L23 Types II-IV Hypersensitivities PDF

https://en.wikipedia.org/wiki/Mantoux_test Types II-IV Hypersensitivities Suggested Reading for L23: Basic Immunology, Chapter 11 MICRG 1553 Immunology Kathryn Leyva, Ph.D. https://nationaleczema.org/eczema/types-of-eczema/contact-dermatitis/ Learning Objectives In Types II-IV hype...

https://en.wikipedia.org/wiki/Mantoux_test Types II-IV Hypersensitivities Suggested Reading for L23: Basic Immunology, Chapter 11 MICRG 1553 Immunology Kathryn Leyva, Ph.D. https://nationaleczema.org/eczema/types-of-eczema/contact-dermatitis/ Learning Objectives In Types II-IV hypersensitivity reactions, be able to describe/identify: ▫ The immune event(s) occurring in both the sensitization and effector phases ▫ The type of antigen eliciting the immune response (e.g., soluble, cell-bound, etc) ▫ The immune response(s) resulting in tissue damage Understand the clinical examples (manifestations) discussed for Types II-IV hypersensitivity reactions and be able to correlate the manifestations observed with the immune response ▫ Type II: Drug-induced hemolytic anemia, transfusion reactions, erythroblastosis fetalis ▫ Type III: Arthus reactions, serum sickness  Understand why antigen or antibody excess is a predisposing factor to these reactions ▫ Type IV: Tubercule (granuloma) formation, contact dermatitis Understand the principle of the specific laboratory tests discussed that are used in detecting Types II-IV hypersensitivity reactions and be able to interpret results ▫ Coombs test ▫ TB tests: intradermal skin test, IFN- release assay ▫ Patch test 2  Introduction: Hypersensitivities Four types of hypersensitivity reactions: ▫ Type I  Immediate hypersensitivity (IgE) ▫ Type II  Cytotoxic hypersensitivity (IgG or IgM) ▫ Type III  Immune complex- mediated cytotoxicity (IgG or IgM) ▫ Type IV  Delayed-type hypersensitivity (T cell-mediated) https://microbenotes.com/hypersensitivity-introduction-causes-mechanism-and-types/ 3 Type II (Cytotoxic) Hypersensitivity Occurs through the production of IgM or IgG that binds to specific allergens located on cells ▫ Intrinsic cell surface components (e.g., blood group antigens) ▫ Extrinsic compounds adsorbed to the cell surface (e.g., some drugs) ▫ Some autoimmune diseases are classified as Type II hypersensitivities (e.g., MG, pemphigus) Two distinct phases: ▫ Sensitization phase: exposure to the antigen leads to IgM or IgG production ▫ Effector phase: re-exposure to the antigen allows allergen- specific IgM or IgG to bind, causing immune-mediated damage or blocks normal function of the cell/tissue (see next slide for details) 4 Type II: Effector Phase Mechanisms Antibody-dependent cellular cytotoxicity (ADCC) ▫ NK cells or macrophages killing antibody- coated targeted cells Complement-mediated lysis ▫ Activation of classical complement pathway to form membrane attack complexes (MAC) to kill target cells Antibody interference ▫ Antibodies can interfere with normal cellular functions when bound to a target cell  Can be stimulatory or inhibitory ▫ This will be covered in more detail in the autoimmunities lectures 5 Type II: Clinical Manifestations/Examples 1. Drug-induced hemolytic anemia ▫ Caused by an immunologic response against drugs (non-self antigens) that have adsorbed to or modified normal RBC membranes  Antibodies bind to antigens on RBCs or immune complexes bind to receptors on RBCs, resulting in lysis 6 Type II: Clinical Manifestations/Examples 2. Transfusion reactions ▫ Reaction to foreign blood group antigens ▫ Mediated by antibodies that bind & lyse transfused RBCs ▫ Manifestations result from intravascular hemolysis of transfused RBCs Cross-matching tests  Blood typing and cross- matching tests are performed to prevent transfusion reactions https://bio.libretexts.org/TextMaps/Map%3A_Microbiology_(OpenStax)/19%3A_Diseases_of_the_Immune_System/19.1%3A_Hypersensitivities 7  Type II: Clinical Manifestations/Examples 3. Erythroblastosis fetalis (hemolytic disease of the newborn) ▫ Mediated by maternal anti-Rh factor (anti-D) antibodies that bind and lyse neonatal RBCs Summary of disease development/symptoms, testing, Pictorial and effect of RhoGam: diagram of how HDNB can develop in a second pregnancy with RhD- (Rh negative) mothers: Owen et al. (2013) Kuby Immunology; Fig 15-11 https://medicalstudystuff.com/erythroblastosis-fetlis/#.WsosvojwaUk 8 Type II: Diagnostic Testing Several immunoassays Coombs’ tests (anti- are available to detect and globulin tests) to quantify antibodies in a detect antibodies to patient serum (recall L20-21) RBCs (recall L20-21) ▫ E.g., ELISAs ▫ Agglutination assays  Direct: tests for RBCs that have bound antibodies  Indirect: tests for serum antibodies that can bind RBCs 