2024_0826_1500_lybarger_bracamonte_hypersen_reactions_final.pdf

HYPERSENSITIVITY REACTIONS Block: Foundations Block Director: James Proffitt, PhD Session Date: Monday, August 26, 2024 Time: 3:00 – 4:00 pm Instructor: Lonnie Lybarger, PhD Department: Cellular & Molecular Medicine Email: lybarger@arizona...

HYPERSENSITIVITY REACTIONS Block: Foundations Block Director: James Proffitt, PhD Session Date: Monday, August 26, 2024 Time: 3:00 – 4:00 pm Instructor: Lonnie Lybarger, PhD Department: Cellular & Molecular Medicine Email: [email protected] Instructor: Erika Bracamonte, MD Department:Pathology Email: [email protected] INSTRUCTIONAL METHODS Primary Method: IM13: Lecture ☐ Flipped Session ☐ Clinical Correlations Resource Types: RE18: Written or Visual Media (or Digital Equivalent) INSTRUCTIONS Please read the lecture objectives and notes. These notes can be used to supplement your study of the concepts from the live lecture READINGS RECOMMENDED Reading: Additional information can be found primarily in chapter 11 of Basic Immunology: Functions and Disorders of the Immune System, 6th ed. (Abbas, Lichtman, and Pillai), 2020, and chapter 6 of Robbins and Cotran Pathologic Basis of Disease (Kumar, Abbas, and Aster). These textbooks are available electronically through the Health Sciences library. LEARNING OBJECTIVES: 1. Explain what is meant by the terms “immunopathology”, “hypersensitivity”, and “allergy”. 2. Explain the basic immunologic pathways that are active in each of the four types of hypersensitivity reactions. 3. Contrast the roles of antibody molecules between Type I, II, and III reactions. 4. Explain the role of mast cells in Type I reactions and the key inflammatory mediators they produce. 5. For the following conditions, list the type of hypersensitivity reaction involved, and pathology observed: urticaria, asthma, anaphylaxis, systemic lupus erythematosus 6. Review the steps which lead to the formation of a granuloma, and provide examples of granulomatous diseases. CURRICULAR CONNECTIONS Below are the competencies, educational program objectives (EPOs), disciplines and threads that most accurately describe the connection of this session to the curriculum. Block: Foundations | BRACAMONTE / LYBARGER [1 of 13] HYPERSENSITIVITY REACTIONS Related Related Competency\EPO Disciplines Threads COs LOs CO-01 LO #1 MK-01: Core of basic sciences Immunology N/A CO-01 LO #2 MK-02: The normal structure and Immunology N/A function of the body as a whole and of each of the major organ systems CO-01 LO #3 MK-02: The normal structure and Immunology N/A function of the body as a whole and of each of the major organ systems CO-01 LO #4 MK-02: The normal structure and Immunology N/A function of the body as a whole Pathology and of each of the major organ systems MK-05: The altered structure and function (pathology & pathophysiology) of the body/organs in disease CO-01 LO #5 MK-05: The altered structure and Pathology N/A function (pathology & Histology & pathophysiology) of the Cellular Biology body/organs in disease CO-01 LO #6 MK-05: The altered structure and Pathology N/A function (pathology & pathophysiology) of the body/organs in disease CONTEXT: As we have seen, the immune system represents a powerful, effective, and essential defense in a world teeming with potentially pathogenic microbes. However, the ability of the adaptive immune system to distinguish “safe” from “harmful” and/or “self” from “non-self” can fail in some cases, leading to disease. Such damaging responses are called hypersensitivity reactions, and they may be directed against foreign- or self-antigens. There are four types of hypersensitivity, and these will be considered in this lecture. Hypersensitivity to foreign- and self-antigens is common and results in a wide range of diseases that can be quite severe. Diseases resulting from these immunopathologies will be encountered in all blocks of the curriculum. The primary goal of this session is to present basic mechanisms of hypersensitivity reactions and use key examples to demonstrate the range of diseases and clinical presentations they can produce. Block: Foundations | BRACAMONTE / LYBARGER [2 of 13] HYPERSENSITIVITY REACTIONS LECTURE NOTES: I. HYPERSENSITIVITY REACTIONS: Immunopathology is the process by which the host’s cells/ tissues are injured through the host’s immunologic reaction to a stimulus. In some instances, the damage may be incidental to the otherwise appropriate immune process (“innocent bystander”); in others, the immune response may be specifically directed toward the host’s cells/proteins/tissues (“self” targets). This latter scenario is termed autoimmune disease and will be addressed in more detail in a subsequent lecture. Hypersensitivity refers to an injurious adaptive immune reaction – usually excessive and harmful, even when directed against a foreign pathogen. The mechanisms of hypersensitivity are the same as those used to control infections, but in this case, are excessive and/or misdirected, leading to immunopathology. - Since these are adaptive immune mechanisms, each requires an initial