Transcript IgE Hypersensitivity

Keri Csencsits Smith
Department of Pathology and Laboratory Medicine
University of Texas Health Science Center at Houston Medical School
May 25, 2009
[email protected]
Hypersensitivity
 Broad-spectrum inflammatory response that results in
significant tissue injury, serious disease, or death
 Not necessarily an increased response, rather, an
inappropriate response to an antigen.
 Hypersensitivity reactions are divided into 4 types
1913 Nobel Prize
 Portier and Richet
 Coined the term
“anaphylaxis”
Portuguese Man O’War
Booster shot
X
The 4 Types of Hypersensitivity
Response
Type I
IgE mediated
hypersensitivity
Ag induces cross-linking of IgE
bound to mast cells and
basophils – release of vasoactive
mediators
Systemic anaphylaxis,
hay fever, asthma,
hives, food allergies,
eczema
Type II
IgG or IgM mediated
cytotoxic
hypersensitivity
Ab directed against cell surface
antigens mediates cell destrcution
via C’ activation or ADCC
Blood transfusion
reactions,
erythroblastosis fetalis,
autoimmune hemolytic
anemia
Type III
Immune complex
mediated
hypersensitivity
Ag-Ab complexes deposited in
tissues induce complement
activation and ensuing
inflammatory response mediated by
massive infiltration of neutrophils
Arthus reaction, serum
sickness, necrotizing
vasculitis,
glomerulonephrits
rheumatoid arthritis,
SLE
Type IV
Cell mediated
hypersensitivity
Sensitized Th cells release cytokines
that activate macrophages or
cytotoxic T cells that mediate
cellular damage
Contact dermatitis,
tubercular lesions, graft
rejection
Type 1 response (the beginning)
 Induced by Allergens
 (nonparasitic antigens antigens capable of stimulating
type I hypersensitivity reactions)
 Distinguished by the secretion of IgE
Overview of IgE-mediated allergic response
What leads to
IgE response?
 Inhaled small protein
allergens
 Low-dose
 Mucosal route of entry
Some enzymes are triggers of allergy
Dust mite cysteine protease Der p 1
Class switching to IgE
•Remember, this is Th2
mediated
•IL-4 is the hallmark Th2
cytokine
•IL-13 associated with allergic
response
Amplification of IgE response
Mast cells orchestrate allergic reactions
Signaling through the FceR1
Gilfillan et al. Nature Reviews Immunology 6, 218-230 (March 2006) | doi:10.1038/nri1782
Consequences of
mast cell
stimulation
Molecules released by mast cells on activation
Effects of mast cell degranulation
9
,
9-13 (January 2009) |
doi:10.1038/nri2458
Don’t forget about basophils!
Karasuyama, et al
9, 9-13 (January 2009) | doi:10.1038/nri2458
The usual sequence of events in an
allergic reaction is as follows:
A. The allergen combines with circulating IgE, then IgE
allergen complex binds to mast cells
B. The allergen binds to IgE fixed to mast cells
C. The allergen is processed by APCs and then binds to
histamine receptors
D. The allergen is processed by APCs and then binds to mast
cells
E. The allergen combines with IgG
B: IgE binds passively to cells expressing high affinity Fc
receptors for IgE, then interacts with the allergen when
present. The result is mast cell degranulation.
A human volunteer agrees to be passively sensitized for IgE specific for a
ragweed antigen. When challenged with the allergen intradermally, he
displayed a typical skin reaction due to an immediate hypersensitivity
reaction. If the injection with sensitizing IgE was preceded by an injection (at
the same site) of Fc fragments of human IgE, followed by intradermal injection
with allergen, which of the following outcomes would you predict?
A. No reaction would occur because the Fc fragments would interact
with the allergen and prevent it from gaining access to the sensitized
mast cells.
B. No reaction would occur because the Fc fragments would interact
with the IgE antibodies, making their ag-binding sites unavailable.
C. No reaction would occur because the Fc fragments would interact
with the FceR receptors on mast cells
D. The reaction would be exacerbated due to increased local
concentration of IgE Fc fragments
E. The reaction would be exacerbated due to the activation of
complement
C: The soluble Fc fragments would saturate the FceRs, and the
allergen specific IgE could not bind to the mast cells.
