Hypersensitivity Flashcards
Hypersensitivity
= Excessive or Aberrant immune response *causing Tissue Damage and Disease
2 Situations may result in Hypersensitivity
1) *Deregulated Responses to Foreign Antigen
2) *Responses to Self (Autologous Antigen) = *Autoimmunity
4 Types of Hypersensitivity
Type I: Immediate Hypersensitivity:
–Allergy / Atopy mediated by IgE and Mast cells. *Most common immunological disorder; affects 20% of Population.
Type II: Antibody-Mediated Hypersensitivity:
–Mediated by Antibodies (other than IgE) and Complement
Type III: Immune Complex Diseases:
–Mediated by Antigen-Antibody Immune Complexes and Complement
Type IV: Delayed-Type Hypersensitivity:
–Mediated by T cells
Type I Hypersensitivity
= Rapid, *Vascular and *Smooth Muscle Reaction, *Within 5-60 Minutes.
*Massive Histamine release,
*Vasodilation,
*Bronchial Smooth Muscle Contraction (Bronchoconstriction),
Exudation of fluid,
Submucosal gland secretion.
-Mediated by *IgE and *Mast cells upon exposure to certain types of *Foreign Antigen called *Allergen
- Requires *Sensitization (Previous Exposure) to the Allergen for the Reaction to occur.
- ->This Sensitization response is mediated by B cells assisted by CD4+ Helper T cells:
During First Exposure
1) **Massive Activation of Th2 CD4+ Helper T cells occurs in response to the Allergen.
2) Th2 CD4+ cells secrete IL-4 and IL-13, which stimulate B cells specific for that antigen to isotype switch to IgE-producing Plasma cells.
3) Massive Amounts of IgE are produced.
4) IgE binds to Fc-eRI Receptors on Mast cells and Basophils, Coating the Mast cells ==> Sensitization.
Second Exposure
5) Antigen binds to the IgE bound to the Mast cells, causing cross-linking of the Fc receptors.
6) –> Activates the Sensitized Mast Cells, causing 3 Mast cell Responses:
(1) Mast Cell Degranulation:
- -Histamine: Vasodilation and Smooth Muscle Contraction. (Vasoactive Amines)
- -Proteases: can cause Tissue Damage.
(2) Mast Cell Lipid Synthesis and Secretion (*Non-Granular Mediators):
- -Lipids derived from *Arachidonic Acid: *Prostaglandins (Vasodilation) and *Leukotrienes (Smooth Muscle Contraction)
(3) Mast Cell Cytokine Release:
IL-4 and TNF:
*Recruit Eosinophils and Neutrophils responsible for Inflammation in *Late Phases (6-24 hrs after new exposure)
Note: Mast cells are localized around blood vessels, enhancing histamine effects.
This Immediate Response produces little tissue damage.
Affected tissues are Edematous and Bronchi Lumens are filled with Mucus.
Late-Phase Reaction of Type I Hypersensitivity
If immediate response is prolonged, secondary mediators recruit additional Eosinophils, Neutrophils, and Macrophages, even Hours after exposure.
Granulocytes (Eosinophils and Neutrophils) release Proteases and Hydrolases, enhancing Inflammation and Tissue Damage.
Necrosis or Ulceration of Mucosal surfaces is Uncommon.
Examples of Localized Anaphylaxis
Allergic Rhinitis, Sinusitis:
- -Hay Fever from plant pollens
- -Increased Mucus secretion
- -Inflammation of upper airways and sinuses
Allergic Conjunctivitis: Watery eyes
Bronchial Asthma: of the allergic type
- -Smooth muscle contraction
- -Inflammation and Tissue injury caused by Late-Phase Reaction
Allergic Gastroenteritis: With Diarrhea: Food allergy from allergens in fish, wheat, milk products.
Systemic Anaphylaxis
Can be Life-Threatening
Edema in many tissues. Most dangerous is Laryngeal Edema.
–Laryngeal Edema along with Extensive Bronchoconstriction contributes to Severe Respiratory Distress. (Airway Obstruction)
Extensive Vasodilation and Exudation –> leads to Hypotension and eventual Shock.
