Immune Pathology I - BMS 150 - PDF

Immune Pathology I Part II – Overview of Hypersensitivity Reactions BMS 150 Week 4 e-learning Videos: Video 1 Video 2 Hypersensitivity Reactions - Objectives Classify the following types of hypersensitivity reactions in terms of time course, pat...

Immune Pathology I Part II – Overview of Hypersensitivity Reactions BMS 150 Week 4 e-learning Videos: Video 1 Video 2 Hypersensitivity Reactions - Objectives Classify the following types of hypersensitivity reactions in terms of time course, pathophysiologic mechanism, and representative disorders: Type I hypersensitivity Type II hypersensitivity Type III hypersensitivity Type IVa, IVb, IVc, IVd hypersensitivity For a type I reaction, describe the difference between the early and late-phase response in terms of pathogenesis and severity What are hypersensitivity reactions? “An excessive and/of pathogenic immune response to either foreign or self antigens” ▪ Very broad ▪ Covers a wide range of allergic and autoimmune diseases Classified in 1963 according to 4 types: ▪ Type I – IgE-mediated hypersensitivity (also called immediate hypersensitivity) ▪ Type II – antibody-mediated cytotoxic reactions ▪ Type III – Immune-complex reactions ▪ Type IV – “Delayed reactions” – also known as T-cell mediated reactions Hypersensitivity Reaction Overview https://commons.wikimedia.org/wiki/File:2228_Immune_Hypersensitivity_new.jpg What are hypersensitivity reactions? More recent reviews have found increased precision in classification to be more useful ▪ Improved ability to explain pathologic and clinical features **Important** → many conditions exhibit more than one type of hypersensitivity ▪ Type I diabetes is likely “mostly” a type IVa reaction However, antibodies may do damage to pancreatic islet cells (IIa) ▪ MS is likely “mostly” a type IVc reaction Antibodies likely are also involved in the pathology and likely directly damage oligodendrocytes to some extent Hypersensitivity – Updated Overview HSN Type Immunology Disorders Mast-cell mediated – acute recruitment of Anaphylaxis, angioedema, I basophils, eosinophils urticaria (hives), asthma, allergic Immediate, usually IgE-mediated rhinitis Antibody-mediated cytotoxic reactions Immune destruction of RBCs or IIa IgG/IgM activation of complement or destruction platelets, med. hypersensitivity, of cells via ADCC RA, rheumatic fever… many Antibody interacts with a receptor, and acts as a Graves disease, chronic idiopathic IIb ligand → inappropriate receptor stimulation urticaria Immune-complex formation with activation of Lupus, med. hypersensitivity, III complement and recruitment of WBCs in vessels some types of vasculitis, renal (vasculitis) and synovial tissue (arthritis) glomerular disorders Th1 inflammation with predominantly Granulomatous disease, T1DM, IVa macrophage-mediated cellular damage contact dermatitis Th2 inflammation featuring eosinophils, typical Chronic asthma & allergic rhinitis IVb Th2 cytokine release Th1 inflammation, predominantly cytotoxic T cell- SJS/TEN, T1DM, MS IVc mediated damage *cross-over with IVa* T cell-mediated neutrophilic inflammation Some types of vasculitis, aspects IVd Likely mostly Th17-mediated of celiac disease, RA Adapted from: Dispenza, M. Allergy Asthma Proc 40:470 –473, 2019; doi: 10.2500/aap.2019.40.4274 Hypersensitivity Reactions – Organizing the Knowledge Are antibodies involved? ▪ What types? IgE → Type I IgG, IgM → Type II, Type III ▪ Are T-cells thought to be the major pathologic players, LESS involvement of antibodies? Type IV Is there a particular Th subtype involved? ▪ Th2 subtypes – prominent in Type I, type IVb ▪ Th1/Th17 subtypes – prominent in Type IVa/IVc/IVd Hypersensitivity Reactions – Organizing the Knowledge Time course of symptoms ▪ Rapid – minutes to < 2 days Type I disorders tend to present with episodes that develop rapidly ▪ Subacute – days to weeks Type IIa, III, IVa, IVc can have a relatively limited time course, especially if due to a limited exposure (medication, poison ivy) ▪ Chronic – months to years Many chronic disorders feature Types II – IV Type IVb is always chronic all type IV