[PATHO] Hypersensitivity Reactions and Prototype Disorders.pdf

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

PATHOLOGY 08/28/2024. MOD 4: HYPERSENSITIVITY REACTIONS AND PROTOTYPE DISORDERS Dr. Joanne Marie R. Pascual, MD Trans Group/s: 5B, 6B I. INTRODUCTION TYPE I HYPERSENSITIVITY The immune system is vital for survival because our environment is dealing with potentially deadly microbes, IgE mediated Immediate and it is our immune system that protects us from infectious pathogens. IgE: primary antibody Rapid, occurring within The immune system can be likened to the proverbial involved minutes double-edged sword that although it normally serves as our defense against infections, a hyperactive immune A. COMMON ANTIGENS/ALLERGENS system may cause diseases that can sometimes be Allergens: antigens that elicit a type I hypersensitivity fatal. reaction ○ Substances or proteins outside our bodies (e.g., II. HYPERSENSITIVITY DISORDERS food, pollen, animal dander, medications) Represent exaggerated or inappropriate immune ○ Can also be from things that one comes in responses to an antigen triggering a pathologic contact with (e.g., talc, latex, insect bites) reaction. An immunologically mediated mechanism of tissue B. PHASES OF TYPE I IMMUNE REACTION injury. Can be elicited by exogenous environmental 1. FIRST EXPOSURE/SENSITIZATION PHASE antigens both microbial or non-microbial in nature or endogenous self-antigens. Results from an imbalance between the effector mechanisms of immune responses and the control mechanisms that serves to limit those responses Often associated with inheritance of particular susceptibility genes. HYPERSENSITIVITY REACTIONS Type I Immediate (IgE) Immunoglobulin Antibody-mediated (IgG, mediated Type II First Phase/Sensitization (Asymptomatic). IgM) hypersensitivity reactions Type III Immune Complex (IgG, IgM) Usually asymptomatic. During an individual’s very first encounter with the Lymphoid antigen, no allergic symptoms will be seen. Cell-Mediated (CD4+ / CD*+ Type IV cell-mediated or An antigen is introduced to a genetically susceptible T cells cell-mediated individual. The introduction of an antigen (i.e. pollen) stimulates Each type goes by another name that usually naive T lymphocytes to differentiate into Type 2 T corresponds to the mechanisms underlying the reaction. Helper Lymphocytes (TH2 cells). Classification is of value to help distinguish the manner TH2 cells play a pivotal role in Type I Hypersensitivity an immune response causes tissue injury and disease reactions because they produce cytokines that initiate and accompanying pathological and clinical the sensitization phase. manifestations of each. CYTOKINES PRODUCED BY TH2 CELLS III. TYPE I HYPERSENSITIVITY Also called IgE mediated hypersensitivity or Involved in the development and Immediate type hypersensitivity Interleukin 5 activation of eosinophils which are Commonly called “allergy” (IL-5) important effectors in Type I Disease examples: allergies, allergic rhinitis, Hypersensitivity. bronchial asthma, and anaphylaxis Enhances IgE production and acts on Rapidly developing immunologic reaction occurring Interleukin 13 epithelial cells to stimulate mucus within minutes after the combination of an antigen (IL-13) production/secretion. with antibody bound to mast cells in individuals previously sensitized to the antigen Promotes the development of Mediated by IgE antibodies directed against specific Interleukin 4 additional TH2 cells and induces antigens (allergens) (IL-4) antibody class switching of B cells. Pathology - Mod 4 Hypersensitivity Reactions and Prototype Disorders 1 of 14 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.  spasmogenic agents. Cause bronchial smooth muscle LEUKOTRIENE C4 AND D4 contraction. Difficulty of breathing Vasodilation Intense bronchospasm PROSTAGLANDIN D2 Increased mucus secretion Vasodilation As the caliber of the blood vessel increases, fluid flow also increases but since the blood vessel is also more permeable, more fluid is allowed to leak into the Class Switching. interstitium. ○ This causes edema or swelling and urticaria or Class switching means that B cells, which would hives. normally produce IgM antibodies in an acute immune ○ The aforementioned symptoms (difficulty of response, will instead make antigen-specific IgE breathing) coupled with an increased mucus antibodies. secretion are typical of an allergic reaction. These IgE antibodies then attach themselves to the Drugs used to treat allergies typically target histamine surface of mast cells. and these other mediators to alleviate the symptoms of The mast cells now become sensitized to the an allergy. antigen and are all geared up for the next encounter with the same antigen. Mast Cell Sensitization. 