Lecture 27 Student Copy - Hypersensitivities III & IV PDF

Final Exam ▪ 42 Questions: ~ _10__ on pre-midterm content that includes: Serology, Titers, Primary and memory antibody responses, seroconversion, incubation period, neonatal immunity, vaccination of neonates, passive immunity ~ _5__ on vaccines ~ _15__ on Immunodiagnost...

Final Exam ▪ 42 Questions: ~ _10__ on pre-midterm content that includes: Serology, Titers, Primary and memory antibody responses, seroconversion, incubation period, neonatal immunity, vaccination of neonates, passive immunity ~ _5__ on vaccines ~ _15__ on Immunodiagnostics ~ _4__ on sensitivity and specificity of diagnostic tests ~ _10__ on Hypersensitivities. ▪ NOTE: some exam questions deal with multiple topics ▪ Review for final exam:…. During class on Thursday, Nov. 28. Have questions/topics to class rep by Wednesday at NOON.  Lecture 27 Hypersensitivities III Hypersensitivities IV  Type III hypersensitivities Due to formation of antigen-antibody aggregates = Immune Complexes immune complexes Immune complexes form all the time. Most removed by phagocytic cells May deposit on inside of blood vessel. Blood vessel This causes inflammation of the blood vessel (vasculitis). Can be deposited in tissues also. Signs related to the vasculitis are variable. Examples ▪ Rash (skin) Antigen-antibody ▪ Protein in the urine complexes (glomerulonephritis) ▪ Joint pain ▪ May observe multiple signs in some cases  Type-III hypersensitivity Immune complex formation, deposition; Immune complex-mediated inflammation Acute inflammation mainly due to activation of complement cascade (classic pathway), mast cells and neutrophils…. Timeline = ~2-8 hrs (after priming) The wet form of FIP infection is due to this mechanism  Remember: Immune complexes = antigen-antibody complexes Type-III Hypersensitivity  Mechanism: ▪ Immune complex formation; ▪ Immune complex deposition; ▪ Immune complex-mediated inflammation ▪ Acute inflammation mainly due to activation of complement cascade (classic pathway), mast cells and neutrophils…. Timeline = ~2-8 hrs (after priming has already occurred … need 7-10 days after first exposure to antigen of interest)  Type-III Hypersensitivity Local Type-III: Complexes form in the tissues Generalized Type-III: ▪ Complexes form in the circulation and then are deposited on blood vessels or in certain tissues and trigger inflammation in the tissues. ▪ They often are deposited in the walls of blood vessels in joints, kidneys. BOTH can result in vasculitis  Localized Type-III mechanism: Immune complexes form in the tissues Local Immune-complex formation activates inflammation via Complement and Mast cells and neutrophils antigen Pre-formed antibody comes out of the circulation to bind with the antigen in the tissues Blood vessel EXAMPLE of localized Type-III hypersensitivity Blue Eye in dogs Blue Eye Immune complex formation resulting from the release of virus (canine adenovirus type 1 or the vaccine strain of the modified live virus), especially from infected corneal endothelial cells, causes corneal endothelial damage and corneal edema. Attenuated (modified live) CAV-1 vaccines can produce transient unilateral or bilateral opacities of the cornea…. Blue eye. (due to immune complexes) NOTE: Things other than ICH or vaccination with CAV-1 can cause “Blue Eye” due to immune complexes. Not all corneal opacities are due to immune complex formation….  Examples of Generalized Type-III reactions ▪Glomerulonephritis ▪Purpura hemorrhagica in horses as a sequela to Strep equi infection or vaccination against Strep equi.  