L22 Type I Hypersensitivities PDF

Type I Hypersensitivities https://www.pathologystudent.com/?p=1440 Suggested Reading for L22: Basic Immunology, Chapter 11 MICRG 1553 Immunology Kathryn Leyva, Ph.D. Learning Objectives In Type I hypersensitivity reactions, be able to describe/identify: ▫ The e...

Type I Hypersensitivities https://www.pathologystudent.com/?p=1440 Suggested Reading for L22: Basic Immunology, Chapter 11 MICRG 1553 Immunology Kathryn Leyva, Ph.D. Learning Objectives In Type I hypersensitivity reactions, be able to describe/identify: ▫ The event(s) occurring in both the sensitization and effector phases  Role of Th2 cells and B cells ▫ The mediators involved in the immune response  Mast cell-derived mediators: pre-formed and newly synthesized ▫ The cause of tissue damage Understand the clinical examples (manifestations) discussed for Type I hypersensitivity reactions and be able to correlate the manifestations with the immune response ▫ Describe the different ways that Type I hypersensitivity reactions present based upon route of exposure to allergen (i.e., localized vs systemic) Understand the principle of the laboratory tests discussed that are used in detecting Type I hypersensitivity reactions and be able to interpret results given: skin prick test and ELISA-based immunoassays Understand the mechanism of action of the following therapies in treating &/or preventing Type I hypersensitivities: ▫ Antihistamines, bronchodilators, corticosteroids, NSAIDs, and epinephrine  You will not be asked to recall specific drug names in the above classes, except for epinephrine ▫ The monoclonal antibodies discussed to treat allergic asthma ▫ Allergen immunotherapy = allergy shots 2 Introduction: Hypersensitivity Defined as an exaggerated, inappropriate, or prolonged immune response to an antigen (allergen) ▫ The effector mechanisms are the same as in a normal response ▫ Two phases: sensitization and effector Clinical manifestations, plus any tissue damage that may result, are due to the immune response to the allergen Hypersensitivity reactions are recognized primarily on: ▫ Type of immune response causing tissue injury ▫ Location of the target antigen 3  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/ 4 Type I (Immediate) Hypersensitivity Inappropriate hypersecretion of IgE in response to allergens = Atopy ▫ Individuals are atopic ▫ Common disorder; there is a genetic predisposition to development of atopy ▫ Environmental factors also play a role  Hygiene hypothesis: prevalence of atopic disorders increases as the environment becomes more hygienic Two distinct phases: ▫ Sensitization phase ▫ Effector phase 5 Type I: Sensitization Phase Initial exposure to allergen elicits a TH2 response B cell activation, resulting in secretion of IgE ▫ IL-4 & IL-13 secreted from effector Th2 cells induces isotype (class) switching to IgE IgE binds FcRs on the surface of mast cells. Once this happens, the mast cells are defined as sensitized mast cells ▫ Mature mast cells reside in connective tissue throughout the body Note: Basophils can be sensitized too 6 Type I: Effector Phase On a repeat exposure to the same allergen, the allergen crosslinks IgE-bound FcRs on mast cells Mast cell activation results in: ▫ Release of granular contents  Vasoactive amines & other substances ▫ Synthesis and release of other mediators  Lipid mediators  Cytokines https://coursewareobjects.elsevier.com/ objects/elr/Abbas/basic6e/animations/# 7 Type I Mediators: Granule Contents Granules contain preformed histamine & proteases; the major mediator is histamine FYI: Bind to H1 receptors Effects of histamine are rapid but short-lived Biologic effects of histamine occur within seconds; part of the early phase reaction: ▫ Vasodilation ▫ Increased vascular permeability ▫ Non-vascular smooth muscle contraction ▫ Increased mucus production 8 Clinical Application: Antihistamines and Cromolyn Treatments: Some antihistamines are H1 receptor antagonists ▫ Examples: diphenhydramine (Benadryl®), cetirizine (Zyrtec®), loratadine (Claritin®) Mast cell stabilizers block calcium channels, preventing mast cell degranulation ▫ Examples: cromolyn sodium (e.g., Nasalcrom®, Opticrom®) https://www.sciencedirect.com/science/articl Modified from https://doctorlib.info/pharmacology/illustrated/31.html e/pii/S0091674911014084 9 Type I Mediators: Lipid Mediators Mast cells begin to quickly