2. SECOND PHASE/REEXPOSURE PHASE Edema and Urticaria. C. RESPONSE PHASES OF THE IMMUNE REACTION Rapid Delayed Within minutes after 2 to 12 hours after re-exposure to antigen re-exposure to the antigen Histamine Cytokines: Leukotrienes ○ TNF ○ IL-5 ○ eotaxin Second Phase/Reexposure. 1. RAPID PHASE Within minutes (5 to 30 min) after re-exposure to the Upon reexposure to the same antigen, the sensitized same antigen. mast cells can now recognize and attach to the The effects of histamine and other mast cell mediators antigen. present during the rapid phase of immune reaction. This attachment triggers mast cells to degranulate In the rapid response phase, vasoactive amines like and release vasoactive amines and other histamine are the key players. proinflammatory mediators that are responsible for Leukotrienes immediate type hypersensitivity reactions. Mediators: ○ Histamine → bronchial smooth muscle VASOACTIVE AMINES AND PROINFLAMMATORY contraction MEDIATORS ○ Leukotrienes → increased vascular permeability and dilatation HISTAMINE ○ Prostaglandin D2 → increased mucus gland Potent vasoactive and secretion Pathology - Mod 4 🏠 Hypersensitivity Reactions and Prototype Disorders 2 of 14 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.  ○ Therefore, treatment of these disorders require the 2. DELAYED PHASE use of broad-spectrum anti-inflammatory drugs, Happens 2 to 12 hours after re-exposure to the such as steroids, rather than antihistamine drugs, antigen. which are of benefit only in the immediate reaction Cytokines like the tumor necrosis factor (TNF), as occurs in allergic rhinitis. Interleukin 5 (IL-5) and chemokines, such as eotaxin, set the stage for the delayed phase. D. SYMPTOMS These cytokines, particularly Interleukin 5 (IL-5), which Immediate hypersensitivity may occur as a systemic or is also called the most potent eosinophil-activating localized reaction cytokine, recruit more eosinophils and other leukocytes like basophil to the site of antigen deposition. 1. LOCAL The recruited leukocytes amplify and sustain the Exemplified by atopic allergies immune response even without additional exposure to Affected individuals tend to develop local type I the triggering antigen. response to common inhaled allergens Of the recruited leukocytes, eosinophils are the most Diverse important because they liberate specific proteolytic Vary depending on the portal of entry of the allergen. enzymes and proteins like the eosinophilic cationic They may take the form of: protein and major basic protein that are toxic to epithelial ○ localized cutaneous rash or blisters (skin allergy cells. or hives) ○ Activated eosinophils and basophils can also ○ Nasal and conjunctival discharge (allergic rhinitis directly activate mast cells to release more or conjunctivitis) mediators. ○ Hay fever Cytokine mediators: TNF α, IL-1,5, GM-CSF, ○ Bronchial asthma chemokines ○ Allergic gastroenteritis (food allergy) ○ Eosinophils cause tissue damage by releasing proteolytic enzymes and proteins. 2. SYSTEMIC ○ Eosinophils + basophils directly activate mast Follows parenteral or oral administration of an cells. allergen (e.g. penicillin, peanuts) More severe Most often follows injection of an antigen into a sensitized individual. This could be in a form of: ○ Bee sting ○ Medication ○ 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. Eosinophil, Mast Cell, Basophil. Vascular permeability and dilation, and the narrowing of the airways can become so severe that blood In addition, eosinophils contain Charcot-Leyden pressure drops and there is a marked decrease of crystals. oxygen delivery to vital organs basically putting a person ○ These are sometimes released to the extracellular into shock within an hour from the onset of symptoms. space that can be detected in the sputum of ○ This severe, systemic, life threatening reaction is patients with asthma called anaphylaxis. ○ Promote inflammation and enhanced Th2 ○ It is considered as a medical emergency response ○ Once you see severe allergic symptoms, it’s time for an epinephrine (adrenaline) shot and head to the emergency room. E. FACTORS FOR ALLERGY DEVELOPMENT SUSCEPTIBILITY Atopy Environmental Factors ”Hygiene Hypothesis 1. ATOPY “Not ALL individuals have allergies” ○ Susceptibility to immediate hypersensitivity reactions is genetically determined. A propensity to develop immediate hypersensitivity reactions Charcot-Leyden Crystals (sputum in Bronchial Asthma). Tend to have a higher serum IgE levels and more IL-4 — producing Th2 cells than does the general It is believed that the delayed phase reaction is a population major cause of symptoms in some Type 1 A positive family history of allergy is found in 50% of hypersensitivity disorders, such as allergic asthma. atopic individuals. Pathology - Mod 4 🏠 Hypersensitivity Reactions and Prototype Disorders 3 of 14 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.  