Glomerulonephritis Most glomerulonephritis in our domestic animal species is due to immune complex disease. Immune complexes lodge in the capillaries of the glomeruli causing vasculitis and protein loss into the urine. Associated with a variety of foreign antigens including antigens from a number of infectious agents. FYI Borrelia burgdorferi (Lyme disease agent) (dogs) Ehrlichia species (dogs) Canine adenovirus 1 and 2 (dogs) Feline leukemia virus (cats).. ▪ FIP virus (cats) WET FORM due to immune complexes forming (Type-III mechanism)  Glomerulonephritis... Due to immune complex formation To diagnose Glomerulonephritis due to Type-III hypersensitivity: Example: Dog: Histo section of kidney from biopsy: Stain with anti-dog IgG antibody tagged with a fluorochrome. Streptococcus equi— can cause purpura hemorrhagica in the horse via a type-III immune complex mechanism Strep equi infection: Clinical signs Abscesses of submandibular LN  Strangles (Streptococcus equi)– can cause Purpura hemorrhagica (vasculitis –skin) 2-4 weeks post-acute Strep equi infection or post vaccination (more likely if a Modified-live vaccine) against S. equi, horses may develop purpura hemorrhagica… Immune complexes acute vasculitis  Vasculitis lesions post Strep. Equi infecction Destruction of Edema due to leaky Purpura hemorrhagica blood vessels blood vessels leads to sloughing of skin Purpura hemorrhagica is observed in a horse associated with a recent Strep equi infection. If an antibody ELISA test to detect antibody to Strep equi is done on a serum sample from the horse, what is the most likely result? A. No detectible antibody to Strep equi B. Low antibody titer to Strep equi C. Low Strep equi antigen titer D. High antibody titer to Strep equi E. High Strep equi antigen titer. Explanation  General Approach to Treatment of immune complex conditions: Treat underlying condition If pathogen is present, give anti-microbials Suppress immune system Glucocorticoids NOTE: May be a balance and/or judgement call if the condition is due to an infectious agent that is still around, as suppressing the immune system may allow the pathogen to survive and continue to replicate. Sometimes both approaches are used at the same time.  FYI: ZUKU review MCQ A horse presents with distal limb edema in all 4 limbs (as seen below), petechiae of the mucous membranes, depression, and a low-grade fever of 101.9°F/38.8°C (N = 99-101°F, 37.2-38.3°C). Multiple horses in the stable recently suffered from an upper respiratory infection of undiagnosed etiology. Which type of immune reaction is most likely responsible for the vasculitis in this horse? A. Cell-mediated immune Cell-mediated immune reactions (type IV) reactions (type IV) Cell-mediated immune reactions (type IV) B.Antigen-antibody complex Antigen-antibody complex (type III) (type III) Antigen-antibody complex (type III) C.Antibody-mediated cytotoxic Antibody-mediated cytotoxic reactions (type II) reactions (type II) Antibody-mediated cytotoxic reactions (type II) D.Immediate hypersensitivity Immediate hypersensitivity and atopy (type I) and atopy (type I) Immediate hypersensitivity and atopy (type I)  TYPE-IV HYPERSENSITIVITY General components of any Type-IV hypersensitivity Antigen-sensitized Th1 CD4 lymphocytes & CD8 lymphocytes Th1 cytokines (mainly IFN-g) Ag-specific Activated macrophages Response peaks at 72 hrs  Delayed-Type Hypersensitivity (DTH) with TB testing in cattle and humans is an example of a Type-IV hypersensitivity mechanism Have already covered…. Think of it as a mechanism… a mechanism involving T-helper 1-specific T- cells that produce IFN-gamma that activate macrophages.  