Hypersensitivity Flashcards
What is the definition of hypersensitivity?
Normal molecular / cellular mechanisms produce an innappropriately vigorous innate or adaptive response to antigens posing little to no threat.
What is type 1 hypersensitivity?
Reactions initiated by interaction between IgE and multivalent antigens
When is IgE normally used and what is its abundance in plasma?
IgE is used against parasitic infections, and is the lowest level of any Ig class.
What are atopic people?
People who are genetically predisposed to developing antibodies against common environmental allergens
What are the three properties of allergenic antigens, and what macromolecule are they typically?
Typically protein or glycoprotein.
- Presence of protease activity that can disrupt epithelial cell junctions to activate complement / immune system
- Presence of PAMPs capable of interacting w/ innate immune system
- Enter at VERY LOW concentrations, which favors Th2 > Th1, leading to IgE secretion
What are the three phases of allergy?
- Sensitization
- Activation
- Effector phase
What happens in the sensitization phase of allergy?
Initial exposure to an allergen activates Th2 response, stimulating B cells to form IgE-secreting plasma cells. The serum half-life of IgE is low, but IgE binds receptors on mast cells and basophils
To what receptors do Ig’s to the allergen bind
Fc regions bind high affinity IgE receptor, but also small contribution of IgG binding the low affinity Fc receptors
What is the activation phase of allergy? What substances does this include?
Second exposure leads to multivalent allergen crosslinking IgE high-affinity receptors, triggering degranulation
Release of vasoactive amines from mast cells and basophils, including primary / secondary mediators.
What is the function of the low affinity IgG receptors on mast cells / basophils?
Activation will inhibit the immune response generated by the IgE receptors
During the effector phase of allergy, what are primary vs secondary inflammatory mediators?
Primary - preformed and stored in granules prior to mast cell / basophil activation
Secondary - Synthesized in target cells after Galphaq activation (Phospholipase C)
How do mast cells in the skin differ from mast cells in the intestinal mucosa / alveoli?
Skin / intestinal submucosa - contains tryptase, chymase, and carboxypeptidase
Intestinal mucosa / alveoli - tryptase-positive only (think alpha-1-antitrypsin)
What is the primary vasoactive amine of the allergic response, and what receptor does it utilize? What does this cause?
Histamine - H1 receptor
Causes:
Contraction of intestinal and bronchial smooth muscles (increasing fluid leakage between them)
Increased permeability of small veins
Increased mucous secretion
Under what pathway are prostaglandins / leukotrienes formed?
Phospholipase A2 cleaves arachidonic acid, leading to their enzymatic synthesis
What is thought to lead to the prolonged bronchospasm and buildup of mucus seen in asthmatics? Is this part of the early or late-phase response?
Leukotrienes, which are released 30-60 seconds following allergen stimulation, 1000 times more potent than histamine at stimulating vascular permeability and mucus secretion.
Still part of the early response
What cytokines mediate the late-phase response?
Th2 mediated and macrophage-mediated.
IL-5 = Th2-produced -> recruit eosinophils along with eosinophil chemotactic factor (produced by mast cells)
IL-8 = macrophage-produced -> recruit PMNs
TNFalpha / IL-1 = macrophage-produced -> inflammatory influx
What causes the most damage during the late-response phase?
PMN degranulation after recruit via IL-1/IL-8. They release more leukotrienes, platelet-activating factor, and lytic enzymes
How is the delayed-phase response different than the late phase response?
Starts 3 days post-antigen challenge, it is unique in that it requires the presence of BASOPHILS.
Basophils will act on fibroblasts which recruit more eosinophils and neutrophils to cause more tissue damage
What is the mechanism by which systemic anaphylaxis is created? What are the symptoms?
Antigen is absorbed through gut or injected into bloodstream, causing massive complement activation and C3a recruitment. Leads to massive degranulation of basophils and mast cells.
Bronchiolar constriction, vasodilation (blood pressure drops) and contraction of other smooth muscles can lead to defecation, urination, and asphyxiation
Why is epinephrine used to treat anaphylactic reactions?
Relaxes smooth muscle of airways by increasing cell cAMP levels, reduces vascular permeability, improves cardiac output, and preventing vascular collapse by constricting blood vessels
What is hay fever and what is one strange treatment of it?
Allergic rhinitis - treated with oral sodium cromoglycate which prevents mast-cell triggering, reducing histamine and vasodilator release.
What is the other name for allergic eczema, what age group is susceptible, and how does it differ from delayed hypersensitivity?
Atopic dermatitis
Young children are susceptible
Differs in that it is mediated by mast cells and Th2 rather than Th1 / macrophages
Why can food allergies cause vomiting? Hives in random places?
Vomiting due to upper or lower GI local smooth muscle contraction and vasodilation
Hives because the antigen can diffuse out of the GI system and cause a local anaphylactic reaction in skin.
What are the origins of childhood vs adult-onset asthma?
Childhood - extrinsic or atopic asthma, due to genetic predisposition
Adulthood - intrinsic or non-atopic
What is the main cause of asthma? Why does it get worse overtime?
Skewed Th2 responses to inhaled antigens, leading to activation and recruitment of effector cells.
Gets worse due to airway remodeling, leading to mucus cell hyperplasia, subepithelial thickening, and loss of epithelial integrity
What is a wheal and flare reaction?
urticaria / hives
What is the mechanism of action of sodium cromoglycate?
Blocks chloride channel activity and maintains cells in normal resting physiological state
What is omalizumab’s role in treating asthma?
Monoclonal antibody directed against IgE, treats astham in early and late phase, which are both IgE dependent