Type I Hypersensitivity Pathophysiology Lecture Notes PDF

Types of Hypersensitivity Reactions • Four major types of hypersensitivity reactions • Classified based on what parts of the immune system mediate the reaction – what Ab (and what type) vs CMI Figure 11-1 – Basic Immunology, 6th ed., 2020 Table 26-1 – Immunology for Medical Students, 3rd ed., 2017...

Types of Hypersensitivity Reactions • Four major types of hypersensitivity reactions • Classified based on what parts of the immune system mediate the reaction – what Ab (and what type) vs CMI Figure 11-1 – Basic Immunology, 6th ed., 2020 Table 26-1 – Immunology for Medical Students, 3rd ed., 2017 Hypersensitivity and Genetics • Susceptibility is due to a combination of genetic and environmental exposures! • Categories of genetic associations – Haplotype diversity – clusters of genes linked to susceptibility, e.g., MHC Class II, IL-4/5/13 gene cluster – Genetic polymorphisms and point mutations – e.g., cytokines (esp. IL-4, IL-13, IL-4R), TCR α chain, STAT-6, IFN-γ, TGF-β – Epigenetic modifications such as DNA methylation (for “gene silencing”) – e.g., FoxP3 • The potential impact – one example – Variants of filaggrin protein are found in >50% of cases of severe atopic eczema and subsequent non-dermal allergies (e.g., hay fever, asthma) in later life Table 20-3– Cellular and Molecular Immunology, 10th ed., 2022 Environmental Influences • In a GENETICALLY SUSCEPTIBLE individual, environmental exposures are critical to development of HS • Environmental exposure in early life has major impact https://www.nature.com/articles/nm0304-232 ‒ Neonates are innately Th2-biased before birth and for several years (epigenetic controls) ‒ So, allergen exposure early in life occurs in Th2-rich setting, increasing Th2 bias; also, shown to decrease Th1 and Treg cell populations • Some factors ‒ Lifestyle – e.g., exposure to pets, viral infections ↑ TNF and Th1 responses and is associated with lower rates of allergy ‒ Dietary – e.g., consumption of ω6 fatty acids (“Western diet”) with ↓ ω3 FA favors Th2 development; also, lower rates of antioxidants with less consumption of fruits and vegetables ‒ Infections and vaccinations • Led to development of “The Hygiene Hypothesis” which says: ‒ Genetics + “clean” environment = high risk for allergies ‒ Hutterite communities and allergies – suppl. slide 52 • Updated thought – it also route of exposure – resp/skin vs GI https://www.jacionline.org/article/ S0091-6749(21)00896-4/fulltext Some Examples • Many different genes can be implicated – some involved in multiple allergic responses, some in fewer • May different environmental factors, but quite a bit of similarity in the general “cast of characters” https://www.frontiersin.org/articles/10.3389/fped.2017.00118/full https://www.mdpi.com/2073-4425/12/12/2004/htm IMMUNOLOGY OF TYPE I HYPERSENSITIVITY Immunologic Events in T1HS • On 1° exposure, allergen binds to a PRR, leading to APC activation – Dust mite Ag (e.g., Der p1) and cat dander (e.g., Fel d1) bind TLR4 and mannose receptor – Molds bind TLR2, TLR4, and dectin 2 • Leads to activation of CD4 Th2 cells – Th2 cells secrete IL-4, IL-5, and IL-13 • • • • Ag-specific B cell gets CD4 Th2 help IL-4 induces isotype switching to IgE IgE binds FcεR on mast cell (can also bind FcεR on basophils and eos) On 2° exposure, IgE binds allergen (complex Ag), leading to mast cell activation – Vasoactive amines (e.g., histamine), lipid mediators (e.g., leukotrienes), and cytokines released • Vasoactive amines and lipid mediators ↑ vascular permeability – early phase • Cytokines recruit eos, Th2, macs which degranulate, recruit more eos and Th2, phagocytose, etc., causing tissue damage – late phase response Figure 11-2 – Basic Immunology, 6th ed., 2020 Phases of Responses to Allergens Sensitization Early Phase Late Phase Three phases • Sensitization – at 1st exposure; activation of allergen-specific B and Th2 cells to produce IgE • Early phase – happens within 30 min (max) of 2nd, 3rd, etc. exposure; mediated by mast cell degranulation products • Late phase – 4-24 hours postexposure when mast cellderived cytokines recruit eos, Th2, and other cells to site; eos degranulate and cause tissue damage EXCERPTED FROM https://njms.rutgers.edu/sgs/olc/mci/prot/2009/Hypersensitivities09.pdf https://www.jacionline.org/article/S0091-6749(19)30478-6/fulltext Kinetics of a T1HS Response • Immediate or Early Phase – MAST CELLS Figure 11-2 – Basic Immunology, 6th ed., 2020 – Primary mediators – histamine, leukotrienes, prostaglandins, enzymes (see slide 20) – Symptoms – sneezing, itching, swelling (↑ vasopermeability) • Late Phase – EOS, Th2, baso, macs – Recruitment mediators – mast cell cytokines (e.g., IL-4, IL-13, GM-CSF) – Clinical mediators – proteases, cationic proteins, from eos – Symptoms – tissue damage https://veteriankey.com/type-i-hypersensitivity/ https://www.researchgate.net/figure/Pathogenic-role-of-IL-33-in-allergicrhinitis-Ragweed-pollen-driven-endogenous-IL-33_fig4_262189815 Type I Hypersensitivity (T1HS) Mechanism https://febs.onlinelibrary.wiley.com /doi/full/10.1111/febs.14465 Atopic Dermatitis • Also called immediate hypersensitivity, atopy (“out of place”), or allergy (see notes) • Most common type of hypersensitivity reaction • Mediated by CD4 Th2 cells producing IL-4, IL-5, and IL-13, IgE, mast cells, and eosinophils • In severe reactions, can lead to anaphylaxis http://eczema.org/wpcontent/uploads/Babyeczema-shutterstock3.jpg • Common T1HS reactions include hay fever (allergic rhinitis), eczema (atopic dermatitis), and allergic asthma (lower airway allergy) https://res.cloudinary.com/pgone/image/upload/c_fill,q_auto,f_auto//pgone /nasivin/content/dam/web/health-care/consumer-health/nasivin/en_za/ Common Allergens Associated with Type I Hypersensitivity • Plant pollens ‒ Rye and timothy grass and ragweed ‒ Birch, elm, and pine trees ‒ Mold spores • Drugs ‒ Penicillin/sulfa drugs and insulin ‒ Anti-inflammatories and anti-convulsants ‒ Iodine contrast dyes ‒ Foreign serum • Foods ‒ Nuts, peas, beans ‒ Seafood and eggs ‒ Milk and wheat • Animal products ‒ Venom – bee, wasp, ant ‒ Cockroach calyx and dust mite feces ‒ Animal hair, dander, and saliva https://www.medindia.net/patients/patientinfo/images/typeallergies.gif Characteristics of Allergens • Small molecular weight (15-45 kD, up to 70 kD for food allergens) proteins or glycoproteins • Metabolically active proteins – Inoculated at low dose – Tend to be enzymes – unclear if enzymatic activity is imp. • Tend to be stable – resistant to heat, acid, proteases • Mucosal exposure – most common route of exposure • Unclear what (biochem, struct) makes them allergenic https://www.onlinebiologynotes.com/anatomical-physico-chemical-barriers-immune-system/ Mast Cells in T1HS Responses Figure 22-3 – Immunology for Medical Students, 3rd ed., 2017 • Mast cells aligned along vessel and in tissues • Bind allergen-specific IgE • Re-exposure to allergen → FcεR crosslinked and exocytoses granule contents • Recruits eos (in tissue) and basophils (in circulation) where FcεR can be bound by allergen-Ab complex and degranulate Figure 20-4– Cellular and Molecular Immunology, 10th ed., 2022 Figure 20-2– Cellular and Molecular Immunology, 10th ed., 2022 Effects of Mast Cell FcεR Binding • Crosslinking of IgE on mast cell by allergen induces phosphorylation of immunoreceptor tyrosine-based activation motif (ITAM) in signaling chains of Fcε receptor. • Signaling pathways activated. • Mast cell degranulates, releasing amines, proteases, and arachidonic acid metabolites (prostaglandins, leukotrienes) while also initiating synthesis of inflammatory cytokines. Figure 20-5– Cellular and Molecular Immunology, 10th ed., 2022 Mast Cells Mediators • Histamine ‒ Bronchial smooth muscle constriction – wheezing ‒ Constricts intestine – cramps, diarrhea ‒ Vasodilation – edema, swelling • Prostaglandin, leukotrienes ‒ Chemotaxis, bronchoconstriction, vasodilation, mucus • Enzymes ‒ Activate C’ (and other pathways) that ↑ inflammation ‒ Break down connective tissue Figure 22-3 – Immunology for Medical Students, 3rd ed., 2017 Figure 22-5 – Immunology for Medical Students, 3rd ed., 2017 Table 22-2 – Immunology for Medical Students, 3rd ed., 2017 https://www.cincinnatichildrens.org/service/c/ eosinophilic-disorders/conditions/eosinophil Eosinophils in T1HS • Mediate effector functions by phagocytosis and exocytosis ‒ Extracellular release of granule content by either path • Produce: ‒ Toxic proteins (acidic, degradative) – tissue damage ‒ Enzymes – tissue damage ‒ ROS – potential tissue damage ‒ Eicosanoids (leukotrienes, prostaglandins) – increase vasopermeability, mucus production, etc. ‒ Pro-inflammatory cytokines – increase inflammation • End results: Sustained inflammation that can become chronic, leading to tissue damage • Persistent attempts to heal can lead to fibrosis. https://www.frontiersin.org/articles/10.3389/fimmu.2017.00484/full T1HS Mediators in Mast Cells and Eosinophils Table 20-2– Cellular and Molecular Immunology, 10th ed., 2022 Effects of Degranulation • Have general and organ-specific responses • Some mediating immediate responses (sneezing, itching) and some later responses (tissue damage) Figure 11-4 – Basic Immunology, 6th ed., 2020 Figure 20-6– Cellular and Molecular Immunology, 10th ed., 2022