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