Updated: 10/13/2018

Hypersensitivity

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Snapshot
  • A 12-year-old boy presents to the emergency department with dyspnea and urticaria. His symptoms began approximately 30 minutes after being stung by bee. Medical history is significant for asthma and an allergy to shellfish. On physical exam, breathing is labored, and wheezes are appreciated on pulmonary auscultation. Airway, breathing, and circulation is intact. The boy is immediately started on intramuscular epinephrine. (Anaphylaxis)
Introduction
  • Hypersensitivity reactions (HSR) can be considered as an overreactive immune response
  • HSR can be classified into four categories
    • type I, II, III, and IV
      • type I, II, and III are antibody mediated
      • type IV is cell mediated
  • Speed of reaction
    • type I HSR is immediate (fastest)
    • type IV HSR is delayed (slowest)
Type I HSR (Anaphylactic and Atopic)
  • Mechanism of action
    • initial exposure to an allergen causes
      • Th2 cells to stimulate (via IL-4 and -13) B-cells to produce
        • IgE antibodies which attaches to
          • mast cells and basophils (these are said to be sensitized)
    • second exposure to the allergen causes
      • IgE cross-linking on mast cells and basophil which results in
        • the immediate release of vasoactive amines (e.g., histamine and heparin) that can cause
          • vascular leakage
          • bronchoconstriction
          • intestinal hypermotility
          • inflammation
    • since the antibodies are pre-formed, the reaction is immediate
      • a few hours after the immediate response ensues, a late-phase reaction occurs
        • which is mediated by downstream products of the arachidonic acid cascade such as
          • prostaglandins
          • leukotrienes
  • Clinical disorders
    • refer to chart
  • Diagnostic testing
    • allergen-specific IgE can be assessed with
      • skin testing for allergic disease
Type II HSR (Cytotoxic)
  • Mechanism of action
    • antibodies are directed against tissue specific antigens which can result in
      • opsonization
      • complement activation
      • neutrophil and macrophage recruitment
      • NK cell killing
      • impair cell function if targetting a cellular receptor
  • Clinical disorders
    • refer to chart
  • Diagnostic testing
    • direct Coombs test
      • assesses antibodies that are attached directly to the erythrocyte surface
    • indirect Coombs test
      • assesses antibodies that are unbound in the serum
Type III HSR (Immune-Complex)
  • Mechanism of action
    • antibodies bind to self or foreign antigen forming immune complexes
      • immune complexes activate the complement cascade and results in
        • systemic manifestations
  • Clinical disorders
    • refer to chart
Type IV HSR (Cell-Mediated)
  • Mechanism of action
    • T-cell-mediated tissue injury resulting from
      • CD8+ T-cells directly killing a target cell
      • pre-sensitized CD4+ helper T-cells are exposed to the insult, which results in 
        • cytokine release (delayed-type HSR), which leads to
          • macrophage activation and
            • inflammation
  • Clinical disorders
    • refer to chart
Summary
 
Hypersensitivity Reactions
Hypersensitivity Reaction Type
Pathophysiology
Clinical Examples
Type I (anaphylactic and atopic)
  • Immediate
  • Antigens cross-link IgE antibodies triggering
    • vasoactive amine release (e.g., histamine) 
  • Anaphylaxis
    • allergens
      • bee sting
      • food (e.g., peanuts)
      • drugs
  • Asthma
    • allergens
      • inhaled materials
  • Allergic rhinitis
    • allergens
      • animals
      • trees
Type II (cytotoxic)
  • Antibodies are directed against cell-surface antigens resulting in
    • opsonization
    • complement activation
    • neutrophil and macrophage recruiting
    • NK cell killing
    • impairment of cellular function
  • Autoimmune hemolytic anemia
    • antigen
      • erythrocyte membrane proteins
  • Acute rheumatic fever 
    • antigen
      • myocardial antigens via cross-reacting with S. pyogenes M protein
  • Goodpasture syndrome
    • antigen
      • type IV collagen
  • Immune thrombocytopenic purpura
    • antigen
      • platelet membrane proteins
  • Myasthenia gravis
    • antigen
      • acetylcholine receptors
  • Graves' disease
    • antigen
      • TSH receptors
  • Erythroblastosis fetalis 
    • antigen
      • Rh antigen
  • Pemphigus vulgaris
    • antigen
      • desmosomes
Type III (immune-complex)
  • IgG antibodies complexes with self or foreign antigens resulting in
    • complement activation
  • Serum sickness  
  • Arthus reaction
  • Systemic lupus erythematosis
  • Polyarteritis nodosa
  • Poststreptococcal glomerulonephritis 
Type IV (cell mediated)
  • CD8+ T-cells directly destroy the target cell
  • Pre-sensitized CD4+ helper T-cell releases cytokines when re-exposed to the offending material
  • Notice this does NOT involve antibodies
  • Type I diabetes meilltus
  • Contact dermatitis 
  • Tuberculin test
 