IV. TYPE II HYPERSENSITIVITY 2. ENVIRONMENTAL FACTORS Also called Antibody-mediated Hypersensitivity Environmental Pollutants Mediated by antibodies directed towards antigens ○ Exposure to such is an important predisposing present on the surface of cells and other tissue factor for allergy development. components. Viral Infections Some authors also refer to this type of hypersensitivity ○ Viral infections of the airways are triggers for as antibody-mediated cytotoxic hypersensitivity bronchial asthma because this reaction is governed by an Non-atopic factors antibody-mediated destruction of healthy cells. ○ 20-30% of cases of immediate hypersensitivity The antibody key players in Type II Hypersensitivity reactions are non-atopic in nature are in the form of either IgG or IgM. ○ Triggered by non-antigenic stimuli (e.g. The antibodies may be specific for exogenous temperature extremes and exercise). antigens such as chemical or microbial proteins, or for ○ DO NOT involve Th2 cells or IgE normal cells or tissue antigens so-called autoantibodies that bind to a cell surface or tissue 3. “HYGIENE HYPOTHESIS” matrix. Sometimes living in a too clean environment can also be These antigens, whether endogenous or exogenous, are bad. This is the idea of the “Hygiene Hypothesis”. present on the surface of cells. The observation that the incidence of many allergic diseases has increased in high income countries A. MECHANISMS has led to the idea that living in a too clean There are three (3) sub-mechanisms by which the environment and the lack of early childhood antibody dependent hypersensitivity causes tissue injury exposure to infectious agents, gut flora, and or disease: parasites increases the susceptibility to allergic diseases by modulating the development of the immune system. Opsonization & Phagocytosis; Antibody IIa This means that the allergic immune response Dependent IIa Cellular Cytotoxicity (ADCC) mediated by Th2 lymphocytes develop more than the immunologic system normally used to fight infections Complement and Fc receptor-mediated IIb which is mediated by Th1 lymphocytes. inflammation IIIb Antibody-mediated cellular dysfunction 1. IIa. OPSONIZATION & PHAGOCYTOSIS/ ANTIBODY-DEPENDENT CELLULAR CYTOTOXICITY (ADCC) 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. Hygiene Hypothesis. Opsonization and Phagocytosis. KEY EVENTS IN TYPE I HYPERSENSITIVITY OPSONIZATION REACTIONS (ALLERGIES) Cells with antigens adsorbed on their surface are Induction Th2 cells opsonized by either IgG or IgM antibodies that are 1 then recognized and phagocytosed by corresponding Production of IgE antibodies phagocytes. Triggering of mast cells Through the activation of complement by the deposition of IgM and IgG antibodies on antigenic Subsequent accumulation of inflammatory cells at cells. antigen-deposition sites The activation of complement via the Classical 2 Pathway generates C3b and C4b, which are potent opsonins that make the antigenic cell extra The clinical features that are seen in Type I delicious for phagocytosis and its subsequent Hypersensitivity ranging from localized allergies to destruction inside the phagocytes. systemic form anaphylaxis result from the release of mast cell mediators as well as the eosinophil-rich inflammation that occur in the rapid and the late phase of this hyperactive immune reaction. Pathology - Mod 4 🏠 Hypersensitivity Reactions and Prototype Disorders 4 of 14 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. 1.1 Antibody-Dependent Cellular Toxicity (ADCC) Antibody-Dependent Cellular Toxicity (ADCC). To a lesser extent, antibody-mediated destruction of cells may also occur by another method called Antibody-Dependent Cellular Toxicity (ADCC) Cells that are coated with IgG antibodies are directly killed by effector cells, mainly the natural killer cells and macrophages. Basically, cell lysis proceeds even without Erythroblastosis Fetalis. phagocytosis. Clinically antibody-mediated cell destruction and Hemolytic disease of the fetus and newborn phagocytosis occur in the following disease examples: Occurs when Rh (-) mother carries an Rh (+) infant ○ The fetal Rh (+) blood is recognized as antigenic 1 Hemolytic Transfusion Reactions by the mother, and the mother develops IgG anti-Rh antibodies, which cross the placenta and 2 Autoimmune Hemolytic Anemia (AIHA) cause lysis and destruction of the fetal red cells. 