sensitization (exposure) to antigen. In the past two decades, allergy incidence has increased sharply in developed nations, and disproportionately affects children. Allergy means “altered reactivity” and refers to a potent immune response against an otherwise innocuous substance. Hypersensitivity reactions divided into 4 types (I-IV), categorized according to the immunologic mechanisms involved. Types I-III = direct involvement of antibodies Type IV = T cells are the main effector cells TYPE I HYPERSENSITIVITY (IgE-MEDIATED) - Sometimes called “immediate hypersensitivity”, as symptoms appear within minutes of antigen exposure MECHANISM: 1) Sensitization phase = initial antigen exposure with B cells becoming IgE-secreting plasma cells. Block: Foundations | BRACAMONTE / LYBARGER [3 of 13] HYPERSENSITIVITY REACTIONS 2) Secreted IgE enters circulation and binds to the high-affinity IgE receptor on mast cells (among some other cell types). The receptor binds to the Fc portion of the IgE molecules in the absence of the antigen. 3) When the antigen is encountered again, it cross-links the IgE molecules on the surface of the mast cells (these cells tend to reside in tissues near blood vessels), triggering granule exocytosis and cytokine release by the mast cells. This is the effector phase. This produces the characteristic symptoms resulting from an acute inflammatory response. 4) Mast cell mediators cause a bi-phasic reaction: There is an initial response (first 1-2 hours) induced by: -vasoactive amines (especially histamine) released from granules that induces vasodilation and vascular leakage - lipid mediators (arachidonic acid metabolites) that also mediate the vascular response and some of which recruit leukocytes - proteases in secretory granules that degrade the extracellular matrix and that activate complement This is followed by a late-phase reaction, this is often more pronounced and prolonged: - cytokines (such as TNF and IL-4) that orchestrate the response. Influx of eosinophils is one hallmark of this phase. Why IgE??? Most antigens do not induce an IgE response. Production of IgE is favored by relatively low antigen dose, but overall, it remains unclear why certain molecules tend to result in IgE production. Genetics plays a factor; individuals predisposed to making more T Helper-2 cytokines (like IL-4 and IL-13) are more prone to IgE production. Such individuals are referred to as atopic. Block: Foundations | BRACAMONTE / LYBARGER [4 of 13] HYPERSENSITIVITY REACTIONS TYPE I DISEASE EXAMPLES: 1) Local reactions: Seasonal allergies, urticaria (hives), asthma - In asthma, bronchioles become constricted due to smooth muscle contraction during a flare-up (encounter with asthmagen). Chronic exposure can lead to remodeling of the airway, leading to obstruction. Remodeling includes smooth muscle hypertrophy and thickening of the basement membrane, decreasing the lumen of the bronchiole. In addition, airflow is also impeded by mucus overproduction. 2) Systemic reaction: Anaphylaxis a. Vascular shock, widespread edema, difficulty breathing b. Involves bronchiole constriction (respiratory distress); laryngeal obstruction; pulmonary edema; shock and death within minutes. c. Severity of response reflects level of immune sensitization - very small antigen exposure (oral, injected) may be life-threatening. Block: Foundations | BRACAMONTE / LYBARGER [5 of 13] HYPERSENSITIVITY REACTIONS TYPE II HYPERSENSITIVITY (ANTIBODY-MEDIATED CYTOTOXICITY) MECHANISM: 1) Sensitization phase = Antibodies (mostly IgM or IgG) produced against cellular (self) antigens. 2) Antibody binds to cells or extracellular proteins, fixes complement & induces lysis or opsonization for uptake by phagocytes. An example is autoimmune hemolytic anemia, where antibody-coated erythrocytes are ingested by phagocytes. The antibodies can engage Fc receptors on phagocytes to enhance uptake. This is the mechanism of blood transfusion reactions. The antibodies can also induce damage without phagocytosis, by recruiting cells such as neutrophils (via local complement activation and by binding to Fc receptors on neutrophils), which become activated and induce inflammation. An example is Goodpasture’s syndrome, where antibodies against the glomerular basement membrane in the kidney can activate complement and can recruit inflammatory cells, leading to tissue destruction and renal failure. The antibodies can also bind to proteins on cells and alter their function. There could be blocking of normal function, or induction of some functions. Examples: i) in myasthenia gravis, antibodies block the function (but without cell damage) of neurotransmitter receptors on muscle cells, leading to muscle weakness. ii) in Grave’s disease, antibodies bind to the TSH receptor on thyroid follicular cells, mimicking the effect of the natural ligand, causing the thyroid cells to become active and secrete thyroid hormones. This leads to various symptoms of hyperthyroidism. Block: Foundations | BRACAMONTE / LYBARGER [6 of 13] HYPERSENSITIVITY REACTIONS TYPE III (IMMUNE-COMPLEX) HYPERSENSITIVITY MECHANISM: 1) Sensitization phase = Antibodies (mostly IgM or IgG) produced against cellular (self) or foreign antigens. 