produced against platelet membrane MOTHER Rh (-) proteins ○ Results in platelet destruction INFANT Rh (+) ○ Patient presents with thrombocytopenia—decrease in platelet count. Mother develops anti-Rh IgG antibodies against fetal red cells 2. IIb. COMPLEMENT AND FC RECEPTOR-MEDIATED INFLAMMATION Hemolytic disease of the fetus and newborn Occurs when Rh (-) mother carries an Rh (+) infant ○ The fetal Rh (+) blood is recognized as antigenic by the mother, and the mother develops IgG anti-Rh antibodies, which cross the placenta and cause lysis and destruction of the fetal red cells. Leukocyte Activation for Inflammation Induction. Dra. Pascual’s Lecture Video, Moodle Inflammation is the end result of this sub-mechanism LEUKOCYTE ACTIVATION FOR INFLAMMATION INDUCTION 1 C5a Action; once antibodies deposit in the basement membrane and extracellular matrix, they activate complement and generate complement cleavage products—mainly C5a. Jaundiced Newborn due to ​Erythroblastosis Fetalis. 2 C5a directs the migration of granulocytes and Dra. Pascual’s Lecture Video, Moodle monocytes (leukocytes), and anaphylatoxins like C3a that increase vascular permeability. Depending on the severity of the antigen-antibody interaction, the fetus is born with anemia, jaundice, 3 In the second mechanism, leukocytes can also be edema, and high bilirubin levels, or may not even activated by the engagement of their C3b and Fc survive in utero because of this hemolytic reaction. receptors to antibodies. 4 Once leukocytes are activated, they now release substances such as lysosomal enzymes including proteases capable of digesting basement membrane, collagen, elastin, and cartilage. 5 Activated leukocytes also generate reactive oxygen species (ROS) that ultimately lead to inflammation and tissue damage. Pathology - Mod 4 🏠 Hypersensitivity Reactions and Prototype Disorders 6 of 16 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited. 2.1 Goodpasture Syndrome 3.2 Grave’s Disease Goodpasture syndrome. Dra. Pascual’s Lecture Video, Moodle Grave’s Disease. Dra. Pascual’s Lecture Video, Moodle An example of an immune disorder that follows antibody mediated inflammation Antibodies recognize the thyroid stimulating hormone A rare disease characterized by diffuse pulmonary receptor as antigenic hemorrhages and acute or rapidly progressive Results in overstimulation of thyroid epithelial cells to glomerulonephritis produce thyroid hormone resulting in hyperthyroidism patients have antibodies against non-collagenous proteins in the basement membrane of the glomeruli 3.3 Antigen-Antibody Interaction and the alveoli present clinically as hemoptysis and hematuria MNEMONIC: organs affected in GoodPasture syndrome ○ Glomerulus ○ Pulmonary 3. IIc. ANTIBODY-MEDIATED CELL DYSFUNCTION Recall: In submechanism IIa and IIb, cell injury and inflammation are the end results Meanwhile, in IIc, the antigen being recognized are cell surface receptors and the antigen antibody interaction This results in impairment or dysregulation of function Grave’s Disease and Myasthenia Gravis Comparison without causing cell injury or inflammation Dra. Pascual’s Lecture Video, Moodle Myasthenia Gravis and Grave’s Disease ○ follow the 3rd submechanism of type II REMEMBER: In Myasthenia Gravis the antigen-antibody hypersensitivity reaction interaction results in inhibition of cell function, while in Grave’s disease the antigen-antibody interaction results 3.1 Myasthenia Gravis in overstimulation of cell function. Ultimately, the end result despite differences is alteration in normal cell function B. SUMMARY In Type II Hypersensitivity (antibody-mediated hypersensitivity) secreted IgG and IgM antibodies ○ Injure cells by promoting their phagocytosis/lysis or ○ Injure tissues by inducing inflammation Antibodies may also interfere with cellular functions and cause disease without tissue injury Diseases caused by Type II Hypersensitivity Myasthenia Gravis. ○ Transfusion reactions Dra. Pascual’s Lecture Video, Moodle ○ Erythroblastosis Fetalis ○ Autoimmune hemolytic anemia Acetylcholine is a chemical messenger