Immunoglobulin E: immunobiology and clinical significance

Immunoglobulin E: Immunobiology
and Clinical Significance
KULLAPORNPAS BENYAJIRAPACH, MD
20TH SEPTEMBER 2019

Immunobiology of
IgE and IgE Receptors
History
IgE VS Parasite
Sites of IgE Production
IgE Structure & Mechanism of
Isotype Switching
IgE Receptors (FcRI, CD23)

Hans C. Oettgen. Middleton’s Allergy. 8th Ed.;2013:364-77.
Introduction
IgE is unique among immunoglobulin isotypes
● Induce very rapid biologic responses
● Extremely sensitive immunologic amplifier, triggering reactions on exposure
to minute quantities of antigen
● IgE receptors: FcεRI and CD23
● Effector cell lineages: mast cells and basophils
● Immune response: controlling infestation with helminths in parasite-
endemic regions
● Occurs in individuals with atopic conditions of eczema, allergic rhinitis, and
asthma

Introduction
IgE functions:
● Triggering acute allergic reactions
● Immune homeostasis
● IgE antibodies regulate IgE receptor expression
● Enhance allergen uptake by antigen-presenting cells
● Modulate mast cell survival, and facilitate antigen transport across intestinal
and respiratory epithelia

Philip H. Smith, et al. Middleton’s Allergy. 8th Ed.;2013:1108-18.
Introduction
• Of the five isotypes, IgE present in the smallest quantity (0.002% of circulating
immunoglobulins)
• Serum concentrations of IgE - nanograms (ng) or international units (IU) per
volume of serum (e.g., IU/mL, kIU/L)
1 IU is equal to 2.44 ng of protein
• IgE has highest affinity for antigens and its receptors
• Even low (ng/mL) concentrations of cell surface IgE can cause life-threatening
reactions by tremendous biologic amplification of IgE and its receptors

Diane F. Jelinek, et al. Middleton’s Allergy. 8th Ed.;2013:39.

History
• In 1921, when Heinz Küstner’s serum (who had been highly allergic to fish) was
injected into Otto Prausnitz’s skin, the immediate sensitivity to fish was
transferred to the site “Prausnitz-Küstner (PK) reaction”
• A serum component was responsible for passively transferring the specific
sensitivity
• Substance = reagin
• Sera containing reagins = reaginic
• Local injection of serum could sensitize skin
for 2 weeks or more  reagins must be
binding to high-affinity receptor
T.A.E. Platts-Mills. Ann Allergy Asthma Immunol 2019;122:2−7.

History
• In 1968, revealed a new immunoglobulin class and the name IgE (E for
“erythema”) by Ishizakas in the United States, Bennich and Johansson in
Sweden, and Stanworth in England
Toshiaki K. et al. The Journal of Immunology 2016;197: 4187-92.

IgE in Parasitic Immunity
• Presence of high IgE levels in populations residing in helminth-endemic regions
• IgE - controlling the host-parasite interaction
• IgE could opsonize Schistosoma mansoni for killing by human eosinophils and
even platelets, enhances granuloma formation in the liver while assisting in the
clearance of adult worms
• IgE accelerates the removal of adult Trichinella spiralis worms from the intestine
and mediates the destruction of tissue cysts

Generation of high-affinity IgG responses and B cell memory is dependent on the
germinal center reaction in secondary lymphoid tissues
1. DCs (in respiratory, GI mucosa, skin) first recognize antigens
2. DCs express IgE receptors FcεRI and CD23, allergen uptake is facilitated in
the presence of specific IgE antibodies
3. Activated DCs display increased MHC class II molecules and express
chemokine receptor CCR7  regional lymph nodes
4. In lymph nodes, B cells in follicles engage & interact with activated T cells (by
DCs)  activation of IL-4 and IL-4R, and CD40L (CD154)–CD40 signaling 
germinal center formation - - - specialized follicular T helper (TFH) cells
(CXCR5+ and ICOS+) and Th2–like TFH cells help for IgE responses

