Type IIII Hypersensitivity Reactions

1
Type I-III Hypersensitivity Reactions

• Parham Chapter 12
• pp 365-392

2
Hypersensitivity reactions Gell and Coombs
classification (1963)

• Antibody-mediated
• Type I IgE
• Type II IgG (cell-bound antigens)
• Type III IgG/IgM (soluble antigens)
• Cell-mediated
• Type IV
• Broad classification of immune responses to
  pathogens as well as innocuous antigens

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Hypersensitivity reactions
4
Type I hypersensitivity - allergies

• At least 50 million Americans suffer from
  allergies
• Most common allergies
• Asthma prevalence 7 of population
• Atopic dermatitis (eczema)
• Most common skin disease in infants and children
  lt 12 years
• Up to 20 prevalence
• Allergic rhinitis (hay-fever) 20 -30
  prevalence
• Food allergy
• Insect bites/stings
• Sensitization followed by challenge/effector phase

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Asthma PrevalenceUnited States, 1980-2004
Lifetime
Current
12-Month
Attack
Source National Health Interview Survey
National Center for Health Statistics
6
Child and Adult Asthma PrevalenceUnited States,
1980-2004

• Child
• Adult

Lifetime
Current
12-Month
Attack
Source National Health Interview Survey
National Center for Health Statistics
7
Cause of increasing prevalence of allergies

• Hygiene hypothesis
• Shift from Th1 to Th2
• Decreased number/activity of regulatory T cells
• Changes in indoor air quality
• Changes in life style

8
Components of allergic reactions

• Sensitization
• production of TH2 CD4 T cells and IgE
• Binding of IgE to Fc?RI on mast cells and
  basophils
• Effector phase
• Acute (immediate reaction)
• Mast cell/basophil degranulation
• Late phase reaction - chronic
• Influx of eosinophils and eosinophil
  degranulation
• Influx of TH2 CD4 T cells

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Mast cells

• Derived from hemopoietic stem cells in bone
  marrow
• Precursors develop into mast cells in tissues
  under influence of c-kit (CD117) and Stem Cell
  Factor (SCF) .
• Mast cells are most numerous in the skin and
  mucosal tissues
• Express high affinity Fc?RI

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Mast cell activation by IgE crosslinking
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Mast cell activation

• Pre-formed mediators stored in granules
• Histamine, heparin
• Cytokines (Tumor necrosis factor)
• Enzymes
• Newly synthesized mediators
• Prostaglandins, leukotrienes
• Cytokines and chemokines

12
Contents of mast cell granules
13
Histamine
histidine
CO2

• H1 receptors
• endothelial cells
• smooth muscle cells

histamine
H1-antagonists
14
Leukotrienes and prostaglandins
aspirin
Montelukast (Singulair?)
receptor
15
Basophils

• Granulocytes with very similar function to mast
  cells
• Express Fc?RI
• Secrete IL-4 and IL-13
• Role in TH2-differentiation

16
Eosinophils

• Granules rich in basic proteins
• Major basic protein, eosinophil cationic protein,
  neurotoxin
• Toxic to cells and parasites
• Production in bone marrow is stimulated by IL-5,
  influx into tissues by chemokine, e.g., eotaxin.
• Activated eosinophils express Fc?RI
• Degranulation is induced by eotaxin, C5a, and
  antigens (via IgE)

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Mediators secreted by eosinophils
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Regulation of IgE synthesis
IgE memory cell
IL-4 (IL-13)
CD40-CD40L
IgE B cell
IgM/IgD naïve B cell
IgE plasma cell
19
Regulation of CD4 T cell differentiation
IFN-g
IL-12
DC
TH1
naïve TH
TH0
IL-4 IL-5 IL-13
TH2
IL-4
allergies
20
Atopy

• Genetic predisposition to IgE production

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Some properties of inhaled allergens