or a ○ Autoimmune thrombocytopenic purpura neurotransmitter that place an important role in brain ○ Goodpasture syndrome and muscle function ○ Myasthenia gravis Antibodies react with acetylcholine receptors in the ○ Grave’s disease motor end plates of skeletal muscles and blocks the binding of the acetylcholine with its receptor This consequently blocks neuromuscular transmission The muscles DO NOT receive the neurotransmitter and CANNOT contract resulting in muscle weakness Pathology - Mod 4 🏠 Hypersensitivity Reactions and Prototype Disorders 7 of 16 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  A. ANTIGENS THAT FORM IMMUNE COMPLEXES REVIEW Disease Target Mechanism 1 Exogenous Include foreign proteins Antigen that are injected or produced by infectious Autoimmune 1. IIa opsonization microbe hemolytic anemia and phagocytosis (AIHA) of erythrocytes 2 Endogenous (self) Individual produced antibody against self Autoimmune Platelet 2. antigens (e.g. thrombocytopeni membrane Autoimmune diseases) c purpura (AITP) proteins 3 Acute Reactions take hours or Goodpasture Noncollagenous 3. days or even weeks to Syndrome protein in BM of develop depending on alveoli and whether or not there is glomeruli immunological memory of the precipitating antigen Myasthenia Acetylcholine 4. Gravis receptor 4 Chronic Happens particularly in autoimmune conditions Grave’s disease 5. IIc (hyperthyroidism) antibody-mediated B. MAJOR FORMS OF IMMUNE COMPLEX-MEDIATED stimulation of TSH HYPERSENSITIVITY receptors Answers: RBC membrane proteins, IIa opsonization & 1 Localized Immune Complex Disease phagocytosis of platelets, IIb complement and Fc receptor mediated inflammation, IIc. Ab inhibits Ach binding; downregulates receptors 2 Systemic Immune Complex Disease PART 3 1. LOCALIZED IMMUNE COMPLEX DISEASE V. TYPE III (IMMUNE COMPLEX) HYPERSENSITIVITY 1.1 ARTHUS REACTION Normally, when antigens combine with antibodies, they are promptly removed. Exemplifies the localized immune complex disease Occasionally, they persist mostly because of: Discovered by Nicholas Maurice Arthus in 1903 ○ They are small in size ○ He repeatedly injected horse serum subcutaneously ○ Form Immune Complexes into rabbits. ○ Deposited in tissues resulting in inflammation and ○ After 4 injections, he found edema and the serum disease. was absorbed slowly. Such is the pathology of Type III (Immune Complex) ○ Further injections lead to gangrene. Hypersensitivity Recognized as a dermal inflammatory reaction due to localized immune complex formation following repeated subcutaneous or intradermal injections of foreign TYPE III VS OTHER HYPERSENSITIVITY REACTIONS antigen ○ There complexes precipitate in the vessel walls Type 1 Type II Type III eliciting inflammation and consequent tissue injury ○ In some cases, the damage to wall is so severe as Ab IgE IgG; IgM IgG; IgM to cause thrombosis and localized ischemic Ag Free in On cell Free in injury circulation surface circulation Type III and Primarily mediated by IgG and IgM Type II antibodies. Combine with soluble antigens that are Type III and not found in cell surfaces Type I Meaning these antigens are free in circulation (unlike in Type II) In the circulation, these antigens react with antibodies and form immune complexes that deposit in tissues. Professor’s/Editor’s Notes: Left: Arthus Reaction, Right: Nicholas Maurice Arthus IMPORTANT: Ag + Ab (Immune Complex) is Type III’s Dra. Pascual’s Lecture Video, Moodle moniker and the foundation of the mechanism of Type III hypersensitivity disorder. Pathology - Mod 4 🏠 Hypersensitivity Reactions and Prototype Disorders 8 of 16 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited. 2. SYSTEMIC IMMUNE COMPLEX DISEASE C. MECHANISM OF IMMUNE COMPLEX-MEDIATED Occurs when soluble antigens combine with antibodies HYPERSENSITIVITY The basic pathophysiologic mechanism governing both the in the circulation, forming circulating immune localized and systemic types of immune complex diseases complexes can be divided into three phases Trapped/Deposited in the: The introduction of a protein antigen