References

 

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Questions (15)
Lab Values
Blood, Plasma, Serum Reference Range
ALT 8-20 U/L
Amylase, serum 25-125 U/L
AST 8-20 U/L
Bilirubin, serum (adult) Total // Direct 0.1-1.0 mg/dL // 0.0-0.3 mg/dL
Calcium, serum (Ca2+) 8.4-10.2 mg/dL
Cholesterol, serum Rec: < 200 mg/dL
Cortisol, serum 0800 h: 5-23 μg/dL //1600 h:
3-15 μg/dL
2000 h: ≤ 50% of 0800 h
Creatine kinase, serum Male: 25-90 U/L
Female: 10-70 U/L
Creatinine, serum 0.6-1.2 mg/dL
Electrolytes, serum  
Sodium (Na+) 136-145 mEq/L
Chloride (Cl-) 95-105 mEq/L
Potassium (K+) 3.5-5.0 mEq/L
Bicarbonate (HCO3-) 22-28 mEq/L
Magnesium (Mg2+) 1.5-2.0 mEq/L
Estriol, total, serum (in pregnancy)  
24-28 wks // 32-36 wks 30-170 ng/mL // 60-280 ng/mL
28-32 wk // 36-40 wks 40-220 ng/mL // 80-350 ng/mL
Ferritin, serum Male: 15-200 ng/mL
Female: 12-150 ng/mL
Follicle-stimulating hormone, serum/plasma Male: 4-25 mIU/mL
Female: premenopause: 4-30 mIU/mL
midcycle peak: 10-90 mIU/mL
postmenopause: 40-250
pH 7.35-7.45
PCO2 33-45 mmHg
PO2 75-105 mmHg
Glucose, serum Fasting: 70-110 mg/dL
2-h postprandial:<120 mg/dL
Growth hormone - arginine stimulation Fasting: <5 ng/mL
Provocative stimuli: > 7ng/mL
Immunoglobulins, serum  
IgA 76-390 mg/dL
IgE 0-380 IU/mL
IgG 650-1500 mg/dL
IgM 40-345 mg/dL
Iron 50-170 μg/dL
Lactate dehydrogenase, serum 45-90 U/L
Luteinizing hormone, serum/plasma Male: 6-23 mIU/mL
Female: follicular phase: 5-30 mIU/mL
midcycle: 75-150 mIU/mL
postmenopause 30-200 mIU/mL
Osmolality, serum 275-295 mOsmol/kd H2O
Parathyroid hormone, serume, N-terminal 230-630 pg/mL
Phosphatase (alkaline), serum (p-NPP at 30° C) 20-70 U/L
Phosphorus (inorganic), serum 3.0-4.5 mg/dL
Prolactin, serum (hPRL) < 20 ng/mL
Proteins, serum  
Total (recumbent) 6.0-7.8 g/dL
Albumin 3.5-5.5 g/dL
Globulin 2.3-3.5 g/dL
Thyroid-stimulating hormone, serum or plasma .5-5.0 μU/mL
Thyroidal iodine (123I) uptake 8%-30% of administered dose/24h
Thyroxine (T4), serum 5-12 μg/dL
Triglycerides, serum 35-160 mg/dL
Triiodothyronine (T3), serum (RIA) 115-190 ng/dL
Triiodothyronine (T3) resin uptake 25%-35%
Urea nitrogen, serum 7-18 mg/dL
Uric acid, serum 3.0-8.2 mg/dL
Hematologic Reference Range
Bleeding time 2-7 minutes
Erythrocyte count Male: 4.3-5.9 million/mm3
Female: 3.5-5.5 million mm3
Erythrocyte sedimentation rate (Westergren) Male: 0-15 mm/h
Female: 0-20 mm/h
Hematocrit Male: 41%-53%
Female: 36%-46%
Hemoglobin A1c ≤ 6 %
Hemoglobin, blood Male: 13.5-17.5 g/dL
Female: 12.0-16.0 g/dL
Hemoglobin, plasma 1-4 mg/dL
Leukocyte count and differential  
Leukocyte count 4,500-11,000/mm3
Segmented neutrophils 54%-62%
Bands 3%-5%
Eosinophils 1%-3%
Basophils 0%-0.75%
Lymphocytes 25%-33%
Monocytes 3%-7%
Mean corpuscular hemoglobin 25.4-34.6 pg/cell
Mean corpuscular hemoglobin concentration 31%-36% Hb/cell
Mean corpuscular volume 80-100 μm3
Partial thromboplastin time (activated) 25-40 seconds
Platelet count 150,000-400,000/mm3
Prothrombin time 11-15 seconds
Reticulocyte count 0.5%-1.5% of red cells
Thrombin time < 2 seconds deviation from control
Volume  
Plasma Male: 25-43 mL/kg
Female: 28-45 mL/kg
Red cell Male: 20-36 mL/kg
Female: 19-31 mL/kg
Cerebrospinal Fluid Reference Range
Cell count 0-5/mm3
Chloride 118-132 mEq/L
Gamma globulin 3%-12% total proteins
Glucose 40-70 mg/dL
Pressure 70-180 mm H2O
Proteins, total < 40 mg/dL
Sweat Reference Range
Chloride 0-35 mmol/L
Urine  
Calcium 100-300 mg/24 h
Chloride Varies with intake
Creatinine clearance Male: 97-137 mL/min
Female: 88-128 mL/min
Estriol, total (in pregnancy)  
30 wks 6-18 mg/24 h
35 wks 9-28 mg/24 h
40 wks 13-42 mg/24 h
17-Hydroxycorticosteroids Male: 3.0-10.0 mg/24 h
Female: 2.0-8.0 mg/24 h
17-Ketosteroids, total Male: 8-20 mg/24 h
Female: 6-15 mg/24 h
Osmolality 50-1400 mOsmol/kg H2O
Oxalate 8-40 μg/mL
Potassium Varies with diet
Proteins, total < 150 mg/24 h
Sodium Varies with diet
Uric acid Varies with diet
Body Mass Index (BMI) Adult: 19-25 kg/m2
Calculator