Type IV Hypersensitivities (DTH response) Mediated by Th-1 cells that provoke an inflammatory reaction against antigens. ▪ Antigen-activated Th-1 cells Memory T-helper-1 cells produce IFN-y. ▪ IFN-y activates macrophages ▪ Inflammation Contact Dermatitis – Delayed Type Memory T-helper-1 cells hypersensitivity Antigens often are haptens ▪ Poison ivy ▪ Topical drugs (some antibiotics) ▪ Often cause Immune-mediated contact dermatitis. Penicillin induced contact dermatitis Lesions resolved after drug removal Allergic Contact Dermatitis: General approach to prevention …and part of treatment: AVOIDANCE Mechanism of poison oak IV hypersensitivity Antigen-specific T-helper-1 cells  Poison Ivy Often pruritic Figure 10-36 FYI: Treatment: Steroids (topical steroids, other prescription medication for dog's itchiness), topical ointments, and/or Hypersensitivity to medicated shampoo, +/-antibiotics, … then AVOIDANCE Poison Ivy Hapten binding to skin Proteins Stimulate Type IV FYI Not everyone sensitive to poison ivy Reaction usually within 2 days (after sensitized) … but can be up to 10 days.. Or as early as 8 hrs. Hyposensitization not very effective. Drug-induced contact dermatitis.  hypersensitivity TOPICAL penicillin applied to ears nose Penicillin induced contact dermatitis Lesions resolved after drug removal  Formaldehyde in cosmetics, textiles (wrinkle resistance), furniture upholstery, newspaper dyes, paper Nickel dissolves in the weakly acid environment of sweat and binds with high affinity to skin proteins ▪ Hypersensitivity to costume jewelry, dog collars, metal eyeglass (humans)  FYI: Type-IV Hypersensitivities in Tissue Transplants Host VS Graft rejection T cells (TCR) of recipient recognize allogeneic MHC molecules (class I) in graft tissue -- leads to direct activation of cytotoxic T lymphocytes. Acute rejection by CTLs (within 7 days) Chronic rejection (months later) involves Th1 and Macrophages (induced by foreign MHC II molecules) Graft VS Host rejection ▪ Occurs in bone marrow transplant recipients: – foreign lymphocytes in the transplanted bone marrow destroy cells and tissues of the recipient (because the foreign lymphocytes see recipient’s tissues as foreign due to MHC expression). The recipient is immunosuppressed because their own bone marrow (full of tumor cells) had to be destroyed first in order to receive the transplant.  Match the disease description with the most likely hypersensitivity type ___Vasculitis secondary to an infection ___Blood transfusion reaction 1. Type –I hypersensitivity ___Immune-mediated hemolytic anemia 2. Type-II hypersensitivity ___Wet form of FIP 3. Type-III hypersensitivity ___Autoimmune disease due to antibody 4. Type-IV hypersensitivity directed against a host cell receptor molecule ___Anaphylaxis reaction to penicillin ___Skin reaction to topical penicillin ___Skin reaction to poison ivy ___Glomerulonephritis associated with an infection (example: Lyme disease)  summary TYPE DESCRIPTIVE INITIATION MECHANISM EXAMPLES TIME After NAME sensitizatio Antigens that trigger the rnx n Immediate Ag induces cross-linking of IgE bound to mast Systemic anaphylaxis, I IgE-mediated 2-30 mins cells with release of vasoactive mediators Local reaction (Hay fever, hypersensitivity Ag: pollens, food, drugs, insect products, animal Asthma; food allergies; ) hair Ab directed against *cell-surface antigens mediates Antibody- cell destruction via ADCC or complement. Blood transfusion reactions, mediated Hemolytic disease of the newborn, II cytotoxic 5-8hrs IgG (+/- IgM) Immune-mediated Hemolytic hypersensitivity Ag: cell-surface Ag such as anemia RBC, platelets, leukocytes Ag-Ab complexes deposited at various sites Localized; blue eye Immune- induces mast cell and PMN degranulation which Generalized: glomerulonephritis; III complex 2-8hrs causes tissue damage Purpura hemorrhagica due to hypersensitivity IgG (+/-IgM) Strep equi infection or vaccination; Ag: Soluble Ag Wet form of FIP DTH (Delayed Positive TB skin test Type Memory TH1 cells release cytokines that recruit Contact dermatitis, such as IV hypersensitivity 24-72hrs and activate macrophages and CTLs Poison ivy reaction; topical cell-mediated Ag: TB test, cosmetics, jewelry, poison ivy antibiotics hypersensitivity