Hypersensitivity Part I Flashcards
Hypersensitivity
Hypersensitivity is a pathologic, acquired, specific immune response against an otherwise innocuous antigen.
Clasification of hypersensitivity disorders
Hypersensitivity disorders can be classified by immunologic mechanism, type of antigen, or time course for development of disease.
Type I: IgE-mediated mast cell/basophil degranulation
Type II: antibody-dependent cellular cytotoxicity (ADCC)
Type III: immune complex reactions
Type IV: cell-mediated immunity (DTH-delayed type hypersensitivity)
Atopy Defined
Atopy refers to the genetic tendency to develop allergic diseases such as allergic rhinitis, asthma and atopic dermatitis (eczema). Atopy is typically associated with heightened immune responses to common allergens, especially inhaled allergens and food allergens.
Type I (Immediate) Hypersensitivity
In general, Atopic individuals are predisposed to develop Type 2/Th2 inflammation and IgEmediated responses to certain antigens, making them more susceptible to type I hypersensitivity reactions.
Type I Immune Mechanism
- Pre-formed, allergen-specific IgE is bound to mast cells and/or basophils (which have the high affinity FcR for IgE).
- Cross-linking of IgE by that allergen results in cellular activation, degranulation and cytokine release causing the Type I hypersensitivity reaction.
Type I Immune Mechanism
Primary exposure and immune reaction cause Sensitization, while Secondary exposure results in the Effector phase and the characteristic symptomatology.
The Nature of Allergens
Allergens are proteins or chemicals bound to proteins that elicit Th2-dominated immune responses.
The main effector cells of Type I Hypersensitivity
- Mast cells
- Basophils
Mast Cells
•Tissue mast cells are found in connective tissue near nerves and surrounding blood vessels, whereas mucosal mast cells are found in the mucosa lining the gut and lungs
. • are large, granulated mononuclear cells derived from bone marrow precursors.
- express high affinity receptors for the Fc portion of IgE.
- synthesize and secrete a large number of mediators, including arachidonic acid metabolites, chemokines, and cytokines
Basophils
- a circulating white blood cell (0.5% to 1.0% of circulating leukocytes) that resembles mast cells.
- exhibit granulated morphology with a multi-lobed nucleus.
- express high-affinity receptors for IgE and receptors for the Fc portion of IgG1.
- synthesize and secrete allergic mediators
Histamine (found preformed in granules)
•Vasoactive amine; smooth muscle contraction, vascular permeability of endothelial cells (capillary leak)
ECF-A (Eosinophil Chemotactic Factor of Anaphylaxis)
•Attracts Eosinophils to site
Leukotrienes C4 and D4 (made de novo)
•Prolonged smooth muscle contraction; increased & prolonged vascular permeability
PAF (Platelet Activating Factor) (synthesized de novo)
•Causes platelets to release histamine resulting in bronchoconstriction, vasodilation and local thrombosis
Thromboxanes and Prostaglandins (made de novo)
•Vasoactive, bronchoconstriction, chemotactic for leukocytes
Cytokines: IL-3, 4, 5, GM-CSF and TNF-a
•Amplifies TH2 IgE response (IL-4/13), promotes eosinophil production (IL-5, GM-CSF), inflammation, increases adhesion molecules on endothelium
The type I reaction occurs in two phases; an immediate reaction that occurs within [], and a later reaction that takes [] to be observed.
The type I reaction occurs in two phases; an immediate reaction that occurs within minutes, and a later reaction that takes hours to a day to be observed.
What causes the late phase?
- The migration of other leukocytes such as neutrophils, lymphocytes, eosinophils and macrophages to the site. The reaction is usually seen 2–24 hours after the original reaction. Cytokines and chemokines released by mast cells drive the late phase reaction.
- Late phase responses contribute to chronic allergic conditions including asthma.
Recap of the mechanism behind Type I hypersensitivity reactions.
1) Antigen stimulates [] to produce antigen-specific [] with []. IL-[] induces eosinophilia.
2) The antigen-specific [] binds to mast cells and/or basophils via [] receptors ([]), which sensitizes the cells.
3) When antigen subsequently encounters the sensitized mast cell/basophil, it cross-links surface bound [] and the cell degranulates, releasing mediators which cause the symptoms associated with Type I hypersensitivity.
Recap of the mechanism behind Type I hypersensitivity reactions.
1) Antigen stimulates B cells to produce antigen-specific IgE with T cell help (IL-4 & 13). IL-5 induces eosinophilia.
2) The antigen-specific IgE binds to mast cells and/or basophils via Fcε receptors (FcεR), which sensitizes the cells.
