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Ch. 15. Hypersensitivities (Allergies) Atopy - hereditary predisposition toward allergies Mechanism not clear- may map to chromosomal region encoding many cytokines Tend to occur on mucous membranes- allergens either inhaled or ingested Immediate or delayed type hypersensitivity (DTH)
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Ch. 15. Hypersensitivities (Allergies) Atopy - hereditary predisposition toward allergies Mechanism not clear- may map to chromosomal region encoding many cytokines Tend to occur on mucous membranes- allergens either inhaled or ingested Immediate or delayed type hypersensitivity (DTH) Gell and Coombs classification – Types I-IV Ch. 15
p. 372 Ch. 15
IgE-mediated Hypersensitivity (Type I) IgE discovered by Ishizakas in 1960s- normally very rare in serum Larger molecule than IgG Not stable in serum Binds to IgE receptors on basophils and mast cells; then is stable for several weeks Ch. 15
p. 374 Ch. 15
p. 373 Ch. 15
What are mast cells and basophils? Basophil- rare blood cell Mast cells- found in connective tissue Granules contain active mediators Also secrete lots of cytokines: IL-1, IL-4, IL-5, IL-6, GM-CSF, etc. Also have high- and low-affinity receptors for IgE Ch. 15
Events in an allergic reaction: First exposure B cells produce allergen-specific IgE Ab Tail of IgE Ab reacts with Fc receptors on mast cells, leaving Fab’s directed away from the cell surface Second exposure Allergen enters body, cross-links IgE on mast cell in mucous membranes, skin, and triggers release of chemicals symptoms Ch. 15
p. 377 Ch. 15
p. 379 Ch. 15
Histamine release occurs within minutes Binds to receptors on target cells smooth muscles contract eosinophils attracted mucus secretion platelet activation blood vessel dilation Blocked by various compounds: antihistamines, epinephrine, corticosteroids Ch. 15
p. 380 Ch. 15
Effects of type I reactions Systemic anaphylaxis Respiration becomes difficult Blood pressure drops Smooth muscles of bladder and GI tract contract Bronchoconstriction Countered by epinephrine relaxes smooth muscles decreases vascular permeability improves cardiac output Ch. 15
Localized anaphylaxis Allergic rhinitis (hay fever)- nasal mucosa Asthma- lower respiratory tract bronchoconstriction, edema mucus inflammation Ch. 15
p. 382 Ch. 15
Early response - histamine, leukotrienes, prostaglandins bronchoconstriction, vasodilation, smooth muscle contraction Late response - IL-4, TNF-, etc. endothelial cell adhesion Also leukocyte migration, leukocyte activation factors Neutrophils (also eosinophils) cause a lot of tissue damage Ch. 15
Food allergies cells are sensitized in GI tract if Ag is blood-borne, can cause symptoms such as asthma or hives Atopic dermatitis (eczema) Late-phase reactions (not asthmatic) mast cells release cytokines eosinophils, neutrophils recruited Ch. 15
Regulation of type 1 hypersensitivity: Antigen stimulation IL-4 induced class switch TH2 cells, also mast cells IFN- reduces IgE production Ch. 15
Detection of type I hypersensitivity (pp. 386-7): Skin test RIST- total serum IgE RAST- IgE specific for a single allergen Ch. 15
p. 386 Ch. 15
p. 387 Ch. 15
Therapies Avoidance of Ag Hyposensitization Drugs antihistamines (block receptors) epinephrine (maintain high cAMP and prevent degranulation cromolyn sodium block calcium flux and more (p. 388) Ch. 15
Type II: antibody-mediated cytotoxic reactions: Antibodies bind to cells and mediate their destruction Transfusion reactions (ABO blood group Ags) Drug-induced hemolytic anemia drugs absorb to RBCs, like hapten-carrier Hemolytic disease of the newborn Ch. 15
Ch. 15 p. 389
p. 389 Ch. 15
Ch. 15 p. 390
Ch. 15 p. 391
Type III: Immune complex disease: Sometimes antibody- (soluble) antigen complexes are not cleared like they should be When deposited in tissue, they cause damage complement activation- produces inflammatory mediators neutrophils are attracted Arthus reaction - sensitized person develops a reaction at site of exposure (slower than type I) Ch. 15
p. 392 Ch. 15
Generalized reaction- large amounts of antigen enter bloodstream Immune complexes form Serum sickness- immunization with foreign serum Complexes tend to accumulate in kidneys, arteries, joints Autoimmune disease Infectious disease (malaria, parasitic disease) Cross-reactivity with bacterial or viral antigens Ch. 15
Type IV (TDTH and TC, or delayed-type): Detected with skin test (e.g., tuberculin or PPD skin test for tuberculosis) Contact dermatitis- when small molecules complex with skin proteins (poison ivy, poison oak, cheap jewelery) Internalized and presented by Langerhans cells; TH1 response; influx of macrophages Can lead to granuloma formation Ch. 15
p. 394 Ch. 15
p. 397 Ch. 15
Helps protect against intracellular pathogens Granulomas form in chronic reactions DTH response declines in immunodeficient people (with T cell deficiency), like AIDS Ch. 15
p. 395 Ch. 15