triggers an immune ○ Glomerulus (Kidneys) response that results in the formation of antibodies, typically ○ Joints about one week after injection of the protein ○ Blood vessels These antibodies are secreted into the blood where they react with the antigen still present in the circulation and form 2.1 Serum Sickness antigen-antibody complexes Prototype of systemic immune complex disease First discovered in 1906 as a sequela to the administration of large amounts of foreign serum ○ This was during the time when vaccination for protection against diphtheria utilized serum from immunized horses 4-10 days after receiving the vaccine, the affected individuals presented with: ○ Arthritis ○ Skin rash ○ Fever ○ Lymphadenopathy PHASES OF BASIC PATHOPHYSIOLOGIC MECHANISMS OF BOTH LOCALIZED AND SYSTEMIC IMMUNE COMPLEX DISEASE PHASE 1: Characterized by the formation of IMMUNE immune complexes COMPLEX Followed by deposition of immune FORMATION Manifestation of serum sickness: skin rash. complexes in blood vessels. Dra. Pascual’s Lecture Video, Moodle The factors that determine whether immune complex formation will lead to The symptoms appear more rapidly with repeated tissue deposition and disease are not injections of the serum fully understood. But, major influences Mechanism of Serum Sickness: seem to be the characteristics of complexes and localized vascular alterations 1 The foreign protein contained in the vaccine is the In general, complexes that are recognized antigen. medium-sized are the most pathogenic 2 Antibodies react with the foreign protein and form Organs where blood is filtered at immune complexes. high pressure to form other liquids 3 These immune complexes are then deposited in (e.g. urine and synovial fluid) are sites tissues and subsequently trigger an inflammatory where immune complexes become response concentrated and tend to deposit. Hence, immune complex disease often 4 Enzymes and cytokines are activated affects the glomeruli and joints Once immune complexes are 5 Reactions with complement attracts neutrophils, deposited in the tissues, they initiate an leading to inflammation acute inflammatory reaction by activating complement PHASE 2: Complement activation marks the IMMUNE second phase COMPLEX Complement fragments like C3a and DEPOSITION; C5a COMPLEMENT ACTIVATION ○ Form as a result of complement activation results in the activation of potent mediators of inflammation and influx of neutrophils and monocytes to the sites of immune complex deposition The attracted neutrophils attempt to engulf the immune complexes ○ Since the complexes are deposited Mechanism of Serum Sickness over tissues, the neutrophils do not Dra. Pascual’s Lecture Video, Moodle succeed Pathology - Mod 4 🏠 Hypersensitivity Reactions and Prototype Disorders 9 of 16 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  ○ Consequently, the neutrophils are compelled to release a number of substances like prostaglandins, lysosomal enzymes, and free oxygen radicals over the complexes, causing damage to the tissues at the site of immune complex deposition PHASE 3: Tissue injury and clinical symptoms INFLAMMATION manifest ○ Clinical features like fever, rashes, urticaria (hives), joint pain, lymph node enlargement, and proteinuria (excretion of protein in urine) appear Immune complexes deposited in the kidney (H&E and Ensues approximately 10 days after immunofluorescence). Glomerulonephritis of varying degrees antigen administration of severity. Dra. Pascual’s Lecture Video, Moodle Consumption of C3 ○ Serum c3 levels are used by E. OTHER EXAMPLES clinicians as an adjunct in monitoring Aside from the arthus reaction in serum complement disease activity in some immune sickness, other examples of immune complex disease complex disorders conditions are: 1. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) D. MORPHOLOGY Acute necrotizing vasculitis Antibodies are formed against double-stranded DNA ○ Morphologic manifestations of the immune complex (dsDNA), nucleoproteins, and other nuclear antigens injury is in the blood vessels The antigen-antibody complexes deposit mainly in the ○ The blood vessel exhibits necrosis of the vessel kidneys, skin and joints wall and intense neutrophilic infiltration Fibrinoid necrosis 2. POST-STREPTOCOCCAL GLOMERULONEPHRITIS ○ Deposits of the immune complexes (complements Occurs when an individual previously infected with and plasma proteins) appear as smudgy streptococcal infection develops antibodies against eosinophilic area of tissue destruction streptococcal wall antigens that have previously planted on the glomerular basement membrane 2. FARMER’S LUNG Localized type of immune complex disorder resulting from inhalation of bacterial spores or molds found in hay or crops leading to hypersensitivity pneumonitis F. SUMMARY Type III Hypersensitivity is also called Immune Complex Hypersensitivity It is characterized by the formation of antigen-antibody complexes that produce tissue damage by eliciting inflammation at the sites of their deposition Such complexes are usually systemically deposited preferentially involving the kidney, joints and small blood vessels resulting in inflammatory lesions called Acute necrotizing vasculitis and fibrinoid necrosis as glomerulonephritis, arthritis and vasculitis displayed in Type III hypersensitivity. respectively Dra. Pascual’s Lecture Video, Moodle These immune complexes may also be deposited locally in the skin and the lungs When deposited in the kidney, the complexes can be ○ Disease examples include serum sickness, SLE, seen as thick granular lumpy deposits on both H&E post-steptococcal GN, arthus reaction and stain and immunofluorescence farmers lung These lumpy deposits contain immunoglobulin and But wherever immune complexes are deposited, they complement. activate the complement system, wherein macrophages and neutrophils are attracted to the site of their deposition where they cause inflammation, leading to tissue injury Pathology - Mod 4 🏠 Hypersensitivity Reactions and Prototype Disorders 10 of 16 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  PART 4 B. INFLAMMATORY REACTIONS STIMULATED BY CD4 T-CELLS OBJECTIVES Involves 2 phases: At the end of the video lecture, the learner is expected to: Explain the pathophysiologic mechanism underlying 1 Activation/Sensitization phase Type IV hypersensitivity reactions 2 Effector phase Correlate the pathophysiology and histomorphology of Type IV hypersensitivity disorders 1. SENSITIZATION PHASE Compare and contrast the 4 types of hypersensitivity based on pathophysiologic mechanisms and disease Occurs with the initial exposure of naïve T-lymphocytes examples to the antigen Results in the development of antigen-specific memory T lymphocytes VI. TYPE IV (CELL-MEDIATED) HYPERSENSITIVITY TYPE I TYPE II TYPE III TYPE IV SENSITIZATION PHASE PROCESS IgE mediated/ Antibody Immune- Cell mediated Immediate mediated complex 1 Naive CD4 T-cells recognize peptides displayed by IgE IgG; IgM IgG; IgM T cell dendritic cells. (CD4+/CD8+) 2 Naive CD4 T-cells secrete Interleukin 2 (IL2) Interleukin 2 (IL2) ○ Autocrine growth factor that stimulates proliferation of the antigen responsive T-cells either as Th1 or Th17 ○ Whether these antigen responsive T-cells become Th1 or Th17 depends on the cytokines produced by the antigen presenting cell (APC) at the time of T-cell activation. 3 IL-2 secreted by naive T-cells causes it to differentiate into Th1 or Th17. Mediators of Type IV Hypersensitivity 4 If the antigen presenting cell produces IL-12, Unlike Type I, II, and III hypersensitivity which are all naive CD4 T-cells will differentiate to Th1 mediated by antibodies, Type IV hypersensitivity ○ Antigen presenting cells: results primarily from the interaction of the lymphocytes, Dendritic cells monocytes, and macrophages, hence, also called cell Macrophages mediated hypersensitivity. ○ Interferon gamma (IFN-γ) produced by Mainly governed by the production of cytokines by CD4 Th1 cells further promotes Th1 T-cell, resulting in inflammation, this is also called CD4 development, thus, amplifying the reaction. mediated inflammation or cytokine-mediated If the antigen presenting cell