3 Erythroblastosis Fetalis 4 Autoimmune Thrombocytopenic Purpura (AITP) 1.1.1 Transfusion Reactions Jaundiced Newborn due to ​Erythroblastosis Fetalis. Depending on the severity of the antigen-antibody interaction, the fetus is born with anemia, jaundice, edema, and high bilirubin levels, or may not even survive in utero because of this hemolytic reaction. 1.2.3 Autoimmune Hemolytic Anemia and Autoimmune Example of a Transfusion Reaction. Thrombocytopenic Purpura (AIHA, AITP) Involves transfusion of incompatible blood Type A blood (donor) to a Type B recipient would ANTIBODY-MEDIATED CELL DESTRUCTION cause a reaction wherein the incompatible donor’s blood would be opsonized by the pre-formed (Anti-A) Individuals produce antibodies to their own blood antibodies in the recipient, causing RBC hemolysis. cells 1.1.2 Erythroblastosis Fetalis AUTOIMMUNE AUTOIMMUNE HEMOLYTIC ANEMIA HEMOLYTIC ANEMIA (AIHA) (AITP) ERYTHROBLASTOSIS FETALIS Antibodies against red cell Antibodies against platelet membrane proteins membrane proteins MOTHER Rh (-) Results in red cell Results in platelet INFANT Rh (+) destruction destruction Mother develops anti-Rh IgG antibodies against fetal red RBC Hemolysis Thrombocytopenia—decre cells. ase in platelet count Pathology - Mod 4 🏠 Hypersensitivity Reactions and Prototype Disorders 5 of 14 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. IIb. COMPLEMENT AND FC RECEPTOR-MEDIATED 3. IIc. ANTIBODY-MEDIATED CELL DYSFUNCTION INFLAMMATION The antigen being recognized are cell surface receptors and the antigen-antibody interaction This results in impairment or dysregulation of function WITHOUT causing cell injury or inflammation e.g., Myasthenia Gravis and Grave’s Disease 3.1 Myasthenia Gravis Leukocyte Activation for Inflammation Induction. 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 Myasthenia Gravis. complement cleavage products—mainly C5a. Acetylcholine is a chemical messenger or a 2 C5a directs the migration of granulocytes and neurotransmitter that place an important role in brain monocytes (leukocytes), and anaphylatoxins like and muscle function C3a that increase vascular permeability. Antibodies react with acetylcholine receptors in the motor end plates of skeletal muscles and blocks the 3 In the second mechanism, leukocytes can also be binding of the acetylcholine with its receptor activated by the engagement of their C3b and Fc This consequently blocks neuromuscular receptors to antibodies. transmission The muscles DO NOT receive the neurotransmitter 4 Once leukocytes are activated, they now release and CANNOT contract, resulting in muscle weakness substances such as lysosomal enzymes including proteases capable of digesting basement membrane, 3.2 Grave’s Disease collagen, elastin, and cartilage. 5 Activated leukocytes also generate reactive oxygen species (ROS) that ultimately lead to inflammation and tissue damage. 2.1 Goodpasture Syndrome Grave’s Disease. Antibodies recognize the thyroid stimulating hormone receptor as antigenic Results in overstimulation of thyroid epithelial cells to produce thyroid hormone resulting in hyperthyroidism Goodpasture syndrome. 3.3 Antigen-Antibody Interaction An example of an immune disorder that follows antibody mediated inflammation A rare disease characterized by diffuse pulmonary hemorrhages and acute or rapidly progressive glomerulonephritis Patients have antibodies against non-collagenous proteins in the basement membrane of the glomeruli and the alveoli present clinically as hemoptysis and hematuria MNEMONIC: organs affected in GoodPasture syndrome ○ Glomerulus ○ Pulmonary Grave’s Disease and Myasthenia Gravis Comparison In Myasthenia Gravis, the antigen-antibody interaction results in inhibition of cell function. Pathology - Mod 4 🏠 Hypersensitivity Reactions and Prototype Disorders 6 of 14 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.  