Hypersensitivity refers to diseases caused
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Transcript of Hypersensitivity refers to diseases caused
Hypersensitivity refers to diseases causedby an immune response:
regardless whether the response is againsta pathogen, non-pathogen or self;
regardless whether the response is directed byantibodies, lymphocytes or innate pathways.
Hypersensitivity
Four types of immune-mediated hypersensitivity reactions causing tissue damage
A 65 y/o collapsed 20 minutes after a penicillin injection.
PI: One day prior to admission ~ sore throat and fever. On the morning of admission ~ MD prescribed penicillin injection. 10-15 min after injection weak and diaphoretic, dyspnea, chest pain and slid to the ground.
PMH: coronary artery disease. No allergic rhinitis, asthma or dermatitis. Received penicillin 4x in the past for respiratory infections without adverse reaction until the last time → urticaria that resolved spontaneously.
ER: ashen in appearance; cold, clammy skin; tachycardia (160); hypotensive (systolic BP 50); labored respiration with wheezing.
Rx: epinephrine SQ, IV fluids and diphenhydramine. Within 20 minutes BP, P & R improved. Additional Rx: diphenhydramine; oral prednisone. ECG (electrocardiogram) ~ new T-wave inversions ~ small MI. Uncomplicated post-MI course.
5 days later: negative allergy skin tests to penicillin.
CASE 15
(1) Was penicillin appropriate?
(2) Immunological events leading to this reaction? Why no reaction to initial penicillin?
(3) Which therapeutic agent (Benadryl, prednisone, epinephrine, fluids) was critical in saving her life? Should prednisone have been given earlier?
(4) Were any other allergic reactions apt to occur after the first day?
(5) Why were skin tests negative?
(6) If the patient later needed penicillin, could she receive it?
(7) What is urticaria and how did it develop?
Case 15 Questions
IgE productionarm
mast cells
triggermediatorrelease
clinical effects
Development of Immediate HypersensitivityDevelopment of Immediate Hypersensitivity
TH0→2
B/→
APCDC v Bas
v NKT
AnaphylaxisAnaphylaxisHives/DermatitisHives/DermatitisAsthma/RhinitisAsthma/RhinitisConjunctivitisConjunctivitis
processing
presentation
help
IL-4
IL-4/13
IL-13/CD40L
Nat.Immunol 9:310-318, 2008.
Response to an Allergen Challenge
skinlung
HistamineHeparinTryptase
LTC4 & PGD2
MC CytokinesBasophils
EosinophilsTH2 Lymphocytes
IgE-Mediated Allergic ReactionsIgE-Mediated Allergic ReactionsSyndrome Common Allergens Route of Entry Response
SystemicSystemicAnaphylaxisAnaphylaxis
DrugsVenomsFoods
Parenteralor
Oral
EdemaVasopermeabilityLaryngeal edema
ShockDeath
Acute UrticariaAcute Urticaria(wheal & flare)(wheal & flare)
Insect stingsAllergy testing Subcutaneous
Local increasedvasopermeability
& blood flow
Allergic RhinitsAllergic Rhinits(hay fever)(hay fever)
Pollens, animaldust mites,
mold, cockroachInhaled
Nasal congestion,rhinorrhea, itch
& sneeze
AsthmaAsthma InhaledPollens, animal
dust mites,mold, cockroach
Bronchospasm,mucus, inflammation
& remodeling
Food AllergyFood Allergy OralShellfish, tree nuts,
Peanuts, Milk, Eggs, Fish, Wheat
Nausea, vomiting,diarrhea, cramps,
urticaria, asthma &anaphylaxis
Features of inhaled allergens that may promote the Features of inhaled allergens that may promote the priming of Tpriming of THH2 cells that drive IgE responses2 cells that drive IgE responses
ProteinProtein(rarely carbohydrate)(rarely carbohydrate)
Proteins induceT-cell response
EnzymeEnzyme Some are proteases
Low doseLow dose Favors activation ofIL-4-producing T cells
Low mw proteins,Low mw proteins,High solubilityHigh solubility
Diffuses off particle,into mucus
StableStable Survival after dessication
Peptides bind MHCIIPeptides bind MHCII Needed for T cell priming
