Flashcards in Allergy and Hypersensitivity Deck (10):
Define hypersensitivity, allergy, and atopy.
Hypersensitivity: Heightened host responsiveness to normally innocuous substances
Allergy: Immunologically-mediated hypersensitivity;
IgE-mediated vs. other mechanisms
Atopy: Genetic predisposition to IgE-mediated responses
What is the pathophysiologic mechanism of Type I hypersensitivity?
-Th2 cells, IgE antibody, mast cells, eosinophils
-mast cell derived mediators and cytokine mediated inflammation
1. First exposure to allergen
2. Antigen activation of Th2 cells and stimulation of IgE class switching in B cells
3. Production of IgE
4. Binding of IgE to FceRI on mast cells and basophils
5. Repeat exposure to allegen, bridges IgE molecules occopying FceRI
6. Activation of mast cell: release of mediators: vasoactive amines, lipid mediators-immediate hypersensitive rxn minutes after exposure
late phase rxn: cytokine mediated hours after exposure
What is the pathophysiologic mechanism of Type II hypersensitivity?
Antibodies produced by immune response bind to antigens on patient's own cells surfaces
-IgG and/or IgM antibodies fix to tissue antigens
(e.g. cell or basement membranes)
-Complement activation at the membrane
--Chemotaxis & activation of phagocytic cells
--C3b generation – opsonization
--MAC – cell lysis
-Complement-independent, antibody-mediated immunopathology
-Abnormalities in cellular function, e.g. hormone receptor signaling
-Disorders: autoimmune cytopenias, myastheia gravis (antibodies block acetycholine receptors), goodpasture's syndrome
What is the pathophysiologic mechanism of Type III hypersensitivity?
-Immune complexes of circulating antigens and IgM or IgG antibodies deposited in vascular basement membrane
-complement and Fc receptor mediated recruitment and activation of leukocytes
-deposition of ICs in blood vessel wall induces inflammation-vasculitis
-local IC disease: arthus rxn, e.g. local rxn to tetanus shot
-systemic: serum sickness
What is the pathophysiologic mechanism of Type IV hypersensitivity?
-CD4 and CD8 CTL T cells
-macrophage activation, cytokine mediated inflammation
-direct target cell lysis, cytosine mediated inflammation
e.g. allergic contact dermatitis, Tb skin test,
What are critical pathways in production of allergy and asthma?
-Impaired epithelial barrier function: Infection, allergen exposure, Upper and lower respiratory tracts, G.I. tract, skin, Chronic inflammation and aberrant repair (remodeling)
-Generation of thymic stromal lymphopoietin (TSLP) by local epithelial cells, fibroblasts and mast cells
-TSLP activates immature dendritic cells to drive TH2 cells
-TH2 cells produce IL4, IL5, IL13
-Net reduction in IL12 (down regulates TH1)
-IL4 drives B-cells to switch to IgE production
IgE mediates an inflammatory cascade involving mast cells, basophils, eosinophils and soluble inflammatory mediators
-IL5 drives eosinophilia and eosinophil activation
-IL13 directly induces smooth muscle proliferation, mucus hyper secretion, goblet cell metaplasia, eosinophil recruitment, fibrosis (all characteristics of asthma) independent of IgE
What are the differences between mast cells and basophils?
-found in tissue
-found in circulation
What are the mast cell associated mediators of inflammation?
a. Vasoactive amines: vascular dilation, smooth muscle contraction
b. Proteases: tissue damage
2. Lipid mediators
a. Prostaglandins: vascular dilation
b. Leukotrienes: smooth muscle contraction
a. Cytokines: inflammation/leukocyte recruitment
What are the functions of eosinophils?
1. PMNs with basic protein containing granules
2. activated by Th2 and Il-5
3. Granule proteins: neurotoxin, cationic protein, and major basic protein at core
4. Cytokines: Il-1, TNF-a, TGF-a, b
5. Effector functions: protect against helminths and capable of inducing tissue damage