In Grave’s disease, the antigen-antibody interaction Free in On cell Free in results in overstimulation of cell function. Ag circulation surface circulation Ultimately, the end result despite differences is alteration in normal cell function Type III and Primarily mediated by IgG and IgM B. SUMMARY Type II antibodies. In Type II Hypersensitivity (antibody-mediated hypersensitivity) secreted IgG and IgM antibodies Combine with soluble antigens that are ○ Injure cells by promoting their phagocytosis/lysis Type III and NOT found in cell surfaces ○ Injure tissues by inducing inflammation Type I Meaning these antigens are free in Antibodies may also interfere with cellular functions circulation (unlike in Type II) and cause disease without tissue injury Diseases caused by Type II Hypersensitivity In the circulation, these antigens react with antibodies and ○ Transfusion reactions form immune complexes that deposit in tissues. ○ Erythroblastosis Fetalis ○ Autoimmune hemolytic anemia A. ANTIGENS THAT FORM IMMUNE COMPLEXES ○ Autoimmune thrombocytopenic purpura ○ Goodpasture syndrome ○ Myasthenia gravis Include foreign proteins that are ○ Grave’s disease 1 Exogenous injected or produced by infectious microbe SUMMARY Individual produced antibody Endogenous 2 against self antigens (e.g. Disease Target Mechanism (self) Autoimmune diseases) Antigen Reactions take hours or days or Autoimmune RBC membrane IIa opsonization even weeks to develop depending hemolytic anemia proteins and phagocytosis 3 Acute on whether or not there is (AIHA) of erythrocytes immunological memory of the precipitating antigen Autoimmune Platelet IIa opsonization & thrombocytopeni membrane phagocytosis of Happens particularly in autoimmune c purpura (AITP) proteins platelets 4 Chronic conditions Goodpasture Non-collagenou IIb complement Syndrome s protein in BM and Fc receptor B. MAJOR FORMS OF IMMUNE COMPLEX-MEDIATED of alveoli and mediated HYPERSENSITIVITY glomeruli inflammation 1 Localized Immune Complex Disease Myasthenia Acetylcholine IIc. Ab inhibits Ach Gravis receptor binding, 2 Systemic Immune Complex Disease downregulates receptors 1. LOCALIZED IMMUNE COMPLEX DISEASE Grave’s disease TSH receptor IIc (hyperthyroidism) antibody-mediated 1.1 ARTHUS REACTION stimulation of TSH Exemplifies the localized immune complex disease receptors Discovered by Nicholas Maurice Arthus in 1903 ○ He repeatedly injected horse serum subcutaneously into rabbits. V. TYPE III (IMMUNE COMPLEX) HYPERSENSITIVITY ○ After 4 injections, he found edema and the serum Normally, when antigens combine with antibodies, they was absorbed slowly. are promptly removed. ○ Further injections lead to gangrene. Occasionally, they persist mostly because of: Recognized as a dermal inflammatory reaction due to ○ They are small in size localized immune complex formation following repeated ○ Form Immune Complexes subcutaneous or intradermal injections of foreign ○ Deposited in tissues resulting in inflammation and antigen disease. ○ These complexes precipitate in the vessel walls Ag + Ab (Immune Complex): type III’s moniker and the eliciting inflammation and consequent tissue foundation of the mechanism of Type III hypersensitivity injury. disorder. ○ In some cases, the damage to the wall is so severe Such is the pathology of Type III (Immune Complex) as to cause thrombosis and localized ischemic Hypersensitivity injury. Type 1 Type II Type III Ab IgE IgG; IgM IgG; IgM Pathology - Mod 4 🏠 Hypersensitivity Reactions and Prototype Disorders 7 of 14 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.  Left: Arthus Reaction, Right: Nicholas Maurice Arthus Mechanism of Serum Sickness 2. SYSTEMIC IMMUNE COMPLEX DISEASE C. MECHANISM OF IMMUNE COMPLEX-MEDIATED Occurs when soluble antigens combine with antibodies HYPERSENSITIVITY in the circulation, forming circulating immune The introduction of a protein antigen triggers an immune complexes response that results in the formation of antibodies, Trapped/Deposited in the: typically about one week after injection of the protein ○ Glomerulus (Kidneys) These antibodies are secreted into the blood where they ○ Joints react with the antigen still present in the circulation and form ○ Blood vessels antigen-antibody complexes. 2.1 Serum Sickness 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 complexes in blood vessels. The factors that determine whether Manifestation of serum sickness: skin rash. immune complex formation will lead to tissue deposition and disease are The symptoms appear more rapidly with repeated not fully understood. But, major injections of the serum influences seem to be the characteristics of complexes and MECHANISM OF SERUM SICKNESS localized vascular alterations In general, complexes that are 1 The foreign protein contained in the vaccine is the medium-sized are the most recognized antigen. pathogenic. Organs where blood is filtered at 2 Antibodies react with the foreign protein and form high pressure to form other immune complexes. liquids (e.g. urine and synovial fluid) are sites where immune 3 These immune complexes are then deposited in complexes become concentrated tissues and subsequently trigger an inflammatory and tend to deposit. response Hence, immune complex disease often affects the glomeruli and 4 Enzymes and cytokines are activated. joints 5 Reactions with complement attracts neutrophils, Once immune complexes are leading to inflammation. deposited in the tissues, they initiate an acute inflammatory reaction by activating complement Pathology - Mod 4 🏠 Hypersensitivity Reactions and Prototype Disorders 8 of 14 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.  