questions 11

Hypersensitivity

Topic updated on 02/08/17 5:20pm

Overview
  • Autoimmune disease or excess response to foreign stimulus
    • categorized by
      • type of effector mechanism
        • types I, II, and III are antibody-mediated
        • type IV is T cell-mediated
  • Common themes
    • requires a sensitizing exposure
    • reactions occur in later exposures
  • Timeline
    • [Fastest] type I < type II / III < type IV [Slowest]
Type I
  • Immune relationship 
    • only IgE-mediated reaction
      • fast!
        • occurs within minutes of exposure
      • is protective against parasites
      • present in atopic or allergic responses
      • effector cells
        • basophil, mast cell, eosinophils
  • Mechanism of tissue injury 
    • initial sensitizing exposure
      • Th2 cells stimulate B-cells to produce IgE via class switching
      • IgE antibodies bind to mast cells
    • secondary reaction exposure
      • antigen cross-links mast cell-bound IgE molecules 
      • stimulates mast cell to react via degranulation 
        • preformed granules contain histamine, heparin, eosinophil chemotactic factor A, and tryptase 
      • 2-4 hours later
        • late-phase reaction
        • release of newly synthesized chemical mediators
          • prostaglandins, leukotrienes
  • Presentation
    • vasodilation of postcapillary venules
    • inflammation
    • bronchoconstriction
    • intestinal hypermotility
    • tissue damage
  • Disorder
    • anaphylaxis 
      • bronchial/tracheal constriction
      • systemic vasodilation
      • death
      • e.g. bee sting, some food/drug allergies
      • treat with EpiPen (epinephrine)
        • epinephrine is a nonselective α and β agonist which results in an increase in cardiac output as well as peripheral vascular constriction
    • allergic rhinitis
      • "hay fever"
    • asthma
      • bronchial/tracheal constriction
      • inflammation
      • mucus
  • Test
    • scratch test
      • wheal and flare
      • in vivo
      • skin edema, reddening near scratch introduction
    • radioimmunosorbent test
      • detects IgE antibodies in serum specific to given antigens
Type II
  • Immune relationship 
    • Antibody-mediated
      • IgM and IgG bind to antigen
      • complement activation
      • results in lysis via membrane attack complex or phagocytosis
    • effector cells
      • cytotoxic cells
        • PMN, macrophages, and NK cells
      • non-cytotoxic
        • none
  • Mechanism of tissue injury
    • antibodies lead to damage via three different processes
      • complement activation 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 proteins)
        • destruction of RBC
          • hemolysis, anemia
      • idiopathic thrombocytopenic purpura
        • anti-platelet antibodies
        • destruction of platelets
          • 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 proteins 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 hemorrhage
          • kidney glomeruli
            • nephritis
            • linear deposits
              • unlike post-streptococcal glomerulonephritis
                •  which has a lumpy bumpy pattern
      • bullous pemphigoid/pemphigus vulgaris
        • anti-hemidesmosomes (bullous) and anti-desmosome (vulgaris) of skin antibodies
          • separation of epidermis from basement membrane
          • severe blistering
    • 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 (IF) antibody
          • inhibits binding of IF to receptor
            • decreased vitamin B12 absorption results in macrocytic anemia
  • 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 (Ag-Ig) complexes form
      • antigens can be self or foreign
    • effector cells
      • PMN and macrophages
  • Mechanism of tissue injury
    • complexes are deposited in healthy tissue
    • neutrophils attracted and complement activated by Ag-Ig complex
    • neutrophils release lysosomal enzymes
    • healthy tissue damaged
  • Presentation
    • widespread mobility of Ag-Ig complexes allows for vasculitis and systemic manifestations
      • compared to type II with generally localized reactions
  • Disease
    • SLE 
      • anti-dsDNA, anti-Sm, and 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
        • fever, urticaria, arthralgias, proteinuria, and lymphadenopathy
          • 5-10 days after antigen exposure
    • Arthus reaction
      • Ag-Ig 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 and 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 syndrome (small IgG)
    • hypersensitivity pneumonitis
      • inhaled dust forms an Ag-Ig complex
      • e.g. farmer's lung
  • Test
    • immunofluorescent staining
Type IV
  • Immune relationship 
    • sensitizing antigen exposure
      • memory T lymphocytes generated
    • effector cells 
      • CTL, Th1 , macrophages
  • Mechanism of injury
    • sensitized T lymphocytes encounter antigen and then release cytokines
      • 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, and 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
    • rheumatoid arthritis
      • T cells against the synovial joint membrane (possibly type II collagen)
    • exanthematous (maculopapular) drug reaction Exanthamatous drug reaction - can occur with a low-grade fever after starting a new medication.
      • diffuse rash + low-grade fever
  • Test
    • patch test
      • e.g. PPD, patch containing any antigen placed on skin

References



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Qbank (9 Questions)

TAG
(M1.IM.1) While playing in the woods with friends, a 14-year-old African-American male is bitten by an insect. Minutes later he notices swelling and redness at the site of the insect bite. Which substance has directly led to the wheal formation? Topic Review Topic