synthesize prostaglandins (PGs) and leukotrienes (LTs) from arachidonic acid within minutes of stimulation ▫ Secondary mediators as these are NOT preformed ▫ Are also part of the early phase reaction Biologic effects are similar to histamine, but PGs and LTs are 1000x more potent and longer-lasting! Copyright QUT, Sheila Doggrell 10 Clinical Application: PG & LT Inhibitors Corticosteroids inhibit synthesis of both PGs & LTs ▫ Examples: prednisone, hydrocortisone, budesonide (Pulmicort®) NSAIDs block synthesis of PGs ▫ Examples: aspirin, ibuprofen, naproxen LT inhibitors block action of LTs ▫ Examples: zafirlukast (Accolate®), montelukast (Singluair®) 11 Type I Mediators: Cytokines Mast cells also synthesize several cytokines within hours after stimulation by allergen. Main cytokines: ▫ TNF & IL-6: inflammation ▫ IL-4 & IL-13: Th2, IgE ▫ IL-5: eosinophils ▫ FYI: Chemotactic cytokines too https://www.immunology.org/public-information/bitesized-immunology/cells/mast-cells 12  Type I Mediators: Cytokines Cytokines are responsible for the late- phase reaction (late response in fig) ▫ Inflammatory responses ▫ Recruitment and activation of neutrophils and eosinophils Release of cytotoxic granular contents Eosinophil (eg: MBP, EPO, ECP) Cytokine receptors Synthesis of lipid mediators Modified from: Renz (eg: PAF, LTs) et al. (2021) Physiology and pathology of eosinophils: Recent GPCRs Cytokine secretion developments. Scand J Immunol (eg, IL-12, IL-31, TNF) Clinical Application: 93(6). PRRs Corticosteroids are used to prevent damaging inflammation by decreasing PG/LT ▫ Can lead to tissue damage and release of synthesis, inhibiting inflammatory cytokine additional inflammatory cytokines/mediators production, etc. 13 Type I: Localized vs Systemic Anaphylaxis Anaphylaxis = an acute, hypersensitive allergic reaction to an antigen Anaphylactic reactions manifest in different ways based upon the location of the allergen; range from mild to life threatening Localized Anaphylaxis = local release of mediators ▫ The specific clinical manifestations that result are dependent on the site of allergen exposure and location of mast cell activation Systemic Anaphylaxis = systemic release of mediators Systemic clinical manifestations resulting from the allergen in/spread through the bloodstream https://doctorlib.info/immunology /microbiology/67.html 14  https://www.medicinenet.com/best_treatments _for_allergic_conjunctivitis/article.htm Type I: Localized Anaphylaxis Reactions 1. Allergic rhinitis and conjunctivitis ▫ Activation of mast cells in the upper respiratory tract and/or eyes ▫ Clinical manifestations include itchy, watery eyes, sneezing, runny nose  Very common! Treatment varies, but includes antihistamines & intranasal corticosteroids https://granthealth.org/pink-eye-conjunctivitis/ https://www.ent-phys.com/ent-services/nose/chronic-rhinitis/ 15 Type I: Localized Anaphylaxis Reactions https://sites.google.com/a/gertzresslerhigh.org/ap-biology- allergies-and-the-immune-system/allergies-asthma 2. Allergic asthma ▫ Activation of mast cells in the lower respiratory tract causing bronchoconstriction &increased mucus secretion ▫ Clinical symptoms include coughing, wheezing, open mouth breathing and/or gasping for breath ▫ Treatments include:  Biologics (see next slide)  Bronchodilators: fast-acting FYI: examples include albuterol (2-agonist) and theophylline  Corticosteroids: prevent late-phase response Tashkin and Fabbri, Respir Res. 2010; 11:!49 https://www.assignmentpoint.com/science/health/bronchodilator.html 16 Clinical Application: Immunotherapies for Asthma https://youtu.be/ Monoclonal Antibodies f8iGMYmdm6U ▫ Anti-IL-4R ▫ Anti-IgE  Dupilumab (Dupixent®)  Omalizumab (Xolair®) https://www.dupixenthcp.com/ atopicdermatitis/about ▫ Anti-IL-5  Reslizumab (Cinqair ®)  Mepolizumab (Nucala®) ▫ Anti-IL-5Rα  Benralizumab (Fasenra®) http://tmedweb.tulane.edu/pharmwiki/doku.php/treatment_of_asthma Pelaia C, et al. 2019. Interleukin-5 in the Pathophysiology of Severe Asthma. Frontiers in Physiology. 