Hypersensitivity III & IV PDF

Hypersensitivity III&IV Cindy Leifer [email protected]  Clinical Correlate A dog, Shaggy, is brought into the ER for a rattlesnake bite. Supportive therapy is administered, including anti-venom. The anti-venom is a mixture of ant...

Hypersensitivity III&IV Cindy Leifer [email protected]  Clinical Correlate A dog, Shaggy, is brought into the ER for a rattlesnake bite. Supportive therapy is administered, including anti-venom. The anti-venom is a mixture of antibodies to the snake venom antigen. It turns out this is not the dogs first run-in with a rattlesnake. The dog responds to the therapy and appears to be recovering fine until discontinuation of the anti-venom therapy. Within a few hours, the dogʼs blood pressure decreases, his kidneys fail, and breathing becomes labored. What happened to Shaggy?  Learning Objectives 1.Explain the mechanisms of type III hypersensitivity sensitization and effector phases. 2.Explain the mechanisms of type IV hypersensitivity sensitization and effector phases. 3.Give examples of where hypersensitivity (III and IV) mechanisms are used in a protective immune response. 4.Give examples of where hypersensitivity (III and IV) mechanisms are used in a pathological immune response. *Note: Learning objectives generally describe the minimum knowledge needed to pass the course. Type III Hypersensitivity Gell and Coombs Classification  Hypersensitivity III: Immune complex mediated Soluble antigens induce immune complexes passive immunized antibody injection of therapeutic proteins inhalation of molds or particulates chronic infections (e.g. viral) self antigens (systemic lupus erythematosus) Sensitization phase: antibody production, present in blood Effector phase: re-exposure to antigen in tissue or blood (different responses), formation of immune complexes  Immune complexes Formed when antigen and antibody are at equivalence concentrations Due to antibodies having two binding sites Can form small or large complexes Fig 16.7  Type III Hypersensitivity sensitization Sensitization phase Antigen uptake by BCR Antigen processing and presentation in MHCII Help from activated T cells Plasma cell differentiation Specific IgG antibody produced IgG secreted Antigen no longer present, so no immune complexes* Plasma cells make IgG Adapted figure *Persistent antigen or long half-life antigen could lead to immune complexes on first exposure but only after antibodies are made and reach equivalence concentration with the antigen Type III effector: Immune complexes in tissues Effector phase Soluble antigen enters blood and encounters antibody Equivalence causes immune complexes Immune complexes activate innate immune cells Immune complexes activate complement and release C3a and C5a (systemic vasodilation, activation of phagocytes) Inflammatory cytokine/chemokine production recruit other cells (PMN) ROI and RNI induce tissue damage PMN express FcR bind antibody complexes and are activated and degranulate Induce tissue damage Type III effector: Immune complexes in blood Effector phase Soluble antigen enters blood and encounters antibody Equivalence causes immune complexes Small and/or large complexes form Larger complexes cleared by phagocytes, can activate them Smaller complexes (soluble) activate complement Complement C3 attached to endothelium, activates MAC Hemorrhage  Serum Sickness Occurs when individual is treated with proteins from another species (could be antibody: gamma globulin) Antibodies to the foreign protein develop in 5-7 days Immune complexes form and cause vasculitis Transient and spontaneously resolves as antigen concentration decreases Can occur rapidly upon second exposure when Agn and aby at equivalence immediately Merck Manual: Antivenoms available against North American pit vipers include equine-derived polyvalent antivenin, ovine- origin polyvalent F(ab) fragment antivenin, and equine-origin polyvalent F(ab)2 fragment antivenin. Immune complexes: normal function Clearance of virus Clearance of foreign substances  Summary Hypersensitivity Type III 1. Type III hypersensitivity is mediated by immune complexes. 2. Immune complex disease can trigger in tissues or in blood. 3. Arthritis, enteritis, glomerulonephritis, etc are often associated with specific infections and are the result of Type III hypersensitivity as a host defense. 4. Type III hypersensitivity reactions are typically temporary, antigen concentration dependent, and spontaneously resolve upon removal of antigen. Type IV Hypersensitivity Gell and Coombs Classification Hypersensitivity IV: T cell mediated, delayed type Sensitization phase CD4 or CD8 Upon contact with antigen, some of the antigen enters the tissue and is directly presented by skin APC, or is trafficked to the LN and presented T cells are activated but often the initial antigen is no longer present so the animal is sensitized Some delayed type hypersensitivity antigens Tuberculin reaction Insect saliva or venom Metals Wood preservatives Poison ivy Ointments House plants Hypersensitivity IV Effector phase Upon contact with antigen tissue DC or macrophages present the antigen and induce inflammation Memory T cells are recruited and activated in the tissue CD8 T cells can attack cells presenting antigens (eg keratinocyte/epithelial cells) CD4 T cells produce cytokines that cause inflammation Called ”delayed type” since it takes 24-48 hours for memory T cells to be activated Local tissue destruction and inflammation  Allergic Contact Dermatitis T cells attack T cell–mediated rejection of sensitized epidermal Sensitizing cells creating vesicles chemical chemically altered skin cells Epidermis Classically poison ivy dermatitis Can be any sort of reactive Langerhans cells chemical Activated T cells Lymph node Copyright © 2018, Elsevier Inc. All rights reserved. 18  The pathogenesis of the tuberculin reaction Basophils serotonin Antigen Antigen enters skin enzymes Macrophages oxygen INFLAMMATION APC take up antigen and move to LN metabolites T cells activated IL-1 T cells move into skin and cause T cell- TNF-α mediated inflammation IFN-γ chemokines Langerhans Lymphotactin cells Sensitized T cells Afferent lymph Draining lymph node Copyright © 2018, Elsevier Inc. All rights reserved. 19  Tuberculin reaction as a diagnostic Single intradermal test w/purified protein derivative (PPD or tuberculin) for M. bovis or M. tuberculosis Read the result 48-72hours post injection  One allergen, multiple types of hypersensitivity The same antigen may induce different types of responses The different responses can occur at the same time Not all responses occur in all individuals (doesn’t occur at all in many individuals) IgE to penicillin-modified antigens Anaphylaxis Type I hypersensitivity IgG to penicillin-modified soluble antigens Immune complexes IgG to penicillin-modified surface antigens Endothelial damage Phagocytosis of modified RBC MAC complement lysis of RBC Antibody dependent cell cytotoxicity by NK cells T cells to penicillin-modified antigens Cytokine induced tissue damage CD8 cell attack of cells presenting modified antigens  Summary Hypersensitivity Type IV 1. Type IV hypersensitivity is T cell mediated. 2. Can be delayed type hypersensitivity mediated by CD4 T cells producing cytokines and activating other cells in the tissue. 3. Can be contact hypersensitivity mediated by CD8 T cells damaging cells presenting modified peptide. 4. To prevent or resolve Type IV hypersensitivity avoidance is key. 5. Different hypersensitivities can exist in parallel.