2) Antibodies combine with soluble antigen to make insoluble complexes, which deposit on blood vessel walls. Glomerular capillaries in the kidney, synovium of joints, and dermal capillaries of skin are common sites of deposition. 3) Antigen-antibody complexes (immune complexes) can activate complement, which is a chemoattractant. 4) Neutrophils can be recruited and can release enzymes that damage the vessel and adjacent tissue. Block: Foundations | BRACAMONTE / LYBARGER [7 of 13] HYPERSENSITIVITY REACTIONS IMMUNE COMPLEXES are generated in most antibody responses and do not cause problems. In certain cases, the nature of the antigen and the antibody titers create conditions that favor the formation of relatively small immune complexes, which favors type III reactions. Note: at least two antibody molecules must be in a complex to fix (activate) complement. The kidneys are a frequent site where immune complexes settle in blood vessel walls and induce inflammation. Block: Foundations | BRACAMONTE / LYBARGER [8 of 13] HYPERSENSITIVITY REACTIONS TYPE III DISEASE EXAMPLES: 1) System lupus erythematosus is a classic example of a Type III hypersensitivity disease. It will be discussed in more detail in the upcoming Tolerance and Autoimmunity lecture. 2) Post-Streptococcal glomerulonephritis is a kidney disease which can occur 2-4 weeks after a Strep infection of the skin or nasopharynx. Antibodies are produced in response to the infection, and these can form immune complexes with residual bacterial antigens in circulation. The resulting immune complexes deposit in the glomeruli and cause inflammation with acute kidney injury. TYPE IV HYPERSENSITIVITY (T CELL-MEDIATED) In Types I-III hypersensitivities, T cells may help with antibody production, but antibodies cause the initial problems. Here (Type IV), T cells are the effectors of disease. Sometimes called delayed-type hypersensitivity (DTH), due to kinetics of response (1-3 days), which is slower than the effects of antibodies (once the antibodies have been formed, of course). DTH refers to the observed reaction after an antigen encounter, such as following an injection of antigen. MECHANISM: 1) Sensitization phase with primary exposure to antigen, involving all the steps typical of a T cell response; takes 1-2 weeks. Hypersensitivity response occurs on subsequent antigen challenge and takes 2-3 days. 2) TH1 CD4 T cells enter tissues where resident antigen-presenting cells such as macrophages have phagocytosed and are presenting antigen on MHC Class II molecules. (Or, they may already reside in the tissue as memory CD4 T cells.) 3) TH1 cells secrete cytokines that result in recruitment and potent activation of additional macrophages. 4) Activated macrophages can damage the tissue with reactive oxygen species and degradative enzymes. NOTE: Can also involve CD8 T cells and MHC class I. The reaction to poison ivy is an example a Type IV reaction involving CD8 T cells. Block: Foundations | BRACAMONTE / LYBARGER [9 of 13] HYPERSENSITIVITY REACTIONS GRANULOMA REACTION: A special example of the Type IV hypersensitivity is the formation of a granuloma. When antigen persists, granulomas can form. If the immune system cannot clear the offending agent, the site can be “walled off” to limit spread. This involves prolonged activation of the macrophages due in large part to Interferon (IFN)- produced by CD4 T cells. Block: Foundations | BRACAMONTE / LYBARGER [10 of 13] HYPERSENSITIVITY REACTIONS TYPE IV DISEASE EXAMPLES: 1) Contact dermatitis: Skin reaction following initial exposure to an allergen, characterized histologically by mononuclear cell infiltration of the dermis. a) This can be a cytokine-mediated response in which CD4 T cells secrete cytokines that promote inflammation. Allergy to nickel and the tuberculin skin test are examples. b) This can be a cytolytic T cell response in which CD8 T cells are the effectors. The response to poison ivy is an example of this process. Chemicals in poison ivy become conjugated to self-proteins, creating new epitopes that are recognized by CD8 T cells. 2) Granulomatous inflammation: Mycobacterium tuberculosis infection can lead to pulmonary granulomas in which the bacteria persist long-term within macrophages. Sarcoidosis also presents with pulmonary granulomas, of largely unknown cause. Block: Foundations | BRACAMONTE / LYBARGER [11 of 13] HYPERSENSITIVITY REACTIONS 3) Transplant rejection and some forms of autoimmunity, in which CD4 T cells produce inflammatory cytokines and/or CD8 T cells kill target cells. Autoimmune examples include Type 1 Diabetes Mellitus and Multiple Sclerosis, where T cells are the main effector cells of tissue damage. Basic Immunology Figure 11-1 Block: Foundations | BRACAMONTE / LYBARGER [12 of 13] HYPERSENSITIVITY REACTIONS NOTE: Many diseases involve more than one type of hypersensitivity reaction, but are typically classified by the initial cause of disease. Block: Foundations | BRACAMONTE / LYBARGER [13 of 13]