PHASE 2: Characterized by immune complex When deposited in the kidney, the complexes can be IMMUNE deposition and complement seen as thick granular lumpy deposits on both H&E COMPLEX activation stain and immunofluorescence DEPOSITION; Complement fragments like C3a ○ These lumpy deposits contain immunoglobulin COMPLEMENT and complement. ACTIVATION and C5a 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 over tissues, the neutrophils do not succeed. ○ Consequently, the neutrophils are compelled to release a number of substances like prostaglandins, lysosomal Immune complexes deposited in the kidney (H&E and enzymes, and free oxygen immunofluorescence). Glomerulonephritis of varying degrees radicals over the complexes, of severity. causing damage to the tissues at the site of immune complex deposition E. OTHER EXAMPLES PHASE 3: Tissue injury and clinical 1. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) INFLAMMATION symptoms manifest Antibodies are formed against double-stranded DNA ○ Clinical features like fever, (dsDNA), nucleoproteins, and other nuclear antigens rashes, urticaria (hives), joint The antigen-antibody complexes deposit mainly in the pain, lymph node enlargement, kidneys, skin and joints and proteinuria (excretion of protein in urine) appear 2. POST-STREPTOCOCCAL GLOMERULONEPHRITIS Ensues approximately 10 days Occurs when an individual previously infected with after antigen administration streptococcal infection develops antibodies against Consumption of C3 streptococcal wall antigens that have previously ○ Serum c3 levels are used by planted on the glomerular basement membrane clinicians as an adjunct in monitoring disease activity in 2. FARMER’S LUNG some immune complex Localized type of immune complex disorder resulting disorders from inhalation of bacterial spores or molds found in hay or crops leading to hypersensitivity pneumonitis D. MORPHOLOGY Acute necrotizing vasculitis F. SUMMARY ○ Morphologic manifestations of the immune complex Type III Hypersensitivity is also called Immune Complex injury is in the blood vessels Hypersensitivity. ○ The blood vessel exhibits necrosis of the vessel It is characterized by the formation of wall and intense neutrophilic infiltration antigen-antibody complexes that produce tissue Fibrinoid necrosis damage by eliciting inflammation at the sites of their ○ Deposits of the immune complexes (complements deposition. and plasma proteins) appear as smudgy Such complexes are usually systemically deposited eosinophilic area of tissue destruction preferentially involving the kidney, joints and small blood vessels resulting in inflammatory lesions called glomerulonephritis, arthritis and vasculitis respectively. These immune complexes may also be deposited locally in the skin and the lungs. ○ Disease examples include serum sickness, SLE, post-streptococcal GN, arthus reaction and farmer's lung. But wherever immune complexes are deposited, they activate the complement system, wherein macrophages and neutrophils are attracted to the site of their deposition where they cause inflammation, leading to tissue injury. VI. TYPE IV (CELL-MEDIATED) HYPERSENSITIVITY TYPE I TYPE II TYPE III TYPE IV Acute necrotizing vasculitis and fibrinoid necrosis as IgE mediated/ Antibody Immune- displayed in Type III hypersensitivity. Cell mediated Immediate mediated complex Pathology - Mod 4 🏠 Hypersensitivity Reactions and Prototype Disorders 9 of 14 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.  T cell IgE IgG; IgM IgG; IgM presenting cell (APC) at the time of T-cell (CD4+/CD8+) activation. 3 IL-2 secreted by naive T-cells causes it to differentiate into Th1 or Th17. 