Hypersensitivity - Type I Flashcards
What are the principal cells and antibodies that mediate Type I Hypersensitivity?
APC w/ allergen on MHC-II and B7 costim bind to Naive CD4+ cell’s CD4 and CD28—>IL-4 floatin’ around—>maturation into Th2-cell—>induce B-cell (plasma cell) class ∆ing—>”IgE (usually); other immunoglobulins e.g. IgG4
Which Hypsensitivity Types are Ab-mediated? Which are cell-mediated?
I, II and III are Ab-mediated. IV is cell-mediated
Define atopy
presence of specific IgE directed against environmental allergens
Name 3 majors processes in anaphylaxis
dilation and leakage of post-capillary venules (causing edema, life-threatening hypotension and cardiovascular collapse) and constriction of airway smooth muscles, (bronchoconstriction, which can result in hypoxia and death).
Contrast first and second exposures in Type 1.
First exposure = sensitization where IgE “arms” the FcER1 receptors and basophils and mast cells.
2nd exposure: allergen cross-links these and causes release of immediate hypersensitivity mediators
Define mast cell role in Type 1
releases granules full of mediators when allergens bind the allergen-specific IgEs that are residing in its FcεR1 receptors
histamine
most common vasoactive amine; stored in granules of mast cells and basophils; causes increase vasc permeability, (Abbas: also vasodilation), SMM constriction and incr mucous prod in goblet cells, via H1 receptors.
increases gastric secretions via H2 receptors (target of some heartburn meds!)
basophil
Orig. in marrow and circulate in blood responding to chemotactic stim.; have FcεR1 receptors; release mediators
IgE
Ab that mediates Type I; plasma [IgE] incr in atopic individuals; made predom. in GI and resp. epith. plasma cells; binds FcεR1 on: mast cells, eosinophils, basophils, lymphocytes and monocytes; dunno what it’s for totally, think defense against helminthes and some protozoans
you only need tiny bit (10^-10 IgEs will sat. 1/2 all FcεR1s)
FcεR
receptor for IgE; found on mast cells, eosinophils, basophils, lymphocytes and monocytes
prostaglandin D2
lipid mediator that causes periph. vasodilation, coronary vasoconstriction, bronchoconstriction, inhibits platelet agg, and attracts neutrophils; made in response to cross-linking of IgE in FcεR on surface of ?basophils and ?mast cells
allergen
an antigen that causes a Type I hypersensitivity rxn in an atopic pt.
hyposensitization
(a.k.a. immunotherapy) tx for atopic pts; give grad. incr. doses of allergen either subQ or SL; idea: will incr IgG and IgA to allergen
lekotriene
lipid mediator (from arachadonic acid 1°ly): bronchoconstr., vasodilator and incr vasc perm —> edema; incr mucous, constriction coronary and cerebral aa., decr contractility and incr gastric acidity
sensitization
initial exposure to allergen that causes initial generation of IgE against allergen and then coating of FcεR-bearing cells with that IgE
anaphylaxis
a severe, whole-body allergic reaction resulting from the sudden release of mast cell- and basophil-
2
derived mediators into the circulation
LTB4
Leukotriene B4: Binding to a different receptor from SRS-A, LTB4 causes neutrophil
chemotaxis, adhesion of neutrophils to endothelium of post capillary venules, and neutrophil degranulation. LTB4 also induces leakage of post capillary venules, leading to edema.
SRS-A
Slow Reacting Substance of Anaphylaxis (SRS-A): SRS-A is an older name for the cysteinyl-leukotrienes (LTC4, LTD4, LTE4).
describe the time course and clinical consequences of Type I hypersensitivity reactions.
- Sensitization
- 2nd exposure:
—initial rxn (few mins.) = Immediate Hypersens. (e.g. anaphylaxis)
——caused by pre-formed mediators in granules
—later (6-24hrs) = Late Phase Rxn: cytokines attract leukocytes in inflamm.
——caused by newly-formed gene products (cytokines) and lipid metabolites (prostaglandins and leukotrienes)
allergic rhinitis, bronchial asthma, urticaria, GI allergy, and anaphylaxis 2° to drugs, foods and venoms.
–anaphylaxis is the prototype reaction. occurs after prior sensitization; obvious within mins. in a sensitized individual. small amt of antigen can elicit deadly response.
pathophys ∆s include mast cell degranulation, infiltration of eosinophils and neutrophils, contraction of smooth muscle, increased vascular permeability and finally, infiltration of mononuclear cells.
Clinical symptoms may involve:
a) skin: pruritis (itching); edema (swelling); wheal and flare (raised skin with radiating redness) = urticaria (hives).
b) Pulm: bronchospasm, mucosal edema with airway obstruction, laryngeal edema.
c) Cor: hypotension, arrhythmias, cardiovascular collapse
d) GI: cramps, vomiting, diarrhea.
hypersensitivity
inflammation due to an exaggerated, inappropriate or ineffective immune response to antigens that, in the absence of immunity, are usually innocuous (eg. pollen)
Txs to inhibit mediator action
- H1 antagonists (e.g. diphenhydramine, chlortrimeton) work for sneezing, rhinorrhea, itchy eyes
- leukotriene receptor antagonists (motelukast) or antibody to IgE for chronic asthma and syst. anaphyl.
- epi and long-acting beta2 recept. agonists (e.g. salmeterol) for bronchospasm and hypotension
Txs to inhibit inflamm. mediator production
glucocorticoids (e.g.dexamethasone, beclomethasone, and fluticasone) = potent inhibitors of inflamm. cytokine prod.; inhibit leukotriene synthesis
cromolyn blocks hist release
ziletuon blocks leukotriene synth
Omalizumab (Xolair) = Anti-IgE subQ
SCIT/SLIT Mechanism
subQ or SL immunotherapy works by hyposensitization; increase Treg and Th1 proliferation
explain genetic and environmental factors that influence predisposition to allergy
air pollution, water pollution, pesticides, C-section, bottle feeding, hygiene hypoth
genetic: female sex (auto-imm more common in females); heredity (concordance: DZ twins = ~35% MZ = ~55%)
CLICKER QUESTION:
IgE that is bound to a mast cell in a person with type I hypersensitivity is most likely to be…
A) monospecific B) monoclonal C) polyclonal D) complement-activating E) mono-allotypic
correct answer: C; the only time you would have monoclonal antibodies in your body would be if you had (cancerous) myeloma in which you have a clonal expansion of a single B cell
What critical cell type, CD molecule and cytokine favor the production of IgE rather than IgG?
B-cell’s CD40 interacts w/ TH2’s CD40L (a.k.a. CD154, wtf immunologists) —> TH2 releases IL-4 —> B-cell class ∆ing to IgE
Why bother with IgE at all?
(we think) to kill helminths, schistosomes, etc. via ADCC (Ab-dependent cellular cytotoxicity): opsonization w/ IgE binds high-affininty FcεR1 on eosinophil
T/F?: Chocolate consumption increases the likelihood of winning the Nobel Prize?
Likely true; high correlation. =)