–Caused by Widespread Mast cell Degranulation in response to Systemic Exposure to Allergen.
Examples: –in *Sensitized person!
- -Penicillin
- -Bee sting
Type I Hypersensitivity Therapy
for Anaphylaxis
Anaphylaxis: Epinephrine
- -Causes Vascular Smooth Muscle Contraction
- -Increases Cardiac Output (to counter Shock)
- -Inhibits further Mast Cell Degranulation
Type I Hypersensitivity Therapy
for Bronchial Asthma
Corticosteroids: Reduce Inflammation
Phosphodiesterase Inhibitors: Relax Bronchial Smooth Muscles
Type I Hypersensitivity Therapy
for Various Allergic Diseases
“Desensitization” (Repeated administration of low doses of allergens):
- -Unknown Mechanism. May inhibit IgE production and Increase production of other Ig Isotypes.
- -May induce T cell Tolerance.
Antihistamines: Blocks actions of Histamine on Vessels an Smooth Muscles
Cromolyn: Inhibits Mast Cell Degranulation
Type II Hypersensitivity: Antibody-Mediated
= Antibodies against Cells and Extracellular Matrix deposit in Tissues that express the Target Antigen
–These diseases are usually localized to a Particular Tissue.
–Common to many Chronic Immunologic diseases.
Mediated by Antibodies (other than IgE):
Fc Receptor-Mediated Inflammation:
(1) Antibodies deposit on Target Tissue/Cell Antigens. (IgG1, IgG3)
- -Fc Receptors on Neutrophils and Macrophages bind to them and are activated to induce Inflammation.
Ig-Complement-Mediated Inflammation, Tissue Damage:
(2) IgG and IgM can both bind to the target tissues and activate Complement (Classical Pathway).
- -Production of Complement byproducts (C5a and C3a) Recruit Neutrophils, inducing Inflammation.
- -Neutrophil Activation causes release of ROS and lysosomal enzymes –> Tissue Damage
Ig-Mediated Opsonization, Phagocytosis
(3) Antibodies opsonize the Target cells.
- -Opsonization can activate Phagocytosis or can activate Complement, which can also activate Phagocytosis.
- -Phagocytes have Fc receptors and C3b receptors.
Abnormal Physiologic Responses without Direct Cell/Tissue Damage:
(4) Antibodies against hormone receptors may inhibit receptor function. Antibodies may also directly activate receptors, mimicking their physiologic ligands.
Blood Transfusion ABO Incompatibility
Type II Hypersensitivity: Antibody-Mediated
-Circulating Antibody can be directed against Antigens on RBC cell membranes.
–In a major transfusion reaction with ABO Incompatibility, naturally occurring Anti-A and/or Anti-B Antibodies in the patient’s serum attach to the Donor RBC and induce Hemolysis in Minutes.
Autoimmune Hemolytic Anemia
Type II Hypersensitivity: Antibody-Mediated
- -Hemolytic disease of the Newborn,
- -Most often due to Rh Incompatibility between Mother and Fetus,
1) Maternal IgG crosses the Placenta and attaches to Fetal RBC,
2) Causing - -Hemolysis,
- -Fetal Anemia,
- -Organomegaly, and
- -Jaundice.
Goodpasture’s Syndrome
Type II Hypersensitivity: Antibody-Mediated
An Auto-Antibody against the Alpha-3 chain of Type 4 Collagen attaches to Glomerular and Pulmonary Alveolar Capillary Basement Membranes.
The attached antibody Activates Complement, resulting in
- Basement Membrane Destruction and
- Pulmonary and Glomerular Hemorrhage.
Immunofluorescence to IgG or IgA antibodies can demonstrate Linear deposition in Glomerular Capillaries on a Renal Biopsy.
Grave’s Disease
Type II Hypersensitivity: Antibody-Mediated
Auto-Antibodies are Functionally Active on Thyroid Stimulating Hormone (TSH) Receptors on Thyroid Follicular cells
–> Resulting in Hyperthyroidism