5. In germinal centers, B cells expand and are induced to activate somatic
hypermutation  AID–dependent genetic process
6. B cell clones which these mutations confer higher antigen affinity are
selectively expanded  affinity maturation
7. Specific cytokine and costimulatory signals drive isotype switching in the
germinal centers
IgE can be produced especially in mucosal-associated lymphoid tissues (e.g.,
Waldeyer tonsillar ring)

• Evidence of IgE switching in the mucosa: detection of IL-4, CD40L, BAFF,
AID, ε-germline transcripts, switch excision circles, and IgE+ plasma cells at
mucosa
• Some of this tissue IgE switching may actually be T cell-independent
• Increased IgE levels in patients with T cell deficiencies
• Bacterial superantigens encountered at mucosal surfaces - help drive IgE+ B
cell expansion

IgE Structure and Mechanisms of IgE
Isotype Switching
• Serum concentration of IgE
in normal individuals: 50-100
ng/mL (IgG: 5-10 mg/mL)
• Very short half-life (1-5 days)
in circulation - small number
of B cells committed to IgE
synthesis and by its localized
production at tissue sites
(bound to FcεRI on mast cells
and persist for months)

Regulation of IgE Synthesis:
Cellular Interactions and Secreted Signals

Molecular Events in IgE Isotype Switching

FcεRI, the High-Affinity IgE Receptor
• Majority of the systemic pool of IgE exists already tightly affixed
to effector cells in tissues by IgE receptors
Two forms of FcεRI:
• Tetrameric αβγ2 - on mast cells and basophils  immediate
hypersensitivity
• Trimeric αγ2 - on Langerhans cells of skin and several DCs
(eosinophils, neutrophils, platelets, and epithelial cells of the
gastrointestinal and respiratory systems)  FcεRI-mediated
antigen uptake by APCs
• FcεRI α chain - IgE binding
• FcεRI γ chain - signal transduction, contains tandem repeats
ITAMs, targets for phosphorylation by receptor-associated
tyrosine kinases
• FcεRI β chain - contains ITAMs and serve as chaperone for α
chain and amplify early events in FcεRI signaling

FcεRI Signaling Pathways

Negative Feedback in FcεRI Signaling
• Inhibitory mechanisms are triggered in parallel with activating pathways
• Downstream of kinase (DOK) family of proteins assemble to recruit inhibitory
elements, including RAS-GAP, (an RAS GTPase), SHIP-1 (SH2 inositol 5′-
phosphatase), and CSK (cSRC tyrosine kinase), which phosphorylates the
inhibitory/regulatory site on LYN and other SRC-family kinases

Soluble FcεRI
• Circulating soluble form of FcεRI-α (sFcεRI, about 40 kD)
• Which cell types releasing soluble receptor? and conditions leading to release?
• Functions of sFcεRI-α: block mast cell and basophil activation  potential
functions in downregulation of allergic responses

Antigen-Independent
IgE-Mediated FcεRI Activation
• FcεRI occupied by IgE = a “loaded gun” ready to fire but inert before
allergen encounter
• In some circumstances FcεRI occupied by IgE - sufficient to induce signaling
events and stimulate cytokine release by mast cells = “cytokinergic”

IgE-Independent Immediate Hypersensitivity
• Animal models: IgE-independent  IgG-mediated immediate hypersensitivity
• IgG1 can mediate anaphylaxis in mice through both mast cells and mast cell–
independent pathways
• Requires IgG receptor FcγRIII, IgG and FcγRIII - so much weaker than IgE and
FcεRI that concentrations of IgG and antigen required for IgE-independent
anaphylaxis are not normally observed outside the lab

IgE Levels Regulate FCεRI
• Binding of IgE to FcεR1 stabilizes the receptor, preventing internalization and
protease degradation
• Depletion of circulating free IgE by treatment with anti-IgE therapeutic
omalizumab  decreased FcεRI levels on mast cells, basophils and DCs
• Anti-IgE therapy  significant reduction in FcεRI levels and  allergen sensitivity
of the effector cells of immediate hypersensitivity

IgE and Mast Cell Homeostasis
• IgE - modulate mast cell proliferation and survival
• Protects them from cell death by inducing expression of antiapoptotic factors
• IgE-FcεRI interactions provoke mast cell expansion