Phases of the allergic reaction
 Immediate
 Within seconds
 Due to activity of histamines, prostaglandins and the
resulting rapid increase in vascular permeability and
contraction of smooth muscle
 Late-phase
 8-12 hours later
 Caused by induced synthesis and release of leukotrienes,
chemokines, cytokines from activated mast cells
 Induces mucosal edema, mucus secretion, leukocyte
infiltration, epithelial damage, bronchospasm
 Responsible for the most serious long -term illness
Asthma
Wheal-and-flare
Immediate and
late-phase allergic
reactions
Response depends on route of entry
and location of mast cells
Chronic inflammation
 IL-5 increases production
of eosinophils, eotaxin
causes them to migrate
 Characterized by influx of
eosinophils and effector T
cells (usually Th2 cytokine
secreting)
 Persistence of antigen
drives further IgE
secretion and eosinophilia
Eosinophil biology section - NIAID
Inflammatory mediators secreted by eosinophils
Consequences of IgE Hypersensitivity
 Hay fever
 (Allergic rhinitis)
 Increase in capillary permeability and localized vasodilation
 Food allergies
 Smooth muscle contraction and vasodilation leads to diarrhea
and vomiting
 Wheal and flare (hives) in skin
 Allergic dematitis
 Inflammatory cytokines cause influx of cells and
development of skin lesions
 Atopic children often develop prolonged inflammatory
response and a persistent skin rash (eczema)
Allergic dermatitis
More Consequences of IgE
Hypersensitivity
 Asthma
 Events are:



Reversible airway obstruction
Augmented bronchial responsiveness
Inflammation
 Cytokine induced recruitment of inflammatory cells,
particularly eosinophils
 Cells release oxygen radicals, nitric oxide, cytokines
 Leads to development of mucus, edema, sloughing of
epithelium
Asthma
Pathology of allergic asthma
Occlusion of airway by mucus plug
Inflammatory infiltrate of
epithelium
Really bad consequences of IgE
hypersensitivity
 Systemic anaphylaxis
 Can lead to anaphylactic shock
 Widespread increase in vascular permeability leads to
catastrophic loss of blood pressure
 Airways constrict
 Epiglottis swells
 Usually in response to quick absorption of allergen from
the gut (peanuts, brazil nuts), or direct introduction
into bloodstream (i.v. drug administration, insect bite)
Kiss of death
Factors that contribute to IgE
mediated allergy
 Genetic
 Atopy: the tendency to mount IgE responses to a wide
variety of common environmental allergens
 As many as 40% in Western populations
 Environmental
 Exposure to infectious disease in early childhood
 Exposure to bacteria in early childhood
 Pollution
 Allergen levels
 Diet
Genetic factors
Genetic factors
“The Hygeine Hypothesis”
 “Dirty” kids have fewer allergies
 Growing up on a farm (1999, 2000)
 Attended day care (2003)
 Pet ownership (1999)
 Lower standard of living (East vs. West Germans, 2002)*
 Role of bacterial products
 Exposure to tuberculosis
 Endotoxin exposure
 Role of the innate immune system?
 PAMPS bind PRR on APC
Toll-like receptors
Signaling through TLR expressed dendritic cells up-regulates Th1 cytokines and responses
Increasing Th1 response prevents
IgE hypersensitivity
So why do we have IgE responses?
Killing of parasitic worms
Treatment of IgE Hypersensitivity
 In use:
 Desensitization – increasing doses of antigen drive Th1
response
 Antihistamines – block histamine H1 receptor (on blood
vessels and on unmyelinated nerve fibers)
 Bronchodilators – act on b-adrenergic receptors, relax
constricted muscles
 Topical or systemic corticosteroids - reduce inflammation
 Epinephrine – stimulates reformation of endothelial tight
junctions, promotes, muscle relaxation, stimulates heart
 Omalizimab (anti-IgE monoclonal antibody)
Treatment of IgE hypersensitivity
 Experimental
 Vaccination – use peptides derived from common
allergens, may induce T cell anergy
 CpG adjuvants – promote Th1 responses
 Inhibit IL-4, IL-5, IL-13
 Give IFNg or IFNa
 Block IgeR1 binding – IgE Fc construct
 Block recruitment of eosinophils (anti CCR3)