10:1514. doi:10.3389/fphys.2019.01514 17 Type I: Localized Anaphylaxis Reactions Eczema 3. Atopic dermatitis/allergic eczema ▫ Activation of mast cells in the skin ▫ Clinical manifestations include red, dry, itchy, inflamed skin lesions and hyperkeratosis ▫ While IgE levels are increased, the etiology is often unknown ▫ Treatments vary but include topical cortisone creams, tacrolimus, antihistamines, dupilumab Wheal and flare 4. Atopic urticaria (hives) reaction ▫ Activation of mast cells in the skin  Often: subcutaneous “injection” of antigen causes local degranulation ▫ Vasodilation and edema at site: wheal and flare reaction 18  This figure is FYI Type I: Localized Anaphylaxis Reactions 5. Food allergies ▫ Activation of mast cells within the GI tract  FYI: Sensitization usually occurs over time ▫ Clinical GI signs/symptoms include vomiting, diarrhea, and gas  FYI: Elimination diet may help to identify allergen(s) ▫ As these allergens can become systemic, symptoms can manifest in the skin & respiratory tract https://www.medexpressrx.com/blog/do-not-ignore-food-allergies.aspx https://www.longstreetclinic.com/food-allergies/ https://www.dietspotlight.com/tag/elimination-diet/ 19 Type I: Systemic Anaphylaxis Systemic Anaphylaxis = systemic release of mediators ▫ Allergens get into the bloodstream and can enter tissues, causing systemic mast cell activation.  Common systemic allergens include drugs, vaccinations, foods, and venoms  Clinical manifestations include (see fig): https://firstaidforlife.org.uk/anaphylactic -shock-acute-allergic-reaction/ 20 Type I: Systemic Anaphylaxis Systemic anaphylaxis is a medical emergency! ▫ Remove inciting substance if possible ▫ Treat w/epinephrine fast & first!  Vasoconstriction  Relaxes bronchial smooth muscle  Increases HR and BP  Inhibits mast cell degranulation ▫ Adjunctive treatments include antihistamines, corticosteroids, bronchodilators, IV fluid therapy https://www.dovepress.com/update-on-the-usage-and-safety-of-epinephrine- auto-injectors-2017-peer-reviewed-fulltext-article-DHPS 21 Type I: Testing for Allergies https://youtu.be/ YCZQpsU_frA Skin testing (skin prick test, intradermal skin test) http://www.medicalook. com/tests/Allergy_Skin _Tests.html ▫ Variety of allergens are injected intradermally on the arm or back (most commonly) ▫ Observe for the development of a wheal and flare; occurs quickly and can test several allergens simultaneously ▫ Some potential disadvantages (FYI):  May sensitize an atopic individual to a new allergen  Late phase responses can lead to some tissue damage  Systemic anaphylactic shock (rare) http://allergyimmunologyspecialist.com/allergy-skin-test/ 22 Type I: Testing for Allergies https://www.intechopen.com/books/allergen/allergen-based-diagnostic- novel-and-old-methodologies-with-new-approaches Immunoassays can be performed to measure allergen-specific IgE levels within the serum ▫ ImmunoCAP®: indirect ELISA  Allergen is coupled to an ▫ ImmunoCAP® Rapid: Lateral flow ImmunoCAP matrix assays (LFAs)  Chemiluminescent assay  Modified ELISAs  Availability? ImmunoCAP® ImmunoAssay FYI: This LFA includes the following allergens: Cat Birch Mugwort Timothy Egg White Dog Olive pollen Wall pellitory House dust mite Cow's milk https://www.thermofisher.com/phadia/us/en/our-solutions/immunocap- Modified from: http://diagnostics.thermofisher. allergy-solutions/specific-ige-point-of-care.html com/partner/us/en/partnering.html 23 Type I: Allergen Immunotherapy (AIT) Also known as hyposensitization therapy ▫ Administration of increasing doses of allergen  SLIT = sublingual (drops under tongue)  SCIT = subcutaneous (injection) ▫ Goal: to alter the immune response to the allergen  AIT results in the induction of regulatory T cells (Treg) that function to suppress:  Mast cells, basophils, eosinophils  Effector helper T cells, especially Th2 cells ▫ This decreases IgE production by B cells and promotes IgG production!  Tissue inflammation & mucus production  Inflammatory DCs ▫ Allow for induction of tolerogenic DCs https://ctajournal.biomedcentral.com/articles/10.1186/2045-7022-2-2 24 Summary Figure This figure shows all four hypersensitivity reactions. We focused only on Type I for this lecture, but the next lecture will cover the other three. Note: I will expect you to be able to compare/ contrast all four hypersensitivities for the exam so refer to L23 for “the rest of the story”! Erythroblastosis fetalis = hemolytic disease of the newborn 25  Summary Figure This figure shows all four hypersensitivity reactions. We focused only on Type I for this lecture, but the next lecture will cover the other three. Note: I will expect you to be able to compare/ contrast all four hypersensitivities for the exam so refer to L23 for “the rest of the story”! 26