4 IL-12 → Th1. ○ Antigen presenting cells (e.g., dendritic cells, macrophages) ○ Interferon gamma (IFN-γ) produced by Th1 cells further promotes Th1 development, thus, amplifying the reaction. IL-1, IL-6, and IL23 → Th17. Mediators of Type IV Hypersensitivity 5 Some of the differentiated effector cells (Th1, Th17), enter the circulation and join the pool of memory Results primarily from the interaction of the T-cells where they persist for a long period, even lymphocytes, monocytes, and macrophages years. Also called cell mediated hypersensitivity or CD4 mediated inflammation or cytokine-mediated inflammation. Mainly governed by the production of cytokines by CD4 T-cell, resulting in inflammation. To a lesser extent, CD8 cytotoxic cells can also result in type 4 hypersensitivity. ○ Mechanism followed by some autoimmune diseases. ○ May also be the dominant mechanism of tissue injury in certain reactions especially those that follow viral infections ○ 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 Differentiation of Naive CD4 T-cells. This immunopathological damage occurs at about 24 – 72 hours after exposure of a sensitized individual to an 2. EFFECTOR PHASE antigen, making the reaction a delayed type Response of Activated CD4+ T lymphocytes ○ In contrast to the first three hypersensitivity Once the host is sensitized, prolonged or repeated reactions (immediate immune reaction), Type 4 has exposure to the antigen results in the development of a delayed reaction. an effector phase. Classical T-cell reaction to antigens given to previously Corresponds to the response of the activated CD4 sensitized individuals. T-lymphocytes. Remember, the naive CD4 T-lymphocytes are activated B. INFLAMMATORY REACTIONS STIMULATED BY CD4 into either Th1 or Th17 cells depending on cytokine T-CELLS produced by the APCs during the sensitization phase. 1. SENSITIZATION PHASE 2.1 Classic Effector Response Occurs with the initial exposure of naïve In the form of production of IFN-γ by Th1 cells. T-lymphocytes to the antigen IFN-γ: key mediator of Type IV hypersensitivity Results in the development of antigen-specific because it activates and turns macrophages into memory T lymphocytes phagocytes and super killers. ○ Most important and the key driver for the activated macrophages’ enhanced powers SENSITIZATION PHASE PROCESS during the effector phase. IFN-γ also enhances the macrophages’ ability to 1 Naive CD4 T-cells recognize peptides displayed present antigens by inducing increased expression of by dendritic cells. class II major histocompatibility (MHC) molecules. ○ MHC molecules bind peptide fragments derived 2 Naive CD4 T-cells secrete Interleukin 2 (IL2) from pathogens and display them on the cell Interleukin 2 (IL2) surface for easier recognition by appropriate T-cells. ○ Autocrine growth factor that stimulates Activated macrophages produce IL-12, which then proliferation of the antigen responsive facilitates the development of other Th1 lymphocytes. T-cells either as Th1 or Th17 Activated macrophages also produce IL-1 and TNF-α. ○ Whether these antigen responsive T-cells Both of which further facilitate the extravasation of become Th1 or Th17 depends on the additional inflammatory cells. cytokines produced by the antigen In the effector phase, the activated macrophages serve to eliminate the offending agent. Pathology - Mod 4 🏠 Hypersensitivity Reactions and Prototype Disorders 10 of 14 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.  ○ If the activation is sustained, the inflammation continues – resulting in a response that first starts as a beneficial response or immunity to a harmful response (tissue damage or hypersensitivity). Tuberculin PPD test. Classic Effector Response. Reactive Tuberculin PPD test. 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 exposure to a number of intracellular organisms. Interleukins associated with Th17. Tuberculin (PPD) Reaction Aside from Th1, CD4 + T-cells can also become activated to the Th17 subtype. Morphology Activated Th17 cells secrete chemokines and cytokines (i.e. IL-17, IL-22) to a lesser extent. ○ These cytokines recruit neutrophils and monocytes to the reaction – promoting inflammation. It is not just the Th1 cells that play a pivotal role in CD4 mediated hypersensitivity. C. CLINICAL EXAMPLES OF CD4+ T-CELL MEDIATED INFLAMMATION Perivascular cuffing in Tuberculin reaction. 1. TUBERCULIN (PURIFIED PROTEIN DERIVATIVE) REACTION Characterized by the accumulation A classic example of late type CD4 mediated type IV of mononuclear cells, mainly CD4 hypersensitivity. T-cells and macrophages around This is produced by intracutaneous injection of venules, producing a perivascular tuberculin, or purified protein derivative (PPD) “cuffing”. ○ PPD: protein-containing antigen of the tubercle In fully developed lesions, the bacillus venules show marked endothelial In a previously sensitized individual (with previous hypertrophy, reflecting exposure to tuberculosis), there is redness and cytokine-mediated endothelial induration at the site of injection that appears in 8-12 activation. hours. ○ This hypersensitivity reaches a peak in 24-72 hours. After which, it slowly subsides. In addition to the tuberculin response, type IV hypersensitivity is the underlying pathogenesis for Pathology - Mod 4 🏠 Hypersensitivity Reactions and Prototype Disorders 11 of 14 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.  