3) When antigen subsequently encounters the sensitized mast cell/basophil, it cross-links surface bound IgE and the cell degranulates, releasing mediators which cause the symptoms associated with Type I hypersensitivity.
Acute Urticaria
- Affect 20% of population, lifetime
- mediated by superficial or deeper histamine release by mast cells
- Can become chronic
- Red
- Raised
- Pruritic
- Migratory
– Usually a few hours but definitely <24-36h
- Resolve completely
- Worsen with heat/rubbing and in dependent areas
Angioedema
- Affect 20% of population, lifetime
- mediated by superficial or deeper histamine release by mast cells
- Can become chronic
- Nonpitting, nondependent
- Without erythema
- Asymmetric
- Resolves completely
- Less pruritic, may be painful
- Lips, tongue, eyelids, genitalia
Anaphylaxis
Acute, life threatening systemic hypersensitivity reaction with varied mechanisms, clinical presentations, and severity that results from the sudden systemic release of mediators from mast cells and basophils.
Anaphylaxis Symptoms
Symptoms of anaphylaxis include flushing/hives/angioedema, abdominal cramping/nausea/vomiting/diarrhea, rhinitis/laryngeal edema/wheeze/cough, hypotension/tachycardia, syncope.
Clinical Diagnosis of Type I Hypersensitivity: Skin Testing
- Using percutaneous or intradermal introduction of specific allergen to look for systemic allergen-specific IgE—> “wheal and flare” reaction
- High sensitivity and specificity when performed/interpreted properly
- Wheal/Edema: due to vascular permeability and vascular dilation
- Flare/Erythema/redness: due to vascular dilation
- takes 15-20 minutes to observe the reaction, inhibited by antihistamines
- may be affected by presence of allergenspecific “blocking” IgG4
- For drug/venom testing, must consider irritant concentrations and relevant metabolites
Clinical Diagnosis of Type I Hypersensitivity: RAST
- Used to determine levels of circulating (serum) antigen-specific IgE.
- RAST (radioallergosorbent test): serum from allergic individual + immobilized antigen + radioactively labelled anti-IgE —> count bound radioactivity.
- This test measures antigen-specific IgE in a radioimmunoassay where the ligand is labeled anti-IgE antibody. The antigen (allergen) is covalently bound to a cellulose disc. The availability of large amounts of antigen on the disc permits the high sensitivity necessary to bind the small quantities of IgE present in the test serum.
- Clinically relevant cutoff values for each antigen RAST depends on the antigen, clinical syndrome, and brand of test (ie ImmunoCap®). This will affect interpretability.
Type I Hypersensitivity Immunopathology: Asthma
•Chronic airway changes:
-Features include eosinophilic-rich inflammation of bronchial wall, goblet cell proliferation with increased mucus production and stasis within the lumens (i.e. “mucus plugs”), thickening/wrinkling of the basement membranes and smooth muscle hypertrophy.
•These changes are most severe within bronchi, although small airways are also affected, and contribute to luminal compromise and obstruction.
Clinical Intervention for Type I Hypersensitivity: Anti-IgE Monoclonal Antibodies
- Omalizumab (IgG1 subclass) binds Fc portion of IgE to block IgE from binding to Fcε receptor.
- Dosed based on weight and serum IgE levels. FDA approved for severe allergic asthma and for chronic urticaria.
- Being studied for additional indications.
Clinical Intervention for Type I Hypersensitivity: Anti-Eosinophil Pathway Biologics
- There are two recently approved anti-IL-5 humanized monoclonal antibody treatments for severe eosinophilic asthma (>150-300cells/uL) called Mepolizumab (Nucala) and Reslizumab (Cinqair).
- Both bind circulating IL-5 to prevent eosinophil recruitment, activation, and degranulation.
- Benralizumab (Fasenra) is an anti-IL-5- receptor humanized monoclonal antibody that blocks IL-5 signaling at the receptor and induces eosinophil apoptosis through antibody-dependent cellular cytotoxicity.
- These are administered SQ (IV for reslizumab) and help reduce steroid requirement and exacerbations.
Clinical Intervention for Type I Hypersensitivity: Anti-IL-4-Receptor pathway Biologics
- Dupilumab (Dupixent) is a monoclonal antibody that blocks the alpha chain of the IL-4 receptor, which is required for both IL-4 and IL-13 signaling.
- Dupixent is administered SQ, and is FDA approved for treatment of severe atopic dermatitis, pending approval for allergic asthma, and in clinical trials for various related conditions.
