Updated: 12/13/2019

Hypersensitivity Reactions

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Overview
  • Auto immune disease or excess response to foreign stimulus
    • categorized by
      • type of effector mechanism
        • Types I, II, and III are all antibody mediated
        • Type IV is TH1 mediated
  • Commonalities between all types
    • requires a sensitizing exposure
    • reactions occur in later exposures
  • Timeline
    • [Fastest] Type I < Type II / III < Type IV [Slowest]
Type I
  • Immune relationship
    • IgE mediated
      • only type
    • fast
      • within minutes of re-exposure
    • protective against parasites
    • atopic or alleric responses
    • effector cells
      • basophil, mast cell
  • Mechanism of tissue injury
    • sensitizing exposure
    • followed by a reaction exposure
  • Presentation
    • vasodilation of post capillary venules
    • inflammation
    • bronchoconstriction
    • intestinal hypermotility
    • tissue damage
  • Disorder
    • anaphylaxis
      • bronchial/trachial constriction
      • systemic vasodilation
      • death
      • e.g. bee sting, some food/drug allergies
      • treat with EpiPen (epinephrine)
    • allergic rhinitis
      • "hay fever"
    • asthma
      • bronchial/trachial constriction
      • inflammation
      • mucus
  • Test
    • scratch test
      • wheal and flare
      • in vivo
      • skin edema, reddening near scratch introduction
    • radioimmunosorbent assay
Type II
  • Immune relationship
    • Antibody mediated
      • IgM, IgG bind to antigen
      • complement activation
      • results in lysis via membrane attack complex or phagocytosis
    • effector cells
      • cytotoxic
        • PMN, macrophages, NK cells
      • non-cytotoxic
        • none
  • Mechanism of tissue injury
    • antibodies lead to disease via three different processes
      • activation of complement or opsonization
      • recruitment of neutrophils and macrophages that incite tissue damage
      • interfere with normal receptor function
  • Presentation
    • disease localized to specific tissues where antibodies are present
  • Disorder
    • cytotoxic
      • autoimmune hemolytic anemia (HDNB)
        • anti-RBC antibodies (other than ABO proetins)
        • destruction of RBC
          • hemolysis, anemia
      • idiopathic thrombocytopenic purpura
        • anti-platelet antibodies
        • destruction of platelet
          • thrombocytopenia, bleeding
      • erythroblastosis fetalis
        • aka Hemolytic disease of the newborn (HDNB)
          • RhD- mother must have had previous RhD+ pregnancy where she was exposed to fetal blood
            • delivery, termination
          • anti-RhD+ IgG that can cross the placenta attack fetus
        • prophylaxis/treatment
          • RhoGAMTM
            • anti-RhD IgG
            • given to Rh- mother at
              • 28 weeks gestation
              • within 72 hours of delivery
            • prevents mother from developing B-cell memory of RhD
      • acute hemolytic transfusion reactions
        • anti-ABO RBC protiens IgM (isohemagglutinins)
          • hemolysis
      • acute rheumatic fever
        • antibody against streptococcal cell wall binds healthy tissue
          • heart and joint inflammation
      • Goodpasture's syndrome 
        • anti-type IV collagen antibody 
          • lung alveoli
            • lung hemmorhage
          • kidney glomeruli
            • nephritis
            • linear deposits
              • unlike post-streptococcal glomerulonephritis
                • lumpy bumpy pattern
      • bullous pemphigoid
        • anti-hemidesmosomes at the dermoepidermal junction
          • separation of epidermis from basement membrane
          • results in formation of tense blisters
      • pemphigus vulgaris
        • autoantibodies against desmoglein 1 and/or 3 in the epidermis
        • results in acantholysis and formation of flaccid blisters 
    • non-cytotoxic
      • Graves' disease
        • anti-TSH receptor antibody
          • stimulates T3/4 release
            • hyperthyroid followed by hypothyroid
      • myasthenia gravis
        • anti-Acetylcholine receptor antibody