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 generally occurs in 5–7 days. ○ 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. 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. Langhans giant cell (encircled). ○ Aggregates of epithelioid cells usually surrounded by lymphocytes form grossly visible, small nodules 3. CONTACT DERMATITIS (ALLERGIC CONTACT called granulomas. DERMATITIS) In this delayed type hypersensitivity reaction, the antigen can be in the form of simple chemicals like nickel, formaldehyde, plant materials like poison ivy, cosmetics, soaps, and other substances which are often too small to elicit an immune response by itself. ○ These antigens must be complexed with larger proteins to become antigenic and are specifically referred to as haptens. Epithelioid cells (red arrows) and aggregates of lymphocytes (encircled). Epithelioid cells sometimes fuse to form multinucleated giant cells. In Tuberculosis, these giant cells are called Simple chemical (represented by Ag) bound to a large Langhans giant cells. protein to form a hapten. Granulomatous inflammation is commonly associated with strong Th1 cell activation and production of interferon-gamma (IFN-γ). SENSITIZATION PHASE In the sensitization phase the 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 lymphocytes → now sensitized to the antigen. In a sensitized host, continuous or more commonly repeated exposure to the antigen results in an effector phase response. Contact dermatitis, is seen as epidermal vesicle formation of erythema, itching, eczema, or necrosis of the skin, within 12 to 48 hours. Granulomatous inflammation marked by asterisks. Sensitization phase of the protein-hapten complex. Pathology - Mod 4 🏠 Hypersensitivity Reactions and Prototype Disorders 12 of 14 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.  permitting the delivery of granzymes into the cell. Granzymes → proteases that cleave and activate caspases which induce apoptosis of the target cells BOTH mechanisms generally result in the killing of infected cells with elimination of the infection. In some cases, these are responsible for cell damage Erythema ,itching, eczema, or necrosis. that accompanies an infection (e.g., viral hepatitis). Perforins drill pores into the infected cells that allow the D. CD8+ MEDIATED HYPERSENSITIVITY entry of granzymes. The granzymes then cleave and Most commonly associated with viral infections. activate caspases that induce apoptosis or killing of the target cells. 1 CD4 mediated Type IV Results in inflammation hypersensitivity E. OTHER EXAMPLES OF BENEFICIAL PROTECTIVE RESPONSE OF T-LYMPHOCYTE MEDIATED HYPERSENSITIVITY 2 CD8 mediated Type IV Results in apoptosis Beneficial protective response of T-Lymphocyte hypersensitivity mediated hypersensitivity ○ NOT LIMITED to intracellular organisms and viruses. ○ CAN BE primary component of transplant rejection and immunity to cancer T-Lymphocyte mediated hypersensitivity: mechanism involved in some autoimmune diseases aside from tuberculosis and contact dermatitis. OTHER DISEASE EXAMPLES Specificity Clinicopat of Mechanism hologic Disease Pathogenic of Injury Manifestati T Cells ons Mechanisms of CD8 T-lymphocyte in a virus infected cell. Chronic In a virus infected cell, viral peptides are displayed by Cytokine-me arthritis; Collagen? Class I Major Histocompatibility molecules (MHC) → the Rheumatoi diated inflammatio Citrullinated complex is recognized by T-cell receptors of CD8 d inflammatio n and self T-lymphocytes. Arthritis n (CD4+ destruction proteins? Recognition of antigens by the cytotoxic lymphocyte is T-Cells) of articular via one of two pathways. cartilage 1. PATHWAYS IN RECOGNITION OF ANTIGEN BY THE Demyelinati CYTOTOXIC LYMPHOCYTES Protein Cytokine-me on in CNS antigens in diated with Multiple myelin inflammatio perivascula Sclerosis PATHWAYS IN RECOGNITION OF ANTIGEN BY (myelin basic n (CD4+ r CYTOTOXIC LYMPHOCYTES protein) T-Cells) inflammatio n; paralysis DIRECTIONAL DELIVERY EXPRESSION OF OF PERFORINS AND FAS-FAS LIGAND Antigens of Insulinitis T-Cell GRANZYMES pancreatic (chronic