hypersensitivity I

what are type IV hypersensitivity reactions characterized by?
TH1, CTLs, and TH2s: cell mediated (delayed). types 1-3 are Ig-mediated, (humoral)
what are type I hypersensitivity reactions mediated by?
IgE
what is a type I hypersensistivity reacion defined as?
immediate or type I, hypersensitivity is a rapid immunologic reaction occuring within minutes after a combination of antigen w/antibody bound to mast cells in individuals previously sensitized to the antigen
what kinds of antigens stimulate a type I hypersensitivity reaction?
proteins, (or chemicals bound to proteins), typically chronic exposure, and inability to stimulate the innate immune system: no IL-12/IFN gamma (may be one of the keys of type I)
what are common causes of hypersensitivity reactions?
inhaled materials: plant pollens, dander of domesticated animals, mold spores, feces of very small animals (such as house dust mites). injected materials: insect venom, vaccines, drugs, therapeutic proteins ingested materials: food (peanut), orally administered drugs
do contacted materials such as plant leaves, industrial products, synthetic chemicals in industrial products, and metals induce allergic reactions?
no, they induce delayed hypersensitivity, (type IV)
what are common properties of allergens?
relatively small, stabile, highly soluble, often carried on dessicated particles, (easily eluted and diffused at mucus membrane). often proteins, (proteases) that favor activation of IL-4 producing CD4 cells/bind MHC class II
once an allergen binds to the mucosal lining of the host, how does it start activation of a type 1 hypersensitivity response?
B cells interact with the allergen and process and present antigen to a TH2 CD4 cell. they also undergo class switching, and become IgE producing B cells.
once the B cells have switched to IgE and started secreting IgE, how does it get to mast cells?
mast cells bind IgE via their Fc receptor epsilon and “arms the mast cell”
what happens when mast cells have been armed by binding to IgE?
they degranulate, releaseing vasoactive amines and lipid mediators which have an immediate effect, and cytokines which have a delayed (2-24 hrs) effect, -> biphasic response
what is the first step in priming for an type I hypersensitivity reaction? what happens to TH0 cells?
the allergen is presented to TH2 cells by APCs, (dendritic cells). processing is possibly enhanced by proteolytic acitivity of the enzyme. TH0 cells diferentiate into TH2 cells, process which is promoted by IL-4, (made from activated mast cells or other TH2 cells)
what happens when TH2 cells secrete IL-4? what other cytokines are produced?
IL-4 favors Ig class switching to IgE and stimulates TH2 differentiation. IL-5 is produced, which activates eosinophils, and IL-6,10 and IL-13 (which promotes IgE/mucus production) are also produced by TH2 cells
what did type I hypersensitivity reactions evolve to fight?
parasitic infections
once B cells (class-switched to IgE by IL-4) start producing IgE where does it go? what can the individual be considered now?
IgE binds to the Fc receptor epsilon on mast cells and other cell including basophils. the individual can now be considered “sensitized” (if this is the first interaction, nothing happens)
if the individual has already been sensitized to an antigen, what happens at the mast cell when it is bound to the FcR epsilon?
cross-linking of the surface bound IgE, sending a signal for the cell to degranulate: immediate reaction, and start denovo synthesis of other cytokines: late rxn
what are the 3 major systems in the body affected by mast cell activation and granule release?
GI, airways, and blood vessels
what is the reaction in the GI due to a type I hypersensitivity reaction?
increased fluid secretions, increased peristalsis: expulsion of GI tract contents, (diarrhea, vomiting) – this evolved as a way to get rid of worms
what is the reaction in the airway due to a type I hypersensitivity reaction?
bronchoconstriction, mucus production: congestion/blockage of airways, (wheezing, coughing, phlegm), and swelling/mucus secretion in nasal passages
what is the reaction in the blood vessels due to a type I hypersensitivity reaction?
increased blood flow, increased permeability: increased fluid in tissues causing increased flow of lymph to lymph nodes, increased cells and protein in tissues. also increased effector response in tissues.
