Updated: 12/13/2019

Hypersensitivity Reactions

Review Topic
  • 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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(M2.DM.17.4769) A five-year-old boy presents with his mother to your clinic complaining of a fever and rash. His mother says the patient was in his usual state of health until two weeks ago when he developed “strep throat.” He was prescribed a ten day treatment with oral amoxicillin by his primary care physician, which he has since completed. The mother reports that he seemed to feel better until two days ago when he began to complain of joint pain and an itchy rash. His mother notes the patient is on an “alternative vaccine schedule.” She is nervous because her son attends day-care three days a week, and there has been a recent “viral" outbreak. The patient’s temperature is 103°F (39.4°C), blood pressure is 99/59 mmHg, pulse is 110/min, and respirations are 20/min with an oxygen saturation of 99% O2 on room air. On physical exam, you note cervical adenopathy, joint swelling, mild peripheral edema, and a diffuse rash (shown in Figure A). Which of the following is the best treatment for this patient’s condition?

QID: 109136




Aspirin and IVIG









Vitamin A



M 7 D

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(M2.DM.14.9) A 14-year-old boy presents to his family physician with a 1-day history of a rash. He denies any history of a similar rash or any dermatologic diagnoses in the past. The mother states that their family was in upstate New York for the past week; however, the child has had no other new events or exposures. His temperature is 98.0°F (36.7°C), blood pressure is 104/74 mmHg, pulse is 87/min, respirations are 12/min, and oxygen saturation is 98% on room air. Physical exam is notable for the finding in Figure A. Which of the following diagnoses shares the same pathophysiology as this patient's diagnosis?

QID: 104220




Goodpasture syndrome



Hashimoto thyroiditis



Serum sickness






M 6 E

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Evidence (5)
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