          • inhibits muscle stimulation
            • muscle weakness, paralysis
      • pernicious anemia
        • anti-intrinsic factor antibody
          • inhibits binding of IF to receptor
            • decreased vit B12 absorbtion >> macrocytic anemia
      • type II diatbetes
        • anti-Inuslin receptor antibody
          • inhibits binding of insulin
            • hyperglycemia
  • Test
    • direct Coombs test
      • measures IgG/C3b bound to RBCs
        • "direct attachment"
    • indirect Coombs test
      • measures free antibodies in serum
Type III
  • Immune relationship
    • Immune complex mediated
      • antigen-antibody (IgG) complexes form
      • antigens can be self or foreign
    • effector cells
      • PMN, macrophages
  • Mechanism of tissue injury
    • complexes are filtered out of circulation and deposited in healthy tissue
    • neutrophils attracted and complement activated by Ab-Ag complex
    • neutrophils release lysosomal enzymes
    • healthy tissue damaged
  • Presentation
    • widespread mobility of Ab-Ag complexes allows for vasculitis and systemic manifestations
      • compared to type II with generally localized reactions
  • Disease
    • SLE
      • anti-dsDNA, anti-Sm, anti-Rho antibodies in complex with antigen
        • butterfly facial rash, nephritis, arthritis, vasculitis
    • Serum sickness
      • antibodies to the foreign proteins are produced and complex formed
        • takes 5 days
        • e.g., horse antithymocyte globulin antibody in transfused serum
          • now more common from drugs
            • e.g., beta-lactams, sulfa drugs, anti-venin
        • fever, urticaria, arthralgias, proteinuria, lymphadenopathy 
          • 5-10 days after antigen exposure 
        • usually self-limited, and will resolve with withdrawal of the offending agent
          • management may also involve symptomatic treatment 
            • e.g., antihistamines or steroids
    • Arthus reaction
      • antigen-antibody complexes cause the Arthus reaction
      • a local subacute antibody-mediated hypersensitivity (type III) reaction
      • intradermal injection of antigen induces antibodies, which form antigen-antibody complexes in the skin
      • characterized by edema, necrosis, and activation of complement
    • rheumatoid arthritis
      • anti-IgM Fc region antibody complex with antigen
        • joint pain, decrease in range of motion
    • polyarteritis nodosa
      • deposition of complexes in medium sized arteries
    • poststreptococcal glomerulonephritis
      • anti-Streptococcal cell wall antibody with antigen
      • nephritis
        • "lumpy bumpy pattern" on immunofluorescence staining
          • large complexes so they cannot coat the entire membrane like in Goodpasture's (small IgG)
    • hypersensitivity pneumonitis
      • inhaled dust forms an Ab-Ag complex
      • e.g. farmer's lung
  • Test
    • immunofluorescent staining
Type IV
  • Immune relationship
    • senstitizing antigen exposure
      • memory T-lymphocytes generated
    • effector cells
      • CTL, Th1 , macrophages
  • Mechanism of injury
    • sensitized T lymphocytes encounter antigen and then release lymphokines
      • mainly IFN-γ
      • leads to macrophage activation
        • TNF secretion
      • no antibody involved
    • cell-mediated toxicity, therefore not transferable by serum
  • Presentation
    • response is delayed and does NOT involve antibodies (vs. types I, II, and III) or complement
  • Disease 
    • type 1 DM
      • T-cells against islet cells, insulin, glutamic acid decarboxylase
    • multiple sclerosis
      • T-cells against myelin of CNS
    • Guillain-Barré syndrome
      • T-cells against myelin of PNS
    • Hashimoto's thyroiditis
      • T-cells against antigen in thyroid
    • graft-versus-host disease
      • T-cells of transplant origin become activated against MHC of host
    • PPD (test for M. tuberculosis)
      • T-cells of skin against tuberculin/mycolic acid
    • contact dermatitis 
      • e.g. poison ivy, nickel allergy
      • pruritus, rash, skin lesions
  • Test
    • patch test
      • e.g. PPD, patch containing any antigen placed on skin

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