9 Type III (Immune Complex) Hypersensitivity Reactions are caused by small immune complexes formed by soluble antigens (allergens) binding to IgG or IgM ▫ Large complexes are typically cleared by phagocytes, whereas small aggregates, caused by antigen or antibody excess, are not as easily cleared ▫ Soluble antigens include some drugs, molds, venoms & anti-venoms, and even nuclear (self) antigens ▫ Some autoimmune diseases are classified as Type III hypersensitivities (e.g., SLE, RA) Two phases: sensitization and effector phases ▫ A separate and distinct sensitization phase, separated by time/antigen exposure is not always necessary; these two phases often occur in a continuum, even after a first exposure 10 Type III: Sensitization and Effector Phases Sensitization phase ▫ Initial exposure to allergen, resulting in immune complex (antigen-antibody complex) formation that deposit into tissues Effector phase ▫ Immune complex activation of complement & recruitment of inflammatory cells to the site of deposition; inflammation results in increased permeability ▫ Immune complexes accumulate in tissues and damage results:  Continual activation of complement  Neutrophil release of tissue-damaging enzymes and reactive oxygen intermediates ▫ Platelet aggregation and possible development of thrombi, hemorrhage, edema, and necrosis in the tissues 11 Type III: Clinical Manifestations/Examples 1. Arthus reactions = localized vasculitis ▫ Sensitization to antigen results in high level of antibody production, leading to antibody excess ▫ Upon repeated exposure to antigen at the same site, IgG antibodies form small immune complexes that deposit in the vasculature at the exposure site  Examples: hypersensitivity pneumonitis (Farmer’s lung), repeated injections Arthus reaction resulting from Arthus reaction resulting a repeated lidocaine injection from DTaP vaccine booster Koo and Dym (2000) Columbia Dental Review, 5: 30-32 https://www2.cdc.gov/nip/isd/YCTS/mod1/ courses/tdap/11055.asp 12 Type III: Clinical Manifestations/Examples 1. Arthus reactions = localized vasculitis ▫ Summary of the pathogenesis of the localized reaction 13  https://oncohemakey.com/kidney-diseases/ Type III: Clinical Manifestations/Examples 2. Systemic vasculitis (Serum sickness) ▫ Can occur in response to a large dose of foreign serum or in response to some infections resulting in antigen excess  Antitoxins, antivenins, drugs, infections, etc Clinical Application: CroFab and ANAVIP are two snake antivenins approved to treat rattlesnake envenomation. Antivenin is one example of passive immunization = administration of preformed antibodies or antibody fragments to provide immediate, transient protection. https://med.virginia.edu/toxicology/wp-content/uploads/sites/268/2020/11/Nov20-Crofab-Anavip.pdf 14 http://vet.uga.edu/ivcvm/courses/VPAT5200/03_inflammation/07_imi/imi04.html Type III: Clinical Manifestations/ Examples 2. Systemic vasculitis (Serum sickness) ▫ Upon exposure to a large amount of antigen, IgG antibodies form small immune complexes that deposit in vessel walls  Immune complex deposition ▫ Systemic immune complex deposition, resulting in tissue damage. Common manifestations:  Vasculitis  Arthritis  Glomerulonephritis https://www.thelancet.com/ journals/lancet/article/PIIS 0140-6736(11)60314- 0/fulltext 15 Type III: Diagnostic Testing & Treatments Immunoassays are available to detect and quantify antibodies in patient serum (recall L16-17) ▫ E.g., ELISAs, immunofluorescent assays (shown) “Post-infectious glomerulonephritis is immunologically mediated, and the immune deposits are widely distributed within the capillary loops. The deposits are seen here with bright green fluorescence in a granular, bumpy pattern because of the focal nature of the immune complex deposition process. In type III hypersensitivity, antigen-antibody complexes tend to filter out and become trapped along basement membranes, such as those in glomerular capillaries.” https://library.med.utah.edu/WebPath/RENAHTML/RENAL086.html Treatments will vary depending on the response and clinical manifestations, but often include: ▫ Corticosteroids ▫ Antibiotics (if infectious cause) ▫ Supportive care: IV fluids, NSAIDs, etc 16 Type IV (Delayed-Type) Hypersensitivity Mediated by TH1 cells (also known as TDTH cells), macrophages, and sometimes CTLs ▫ Allergen is commonly a microbial component, or a chemical, metal, or drug that complexes with proteins in the skin = hapten-carrier complex ▫ Initial exposure is often through direct contact with the allergen ▫ The reaction takes 24-72 hours to develop Two distinct phases: ▫ Sensitization phase: first exposure to the allergen leads to a primary immune response and development of memory T