what are the mast cell granule contents? what is the response?
histamine, proteases, chemotactic factors such as ECF/NCF; these lead to the immediate reaction of vasodilation, vascular leakage and smooth muscle spasms
what are membrane phospholipids released in mast cell response to IgE?
arachidonic acid (becomes prostaglandins & leukotrienes), PAF; these lead to the immediate reaction of vasodilation, vascular leakage and smooth muscle spasms
what is the action of delayed secreted cytokines from mast cells?
leukocyte infiltration, epithelial damage, and bronchospasm
what do lipid mediators such as PAF, PGD, and LTC released from the mast cell granule do?
bronchoconstriction, intestinal hypermobility in the immediate phase, and inflammation in the late phase
what do the enzymes (typtase), released from the mast cell granule in the late phase response do?
tissue damage
what do cytokines like TNF alpha released from the mast cell granule in the late phase do?
cause inflammation
what do cationic granule proteins/enzymes released from eosinophils do when stimulated by IgE?
kill parasites/host cells
what does histamine, (vasoactive amine) bind to? what does it do?
histamine binds to H1-3, with H1 being the most important in allergic responses. it causes smooth muscle to contract, it causes increased vascular permeability and inflammation by acting on the blood vessel endothelium, and causes mucus production in the epithelium of the mucosa
what are heparin, chondroitin sulfate, enzymes, and TNF-alpa?
other first wave mediators released from mast cell granules.
what does heparin do?
acts as an anti-coagulant
what do the enzymes do released in the first wave of mediators from mast cell granules?
these are mostly neutral proteases and acid hydrolases that cause tissue damage; lead to the production of kinins and activated complement components (such as C3a)
what does TNF-alpha do when released in the first wave of mediators from mast cell granules? what is special about mast cells?
mast cells are only cells that can store TNF-a. they act in concert with histamine and activate endothelial cells. TNF-alpha also increases expression of adhesion molecules
what are the second wave of mediators released from mast cells after being synthesized de novo?
chemokines, cytokines IL-4, TNF-alpha, and prostaglandin D2 -> which is the most abundant mediator produced in mast cells by the COX pathway. it promotes dilation and increased vascular permeability, and enhanced mucus secretion. it can also induce intense bronchospasms and is a chemoattractant for neutrophils
how do leukotrienes C4 and D4 compare to histamine? what do they do?
they are the most potent and spasmotic agents known, they activate similar to histamine, but are about 100-1000x more potent. they cause inflammation, smooth muscle contraction, airway constriction, and mucus secretion. (target of sinulair)
what does leukotrience B4 do?
it is highly chemotactic for neutrophils, eosinophils and monocytes
is there a genetic correlation with hypersensitivity?
yes. 1 hypersensitive parent increases risk to 25%, 2 parents = 50% risk. the genes affected include those coding for essenatial immune system components like MHC class II genes etc
of TH1+2, which type works better with type I hypersensitivity reactions?
TH2, b/c they produce IL-4, which induces B cell class switching to IgE. TH2 cells also make IL-5 which activates eosinophils. TH1 cells just help macrophages opsonize (via IFN-gamma/IL-12)
what cytokines is the allergic rxn favored by?
IL-4, not INF-gamma/IL-12
what is perioral exzematous/atopic dermatitis often associated with in children?
a food allergy
what are urticaria?
hives, a dermatologic manifestaion of an allergic reaction
in anaphylaxis, what happens to the heart and vascular system?
increased capillary permability and entry of fluid into the tissues including the tounge. loss of blood pressure, reduced O2 to tissue. irregular heartbeat, anaphylactic shock and loss of consciousness.
in anaphylaxis, what happens to the respiratory tract?
contraction of smooth muscle and constriction of throat and airways. difficulty breathing and swallowing as well as wheezing
in anaphylaxis, what happens to the GI tract?
contraction of smooth muscle, stomach cramps, vomiting, fluid outflow into gut, diarrhea