CD23, the Low-Affinity IgE Receptor
• CD23 - not a member of the Ig superfamily, instead belonging to C-type lectin family
• Each monomer consisting of a long extracellular α-helical coiled-coil stalk, which is
abundantly N-glycosylated, terminating in a globular head domain that binds to IgE
• Only oligomeric CD23 bind to IgE
• IgE-binding heads of CD23 can be cleaved by proteases, including allergens (e.g., Der
p 1 protease of dust mites) and endogenous ADAM family of proteases, ADAM8, -10,
and -33
• Liberated CD23 heads after cleaved, referred as soluble CD23 (sCD23), retain IgE-
binding capacity

CD23 expression stimulated by cytokines (IL-4, IL-5, IL-13, GM-CSF), CD40L
(CD154), and TLR ligands including lipopolysaccharide (LPS)
Functions:
• Facilitated uptake by various cell types and regulation of B cell function
• Mediating transport of antigen across epithelium (GI, respiratory) to basal surface
 gains access to APCs and lymphocytes (protects food allergens from
degradation before their interaction with mucosal immune cells)
• Regulate IgE synthesis and allergic inflammation:
• Engagement of membrane form of CD23 on B cells  suppresses IgE
production
• Alternatively, CD23 bind both IgE and CD21  IgE-inducing effect

Galectin-3 and Macrophage Activation
• Galectin-3: lectin-family pentameric secreted protein
• Present at cell surfaces, major source of secreted galectin-3 is macrophages
• Bind both to IgE and to FcεRI dependent on glycosylation state
• No specific functions to the IgE-FcεRI system, but present at sites of
inflammation and its potent ability to activate mast cells through FcεRI cross-
linking (regardless of IgE occupancy of receptor)  might exert important
functions in allergic pathogenesis

IgE Receptors
and Antigen-Presenting Cell Function
• Both FcεRI and CD23 are expressed on APCs and can mediate uptake of
allergen bound to IgE for processing and presentation to CD4+ Th cells
• Studies of cells in the skin of patients with atopic dermatitis: several FcεRI+ APC
populations, including Langerhans cells and inflammatory dendritic epidermal
cells
• FcεRI is highly upregulated on these cell types during allergic flares

Measurement of Immunoglobulin E
Total IgE
Allergen-Specific IgE

Jeff Stokes, et al. UpToDate 2019.
Total IgE
• Sandwich-type assay
• Anti-IgE antibody is bound to a solid support
• Serum from a patient is added
• Unbound protein washed away
• Second labeled anti-IgE antibody added, and amount bound to the patient's IgE is
measured
1 international unit/mL = 2.44 ng/mL

• First commercial assay for allergen-specific IgE = radioallergosorbent test (RAST)
• Bound allergen-specific IgE detected with radioiodinated polyclonal antihuman IgE
and quantified with a gamma counter
• Modern methods use enzymes instead of radionucleotides

• The terms "in vitro IgE antibody assay" or "allergen-specific IgE immunoassay"
more accurately characterize the three IgE antibody assays clinically available in
North America:
●The HYTEC-288 - colorimetric assay using a paper disc solid-phase support. It is
being replaced by the Falcon autoanalyzer
●The ImmunoCAP - fluoroimmunoassay with a cellulose sponge solid-phase
matrix
●The Immulite chemiluminescent assay - biotinylated allergen and avidin particle
solid phase
• These three autoanalyzers use extracts from different sources immobilized as the
antigen capture allergosorbent, their results are not interchangeable

Kleine-Tebbe et al. J Lab Med 2016; 40(2): 81–96.