• Examples
• pollen
• dust mite feces
• cockroach antigens

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Sensitization to inhaled allergens
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Late phase reactions
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Clinical manifestations of allergy
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Diagnosis of allergies

• Skin testing
• Avoidance
• Antigen-specific IgE
• Radio allergosorbent test (RAST)
• ELISA (ImmunoCap?)
• Total IgE

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Systemic anaphylaxis

• Allergen
• insect venom
• drugs
• food allergens

blood circulation
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Treatment of anaphylactic shock
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Allergic rhinitis
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Treatment of allergic rhinitis

• Avoidance
• Antihistamines
• Corticosteroids
• Prevention of mast cell degranulation

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Asthma

• Extrinsic IgE-mediated
• Intrinsic no evidence of IgE involvement

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Pathogenesis of asthma
Type I hypersensitivity
Type IV hypersensitivity
remodeling
32
Clinical symptoms of asthma

• Coughing
• Wheezing
• Hypersensitive airways

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Treatment of allergic reactions

• Avoidance
• Foods
• Pets
• Dust
• Drugs
• Inhibitors of inflammation
• Corticosteroids (systemic or inhalation)
• Anti-LTC4-R (Montelukast)
• Chromolyn sodium (prevents mast cell
  degranulation)
• Bronchodilators
• Antihistamines
• Anti-IgE (omalizumab (Xolair?)
• Desensitization
• Increasing doses of allergen via subcutaneous
  injection
• Shift response to TH1 or induction of
  IL-10/TGF-ß-secreting regulatory T cells
• Risk induce/enhance allergy or type III
  hypersensitivity

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Type II hypersensitivity
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Drug-induced blood cell dyscrasias

• Related to pharmacologic action of the drug
• Idiosyncratic often immune-mediated
• Thrombocytopenia most common

36
Mechanism of antibody-mediated blood cell
destruction

• Type II hypersensitivity
• Antibodies
• Drug (hapten)-specific
• Antibody binds to cells in presence of drug or
  drug metabolite
• True autoantibodies
• Immune complexes, e.g., heparin
• Fibrinogen receptor (gp IIb/IIIa) antagonists

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Modification of RBC by penicillin
38
Production of anti-penicillin antibodies
39
Lysis and phagocytosis of penicillin-modified RBC
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Clinical Case

• Cynthia Waymarsh was 31 years old when she became
  pregnant for the 3rd time
• First pregnancy was normal
• Second pregnancy positive indirect Coombs test.
  Normal delivery. Father Rh, Cynthia Rh-.
• Third pregnancy positive Coombs test. Bilirubin
  in amniotic fluid at 22 and 29 weeks of
  gestation. Hematocrit of umbilical vein was 6.2
• Transfusion of packed type O, Rh-, red blood
  cells into umbilical vein twice, followed by
  induction of labor at 35 weeks of gestation.

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Rhesus factor
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Questions?

• Rh antigens are sparsely scattered across RBC
  surface and complement fixation does not occur.
  What is mechanism for RBC destruction?
• A preventive treatment is IV treatment of
  pregnant women with anti-Rh antibodies (Rhogam).
  How does this work? Why does it not harm the
  fetus?

43
Passive immunization against Rh prevents
hemolytic anemia of the newborn
44
Type III hypersensitivity

• Caused by immune complexes of IgG and soluble
  antigen
• Clinical symptoms depend on size and localization
  of immune complexes
• Inflammation induced by complement activation and
  neutrophils

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Arthus reaction

• Localized response
• Induced by injection of soluble antigen in
  patient with pre-existing IgG antibodies
• Example
• Desensitization of IgE-mediated allergies

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Systemic immune complex disease

• Serum sickness
• Induced by repeated injection of foreign proteins
  (horse immunoglobulins)
• Chronic infections
• Subacute endocarditis
• Chronic autoimmune disease
• Rheumatoid arthritis
• Systemic lupus erythematosus

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Pathology and symptoms of systemic type III
hypersensitivity depends on the localization of
immune complexes
48
Serum sickness