2008 Mar 13;358(11):1109-17
DerP2 allergenicity results from functional mimicry of a Toll-like receptor 4 complex proteinDivanovic et al. Nature 457:585-588, 2009
LPS:MD2MD2:CD14 TLR4 →
LPS:DerP2DerP2:CD14 ← TLR4(TLR4-dependent, MD2-independent)
Allergic Lung Inflammation
TLR4+ TLR4-
Pollens
Dust MiteDust Mite
Proteolytic Allergens Permeabilize Proteolytic Allergens Permeabilize Epithelial Tight JunctionsEpithelial Tight Junctions
IgE production is amplified following ligationby antigen of IgE bound to mast cells
IgE secreted by plasma cells binds to ahigh-affinity Fc receptoron mast cells & basophils
Activated mast cells provide contact and secreted signals to B cells
to stimulate IgE production
↑IgE → ↑FcεRI → ↑ activation, survival, proliferationPositive Feedback Loop
Th2 Th2 Development Development
is Stat6-is Stat6-dependentdependent
Gene Nature of Polymorphism Possible mechanism of association
IL-4 promoter variant variation in IL-4 expression
IL-4R structural variant increase signaling to IL-4
MHC II structural variant enhanced allergen peptide presentation
TCR microsatellite markers enhanced T cell response to allergens
TIM Genes promotor/structural TH1/TH2 balance
FcεRIβ structural variant variation in signaling via IgE
5-lipoxygenase promoter variants enhanced leukotriene production
2-AR structural variants β2 bronchodilator intolerance
Filaggrin skin barrier deficiency, atopic dermatitis
Susceptibility Genes for Asthma & AtopySusceptibility Genes for Asthma & Atopy
Genes & Environment Genes & Environment ~ Atopy~ Atopy
AllergiesAllergiesAllergiesAllergies
Still Th2Still Th2Still Th2Still Th2
Only childOnly childOnly childOnly childFew infectionsFew infectionsFew infectionsFew infections
No allergiesNo allergiesNo allergiesNo allergies
Th1Th1Th1Th1
Older sibsOlder sibsOlder sibsOlder sibs
Many infectionsMany infections(Th1 stimuli)(Th1 stimuli)
Many infectionsMany infections(Th1 stimuli)(Th1 stimuli)
The Hygiene HypothesisThe Hygiene Hypothesis
β
α
γ2
IgE
FcεRIFcεRITetramer (trimer)1010M Kd α:IgEβ amplifiesγ transduces
IgE4 Constant domains (175 kDa)<250 ng/ml (16x1010 M) (vs IgG 10 mg/ml)Circulation t½ ~ 2 daysHeat-labile Fcε
IgE:FcIgE:FcεεRIRI
IgG-mediatedHypersensitivity
ImmediateHypersensitivity
Cell-mediatedHypersensitivity
Immunity
BacteriaParasites
Viruses
TransplantTolerance
VenomDetoxification
Biologic Fibrosis/FibrolysisVasopermeabilitySmooth muscle contractilityAngiogenesisAnti-coagulation/ thrombosis
MCMCTT & MC & MCTCTC Cells ~ Developmentally & Cells ~ Developmentally &
Functionally Distinct Types of Mast CellsFunctionally Distinct Types of Mast Cells
• MCT
– TTryptase
• MCTC
– TTryptase– CChymase– Carboxypeptidase– Cathepsin G– CD88
Progenitor
SCF+??
SCF
Mast Cell (committed) progenitor
• BasophilIL-3
Bone Marrow
Circulation
Tissue
• EosinophilIL-5
MC
Anti-Tryptase Immunocytochemistry & Anti-Tryptase Immunocytochemistry & Immunogold Electron MicroscopyImmunogold Electron Microscopy
anti-tryptase ~ 5 nm gold
anti-chymase ~ 15 nm gold
MCMCTT MCMCTCTC
Tryptase+/Chymase-MCT
Tryptase+/Chymase+MCTC
Resting Mast Cell Activated Mast Cell
±±FcFcRI-Mediated Activation of Mast RI-Mediated Activation of Mast CellsCells
YY YY YYYY
YYAnti-Ig
E (Fc
)
YY
Anti-FcRI
MultivalentAntigen
C3aC5a
CD88CD88
MCT/TC
MCTC
Substance PNeurokinin A
CGRPMorphine/Codeine
VancomycinMajor
Basic Protein
Anti-Fcblocking Ab
Y Y YUnivalent Ag
IgE
Cell Activation/Proliferation epithelial cells smooth muscle endothelial cells fibroblasts endothelial cells
HistaminePGD2
LTC4
Tryptase/ChymaseCytokines TNFα IL-13 IL-4 IL-5, 6Chemokines IL-8 MIP-1, MCP-1Growth factors bFGF, VEGF, TGFβ amphiregulinHeparin
MediatorsMediators
Bronchospasm hyperreactive
IgE
Edema
Inflammation
Neurogenic
Tissue Remodeling
Mucus
Anticoagulation/Antithrombotic