1. IFN-gamma
2. Histamine
3. IL-22
4. Arachidonic acid
5. IL-4

PREFERRED RESPONSE ▶
TAG
(M1.IM.1) A 32-year-old female presents with a three month history of oral ulcerations and blisters throughout her body. When the physician examined the skin, she noted that when the skin was rubbed it sloughed off and formed blisters within a few minutes. A skin biopsy was performed and analyzed via immunofluorescence using anti-IgG antibodies (Figure A). Which of the following antibodies is also involved or found in a similar type of hypersensitivity reaction as in the case mentioned? Topic Review Topic
FIGURES: A          

1. IgE against the proteins in apitoxin
2. Anti-glomerular basement membrane
3. Anti-dsDNA
4. IgE against pollen
5. Anti-Smith

PREFERRED RESPONSE ▶
TAG
(M1.IM.4) A 32-year-old pregnant woman (para 2) presents to the clinic for a routine ultrasound; Image A displays the ultrasound findings. The fetus has become anemic and levels of unconjugated bilirubin have increased dramatically. Which type of hypersensitivity reaction has occurred and what is mediating the disease state? Topic Review Topic
FIGURES: A          

1. Type I hypersensitivity; antibody-mediated opsonization
2. Type II hypersensitivity; antibody-mediated opsonization
3. Type II hypersensivity; cell killing via cytotoxic T cells
4. Type III hypersensitivity; cell killing via cytotoxic T cells
5. Type IV hypersensitivity; cell killing via NK cells

PREFERRED RESPONSE ▶
TAG
(M1.IM.29) A 28-year-old female suffering from a urinary tract infection is given trimethoprim-sulfamethoxazole (TMP-SMX) by her physician. As a result of the medication, she begins to experience itchiness and joint pain. Laboratory and histologic analysis reveals vasculitis and antibody complexes deposited near the basement membrane of the glomerulus. What other serological finding is expected with this presentation? Topic Review Topic

1. Decreased levels of IgE
2. Increased levels of IgE
3. Decreased neutrophil count
4. Increased serum levels of complement protein C3
5. Lowered serum levels of complement protein C3

PREFERRED RESPONSE ▶
TAG
(M1.IM.37) A 30-year-old Caucasian male presents with hemoptysis and uremia. Blood tests show the presence of anti-basement membrane antibodies specific for collagen located in glomerular and pulmonary basement membranes. The patient undergoes plasmaphoresis to help reduce the amount of anti-basement membrane antibodies. Which of the following diseases is of the same hypersensitivity category as this disease? Topic Review Topic

1. Myasthenia gravis
2. Systemic lupus erythematosus
3. A PPD test
4. Seasonal allergies
5. Poison ivy rash

PREFERRED RESPONSE ▶
TAG
(M1.IM.50) While hunting, a 45-year-old Caucasian male is stung by a bee. He begins to feel unwell and is taken to the hospital. Upon arrival, it is noted that the patient is hypotensive with a blood pressure of 60/40 mmHg. Furthermore, the patient is tachycardic and edematous. What is responsible for this patient's presentation? Topic Review Topic

1. Free IgE binding to the antigen
2. IgE on mast cell surfaces binding to the antigen
3. IgE activation of complement
4. Complexes of IgE binding to the antigen
5. IgE on eosinophils binding to the antigen

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TAG
(M1.IM.60) A 5-year-old African American female has experienced recurrent respiratory infections. To determine how well her cell-mediated immunity is performing, a Candida skin injection is administered. After 48 hours, there is no evidence of induration at the injection site. Of the following cell types, which one would have mediated the reaction? Topic Review Topic

1. Plasma cells
2. Basophils
3. T-cells
4. Mast cells
5. Fibroblasts

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TAG
(M1.IM.61) You are working in the emergency room of a children's hospital when a 4-year-old girl is brought in by ambulance due to "difficulty breathing." The patient had been eating lunch on a school field trip when she suddenly complained of abdominal pain. Shortly thereafter, she was noted to have swelling of the lips, a rapidly developing red rash and difficulty breathing. In the ambulance her blood pressure was persistently 80/50 mmHg despite intramuscular epinephrine. In the course of stabilization and work up of the patient, you note an elevated tryptase level. What is the mechanism behind this elevated tryptase level? Topic Review Topic

1. IgG production by plasma cells
2. IgM mediated complement activation
3. Cross-linking of IgE on mast cells
4. Antibody-antigen immune complexes
5. Cross-linking of IgG on mast cells

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TAG
(M1.IM.86) A 24-year-old male being treated for syphilis is given penicillin. Shortly after receiving the first dose the patient becomes dyspneic. Immediate assessment of the patient reveals a heart rate of 150 bpm and a blood pressure of 88/50. The first-line drug used in the treatment of this condition has what effect on alpha and beta autonomic receptors? Topic Review Topic

1. Alpha-1 agonism, beta-1 agonism
2. Alpha-1 agonism, beta-1 antagonism
3. Alpha-1 antagonism, beta-1 agonism
4. Alpha-1 antagonism, beta-1 antagonism
5. Alpha-1 agonism, no effect on beta-1

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