produces IL-1, inflammation. IL-6, and IL23, naive CD4 T-cells will To a lesser extent, CD8 cytotoxic cells can also result differentiate to Th17. in type 4 hypersensitivity. ○ Mechanism followed by some autoimmune 5 Some of the differentiated effector cells (Th1, Th17), diseases enter the circulation and join the pool of memory ○ May also be the dominant mechanism of tissue T-cells where they persist for a long period, even injury in certain reactions especially those that years. follow viral infections Type 4 hypersensitivity mediated by the action of CD8 T-cells results in apoptosis rather than inflammation. A. CD4+ MEDIATED HYPERSENSITIVITY / CYTOKINE-MEDIATED INFLAMMATION Cytokines produced by T-cells induce inflammation that may be chronic and destructive This immunopathological damage occurs at about 24 – 72 hours after exposure of a sensitized individual to an antigen, making the reaction a delayed type ○ In contrast to the first three hypersensitivity reactions (immediate immune reaction), Type 4 has a delayed reaction Classical T-cell reaction to antigens given to previously sensitized individuals Differentiation of Naive CD4 T-cells. Dr. Pascual’s Lecture Video, Moodle Pathology - Mod 4 🏠 Hypersensitivity Reactions and Prototype Disorders 11 of 16 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited. 2. EFFECTOR PHASE Response of Activated CD4+ T lymphocytes Once the host is sensitized, prolonged or repeated exposure to the antigen results in the development of an effector phase. Corresponds to the response of the activated CD4 T-lymphocytes. Professor’s Notes: Remember, the naive CD4 T-lymphocytes are activated into either Th1 or Th17 cells depending on cytokine produced by the antigen presenting cells during the Sensitization Phase. 2.1 Classic Effector Response The Classic Effector Response is in the form of Interleukins associated with Th17. Dr. Pascual’s Lecture production of IFN-γ by Th1 cells. Video, Moodle ○ IFN-γ is the key mediator of Type IV hypersensitivity because it activates and turns Aside from Th1, CD4 + T-cells can also become macrophages into phagocytes and super killers. activated to the Th17 subtype. ○ IFN-γ also enhances the macrophages’ ability to Activated Th17 cells secrete chemokines and cytokines present antigens by inducing increased expression (i.e. IL-17, IL-22) to a lesser extent. These cytokines of class II major histocompatibility (MHC) recruit neutrophils and monocytes to the reaction – molecules. promoting inflammation. MHC molecules bind peptide fragments derived from pathogens and display them on the cell Professor’s Notes: surface for easier recognition by appropriate It is not just the Th1 cells that play a pivotal role in T-cells. CD4 mediated hypersensitivity. ○ Activated macrophages produce IL-12, which then There is no need to memorize these interleukins. facilitates the development of other Th1 However, it is important to remember that in the lymphocytes. effector phase the result of the actions of both Th1 and ○ Activated macrophages also produce IL-1 and Th17 is inflammation. Additionally, the inflammatory TNF-α. Both of which further facilitate the response is mediated by the action of cytokines. extravasation of additional inflammatory cells. In the effector phase, the activated macrophages serve C. CLINICAL EXAMPLES OF CD4+ T-CELL MEDIATED to eliminate the offending agent. INFLAMMATION ○ If the activation is sustained, the inflammation continues – resulting in a response that first starts 1. TUBERCULIN (PURIFIED PROTEIN DERIVATIVE) as a beneficial response or immunity to a REACTION harmful response (tissue damage or hypersensitivity). A classic example of late type CD4 mediated type IV hypersensitivity. Professor’s Notes: This is produced by intracutaneous injection of IFN-γ is the most important and the key driver for the tuberculin, or purified protein derivative (PPD) activated macrophages’ enhanced powers during the ○ It is a protein-containing antigen of the tubercle effector phase. bacillus In a previously sensitized individual (with previous exposure to