(M1.IM.4) A 32-year-old pregnant woman (para 2) presents to the clinic for a routine ultrasound; Figure 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? Review Topic

QID: 100425
FIGURES:
1

Type I hypersensitivity; antibody-mediated opsonization

4%

(8/206)

2

Type II hypersensitivity; antibody-mediated opsonization

69%

(143/206)

3

Type II hypersensivity; cell killing via cytotoxic T cells

17%

(36/206)

4

Type III hypersensitivity; cell killing via cytotoxic T cells

6%

(13/206)

5

Type IV hypersensitivity; cell killing via NK cells

2%

(4/206)

M1

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(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? Review Topic

QID: 100471
1

Free IgE binding to the antigen

3%

(6/221)

2

IgE on mast cell surfaces binding to the antigen

80%

(177/221)

3

IgE activation of complement

9%

(19/221)

4

Complexes of IgE binding to the antigen

0%

(0/221)

5

IgE on eosinophils binding to the antigen

7%

(15/221)

M1

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(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? Review Topic

QID: 100481
1

Plasma cells

12%

(5/40)

2

Basophils

5%

(2/40)

3

T-cells

60%

(24/40)

4

Mast cells

20%

(8/40)

5

Fibroblasts

0%

(0/40)

M1

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(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? Review Topic

QID: 100422
1

IFN-gamma

4%

(1/24)

2

Histamine

83%

(20/24)

3

IL-22

0%

(0/24)

4

Arachidonic acid

4%

(1/24)

5

IL-4

8%

(2/24)

M1

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(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? Review Topic

QID: 106310
FIGURES:
1

IgE against the proteins in apitoxin

6%

(3/49)

2

Anti-glomerular basement membrane

55%

(27/49)

3

Anti-dsDNA

14%

(7/49)

4

IgE against pollen

12%

(6/49)

5

Anti-Smith

6%

(3/49)

M1

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(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? Review Topic

QID: 100864
1

IgG production by plasma cells

0%

(0/27)

2

IgM mediated complement activation

4%

(1/27)

3

Cross-linking of IgE on mast cells

85%

(23/27)

4

Antibody-antigen immune complexes

4%

(1/27)

5

Cross-linking of IgG on mast cells

0%

(0/27)

M1

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(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? Review Topic

QID: 100458
1

Myasthenia gravis

66%

(74/112)

2

Systemic lupus erythematosus

24%

(27/112)

3

A PPD test

4%

(4/112)

4

Seasonal allergies

2%

(2/112)

5

Poison ivy rash

4%

(4/112)

M1

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PREFERRED RESPONSE 1

(M1.IM.29) A 28-year-old female suffering from a urinary tract infection is given trimethoprim-sulfamethoxazole (TMP-SMX) by her physician. Several days later, 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? Review Topic

QID: 100450
1

Decreased levels of IgE

1%

(1/123)

2

Increased levels of IgE

10%

(12/123)

3

Decreased neutrophil count

4%

(5/123)

4

Increased serum levels of complement protein C3

29%

(36/123)

5

Lowered serum levels of complement protein C3

54%

(67/123)

M1

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