cells ▫ Effector phase: re-exposure to the allergen leads to activation of memory TH1 cells 17 Type IV: Sensitization Phase Initial exposure to allergen is commonly by contact; processing and presentation of hapten-carrier complex by APCs Common allergens include metals, plastic/rubber, chemicals, soaps, herbicides, some infectious organisms… Activation and differentiation of helper T cells into TH1 cells and resulting in development of memory (sensitized) TH1 cells ▫ Can also involve activation of CD8 T cells 18 Type IV: Effector Phase APC activation of memory (or sensitized) TH1 cells upon subsequent exposure to antigen  Release of TH1 cytokines and chemokines to recruit and activate macrophages and neutrophils, resulting in inflammation  Focus on IFN- and IL-8 (CXCL8)  Recall: TH1 cells can also help activate CD8+ T cells 19 Type IV: Effector Phase  Recruitment/activation of macrophages and neutrophils results in tissue destruction due to release of lytic enzymes and ROIs  Effector CTLs can kill host cells  Prolonged reactions can lead to granuloma formation  Can occur in some persistent bacterial infections (e.g., Valley Fever & TB)  Various other causes; chronic inflammatory component https://commons.wikimedia.org/wiki/File: Pulmonary_tuberculosis_- _Non-necrotizing_granuloma_(6545183785).jpg 20  Al Ubaidi (2018) The radiological diagnosis of pulmonary tuberculosis (TB) in primary care. J Fam Med Dis Prev DOI: 10.23937/2469-5793/1510073 Type IV: Clinical Manifestations/Examples Chest x-ray 1. Tubercule formation showing dense ▫ Infection with some organisms, such as M. tuberculosis (TB) can homogenous result in the formation of tubercules within the tissues opacity in  Tubercules = granulomas formed due to infection with TB right, middle and lower  Enhanced Th1 + macrophage responses to contain and prevent lobe of dissemination of the organism primary pulmonary TB Histologic section of lung from a patient with tuberculosis. Arrow pointing to a multinucleated giant cell at the center of one granuloma https://www.lecturio.com/concepts/type-iv-hypersensitivity-reaction/ http://hit-micrscopewb.hc.msu.edu 21 Type IV: Diagnostic Testing for TB In vivo testing: Intradermal tuberculin reaction (Mantoux test, PPD test) ▫ Clinically-induced skin reaction caused by intradermal injection of tuberculin (PPD) proteins This figure is FYI  Look for area of induration within 72 hrs  Used to determine exposure to/infection with TB http://www.guideokey.site/what-does-positive-tb-skin-test-means/ http://studymedicalphotos.blogspot.com/2016/09/interpretation-of-ppd-skin-testing.html 22 Type IV: Diagnostic Testing for TB In vitro testing: IFN- release assay (IGRA) ▫ Eg, QuantiFERON-TB Gold In-Tube (QFT assay) ▫ This assay is designed to measure IFN- released by T cells in response to tuberculin or purified mycobacterial antigens IFN- 23 Type IV: Clinical Manifestations/Examples 2. Contact dermatitis ▫ Sensitizing allergen (e.g., metals, chemicals, topical drugs, plant saps, soaps/fragrances, etc) is a hapten that complexes with proteins in the skin or mucosa ▫ Characterized by an eczematous, blistering reaction at the site of contact with the allergen after 48-72 hrs Henna Shoes (unknown etiology) Poison ivy https://www.dermnetnz.org /topics/shoe-contact- dermatitis http://www.nejm.org/ http://www.allergykc.com/ListGallery. asp?ImageCategory_Code=1005 24 Type IV: Diagnostic Testing & Treatments In vivo test: Patch test ▫ An assay to determine the cause of a Type IV hypersensitivity (e.g., contact dermatitis)  A small square of material (cotton, linen, paper) impregnated with the suspected allergen is applied to the skin for 24-48 hours ▫ The development of redness, edema, and formation of vesicles constitutes a positive test https://en.wikipedia.org/wiki/Patch_test +++ reaction ++ reaction + reaction +/- reaction  You will not be tested on how to score these reactions. Treatments vary but typically include: ▫ Avoidance/removal of the allergen ▫ Oral antihistamines and hydrocortisone to reduce itching & inflammation ▫ Antibiotics to treat any secondary bacterial infections 25 Summary Figure This figure shows all four hypersensitivity reactions. We focused only on Types II-IV for this lecture. Note: I will expect you to be able to compare/ contrast all four hypersensitivities for the exam so refer to L22 for details on Type I hypersensitivities. Erythroblastosis fetalis = hemolytic disease of the newborn 26  Summary Figure This figure shows all four hypersensitivity reactions. We focused only on Types II-IV for this lecture. Note: I will expect you to be able to compare/ contrast all four hypersensitivities for the exam so refer to L22 for details on Type I hypersensitivities. 27