is usually chronic unless associated with a limited exposure Type I Hypersensitivity - Pathogenesis We’ve already discussed the immediate response in atopic individuals in both the skin and airways ▪ Priming of mast cells with IgE and Th2 cytokines ▪ Rapid degranulation → acute effects Edema and urticaria in the skin Edema, mucous secretion, and smooth muscle contraction in the airways However, later events in type I hypersensitivity are important as well ▪ Dangerous complication known as the late-phase response Type I Hypersensitivity - Pathogenesis Severe episodes of type I inflammation lead to the late response ▪ Anaphylaxis ▪ Moderate – severe asthma attacks Chemokines and other inflammatory mediators recruit many basophils and eosinophils from the peripheral circulation ▪ Eosinophils in particular secrete proteolytic enzymes, major basic protein, eosinophilic cationic protein ▪ All can be toxic to normal cells Damage from emigration and activation of eosinophils and basophils takes time → 2 – 12 hours after the acute attack: ▪ In asthma - damage to the epithelium of airways + intense bronchoconstriction → airway obstruction that is difficult to reverse with medications ▪ In anaphylaxis – long-lasting edema and vasodilation that may be as severe as the initial episode of anaphylaxis → shock  Type-1 hypersensitivity – late-phase immediate vascular and smooth muscle reaction to allergen develops within minutes after challenge → vasodilation, congestion, edema late-phase reaction develops 2 to 24 hours later → inflammatory infiltrate rich in eosinophils, neutrophils, and T cells Type II hypersensitivity Antibodies bind to: ▪ A cell component ▪ A matrix component Could bind to self-antigens, or foreign antigens that have become “stuck” to, or adsorbed, onto self components Result: ▪ Inflammation, cellular destruction, destruction of matrix ▪ Idiosyncratic effects Activation of a receptor – Graves disease Inhibition of signaling – myasthenia gravis Type II hypersensitivity Pathophysiology: ▪ Activation of complement by bound antibody, resulting in cell lysis ▪ Both activated complement and antibody can act as opsonins ▪ Antibody-dependent cell-mediated cytotoxicity – neutrophils, NK cells, monocytes, eosinophils can all participate to kill a cell or cell fragment that has been bound by antibody ▪ Binding of antibody to a matrix component can also lead to inflammation Fc receptors on neutrophils recognize the bound antibody Type III hypersensitivity Antigen-antibody complexes produce tissue damage mainly by eliciting inflammation at the sites of deposition ▪ Usually the site of deposition is in or around the walls of vessels –arteries or capillaries ▪ Can also occur at synovial membranes Immune complex? ▪ A complex formed from IgG or IgM antibodies that usually forms a large, insoluble “mass” ▪ These masses stimulate robust inflammation Type III hypersensitivity - steps 1. Antigen exposure results in formation of antibodies > 1 week later 2. Often complexes are deposited in areas where there is higher pressure (arterioles, arteries) or areas where filtration under relatively large pressures occurs (glomeruli, synovium) 3. Damage to tissue – often a large role of complement  Pathology of TIIIHR Typically fibrinoid necrosis of assorted blood vessels ▪ necrotic tissue and deposits of immune complexes, complement, and plasma protein ▪ appear as a smudgy eosinophilic area of tissue destruction Vasculitis can cause severe enough inflammation in the wall of a vessel that the vessel is occluded  Type IV Hypersensitivity Extremely variable – depends on the disease ▪ Granuloma formation, Th1 response – IVa ▪ Infiltration of eosinophils, Th2 lymphocytes, basophils (type II inflammation) – IVb ▪ Activation of cytotoxic T-cells – IVc ▪ Th17 infiltration with a prominent neutrophil component, “innate + adaptive” – IVd In all cases, Th cells are present and play major roles in the pathogenesis and the appearance of the tissue With the exception of acute exposures, TIVHR develops over months – years ▪ Acute exposures – a toxin (i.e. poison ivy or other type of contact dermatitis) or a medication