tuberculosis), there is redness and induration at the site of injection that appears in 8-12 hours. ○ This hypersensitivity reaches a peak in 24-72 hours. After which, it slowly subsides. Classic Effector Response. Dr. Pascual’s Lecture Video, Moodle Tuberculin PPD test. Dr. Pascual’s Lecture Video, Moodle Pathology - Mod 4 🏠 Hypersensitivity Reactions and Prototype Disorders 12 of 16 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  2. GRANULOMATOUS INFLAMMATION With sustained activation, macrophages undergo a morphologic transformation into epithelioid cells. ○ Epithelioid cells are large cells resembling epithelial cells with abundant cytoplasm. ○ Aggregates of epithelioid cells usually surrounded by lymphocytes form grossly visible, small nodules called granulomas. Reactive Tuberculin PPD test. Dr. Pascual’s Lecture Video, Moodle The delayed type hypersensitivity response is generally minimal and short-lived because the concentration of the Tuberculin injected is small and rapidly degraded. A similar reaction can be used to test for previous Epithelioid cells (red arrows) and aggregates of lymphocytes exposure to a number of intracellular organisms. (encircled). Dr. Pascual’s Lecture Video, Moodle Epithelioid cells sometimes fuse to form multinucleated Tuberculin (PPD) Reaction giant cells. In Tuberculosis, these giant cells are called Langhan’s Giant Cells. Morphology Granulomatous inflammation is commonly associated with strong Th1 cell activation and production of interferon-gamma (IFN-γ). Perivascular cuffing in Tuberculin reaction. Dr. Pascual’s Lecture Video, Moodle Delayed type hypersensitivity is characterized by the accumulation of mononuclear cells, mainly CD4 T-cells and macrophages around venules, producing a perivascular Granulomatous inflammation. Granulomas are marked by “cuffing”. asterisks. Dr. Pascual’s Lecture Video, Moodle In fully developed lesions, the venules show marked endothelial hypertrophy, reflecting cytokine-mediated endothelial activation. Professor’s Notes: In addition to the tuberculin response, type IV hypersensitivity is the underlying pathogenesis for other granulomatous inflammatory responses and allergic contact dermatitis. In the tuberculin reaction, the quantity of antigens specifically Tuberculin limits the extent of the inflammatory response and resolution of the response Langhan’s giant cell (encircled). Dr. Pascual’s Lecture Video, generally occurs in 5–7 days. Moodle ○ If the intracellular organism persists or is poorly degradable, the host will be unable to eliminate the organism which results in antigen persistence and sustained macrophage activation. Pathology - Mod 4 🏠 Hypersensitivity Reactions and Prototype Disorders 13 of 16 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited. 3. CONTACT DERMATITIS (ALLERGIC CONTACT D. CD8+ MEDIATED HYPERSENSITIVITY DERMATITIS) Another mechanism for Type IV or Cell-Mediated In this delayed type hypersensitivity reaction, the antigen Hypersensitivity, is that due to the action of CD8 can be in the form of simple chemicals like nickel, T-lymphocytes. formaldehyde, plant materials like poison ivy, cosmetics, CD8 T- Lymphocyte Type IV hypersensitivity is most soaps, and other substances which are often too small commonly associated with viral infections. to elicit an immune response by itself. ○ These antigens must be complexed with larger 1 CD4 mediated Type IV Results in inflammation proteins to become antigenic and are specifically hypersensitivity referred to as haptens. 2 CD8 mediated Type IV Results in apoptosis hypersensitivity Simple chemical (represented by Ag) bound to a large protein to form a hapten. Dr. Pascual’s Lecture Video, Moodle Sensitization In the sensitization phase the Phase protein-hapten complex is taken up and processed by dendritic cells of the skin called Langerhans cells → the host then develops a population of memory Figure. Mechanisms of CD8 T-lymphocyte in a virus infected cell. lymphocytes → now sensitized to the Dr. Pascual’s Lecture Video, Moodle antigen. In a virus infected cell, viral peptides are displayed by