Clinical Significance of Immunoglobulin E
Normal IgE Production
IgE in Allergic Disease
IgE in Infectious Disease
IgE in Non Atopic Disease
Environmental Exposure & IgE

Normal IgE Production
IgE concentrations can be altered by disease processes through 4
mechanisms:
1. Total serum IgE levels can reflect nonspecific changes in protein production
or catabolism
2. Total serum IgE concentrations can reflect the balance or overall regulation
of the immune system
3. In some diseases, factors specifically stimulate IgE production
4. Some diseases may result directly from the production of IgE antibodies
specific for certain allergens

Ontogeny of IgE Production
GA 7-10 weeks: Germline transcripts for the ε chain of IgE detectable
GA 11 weeks: IgE production observed in human fetal tissue cultures
GA 20 weeks: B cells primed to undergo class switching can produce IgE
• Limited IgE production apparently correlates with limited fetal antigenic
exposure
• <1% of cord serum samples contain detectable IgE antibodies to common
allergens
• Most studies failed to find fetal IgE production in the absence of maternal
production
• Serum IgE concentrations gradually increase after birth, reach maximum values
between the ages of 10-15 years, decline throughout adulthood

Philip H. Smith, et al. Middleton’s Allergy. 8th Ed.;2013:1108-18.Philip H. Smith, et al. Middleton’s Allergy. 8th Ed.;2013:1108-18.

Normal IgE Concentrations
• High upper limits of normal and broad overlap between IgE concentrations in atopic and
nonatopic people limit the diagnostic value of total serum IgE measurements for
detecting allergic disease
• Serum IgE levels influenced by age, genetic predisposition, race, immune status,
season of the year, medications, and some disease processes
• Racial factors - consistently higher IgE serum levels in blacks in all age groups, presumably
because of genetic differences and differences in environmental exposures
• Total serum IgE levels may vary twofold - fourfold annually in sensitive patients in pollen
seasons, reached maximum IgE at 4 to 6 weeks after peak of the pollen season, then
gradual decline until onset of next pollen season

• Most clinical assays for total IgE have a lower limit of detection of 2 to 5 IU/mL
• Concentrations of less than 2 IU/mL - reported as undetectable
• Undetectable concentrations of IgE might be related to autoimmune disease or
recurrent infections
Normal IgE Concentrations

IgE in Other Body Fluids
• Total and some allergen-specific IgE levels
• Nasal and bronchial washings, nasal polyp tissue, intestinal fluids, feces, saliva, breast milk,
urine, tears, middle ear effusions, aqueous humor, and cerebrospinal fluid
• Typically at concentrations of <1% of serum concentration
• Local production of IgE in tissues in whom circulating IgE of same specificity could not be
demonstrated  clinical significance of local production has not been well established

IgE in Allergic Disease
• Total serum IgE levels related to the probability of an individual having detectable
allergen-specific IgE to common allergens
• Total serum IgE concentrations tend to be higher in adults and children with
allergic diseases compared with nonallergic individuals
• But measurement of total serum IgE concentrations is of limited value as a
screening test for allergic disease

IgE and Risk of Asthma
• Burrows and associates (1989): Relationship between the rates of self-reported
asthma and the total serum IgE concentrations was stronger than the relationship
between asthma rates and skin test reactivity to a battery of common allergens
• Sunyer and associates (1996): Total serum IgE concentrations of 100 IU/mL or
higher, the odds ratio for asthma was 4.7 compared with those with lower IgE
levels
• Forester (2010): Significantly increased numbers of mast cells and macrophages
bearing high-affinity IgE receptors (FcεRI) in bronchial biopsies from allergic and
nonallergic asthmatics

• Anti-human IgE monoclonal antibody, omalizumab: treatment of allergic asthma in
individuals 12 years old and older
• IgE levels cannot be measured accurately after treatment with omalizumab
• Total IgE levels increase for several months after the initiation of omalizumab
therapy, then decline to very low levels

Total serum IgE levels are of clinical value in ABPA
• Elevated serum IgE level (>416 IU/mL [1000 ng/mL]) is one of the diagnostic
criteria for this condition
• IgE - follow the course of disease ( in disease successfully treated with
glucocorticoids,  in disease exacerbate)
• Association between disease activity and levels of anti-Aspergillus IgE antibodies
• Several studies suggested that treatment of ABPA with omalizumab is effective in
controlling the disease, significantly lower doses of oral corticosteroids
Allergic Bronchopulmonary Aspergillosis

• Treating allergic patients with oral corticosteroids can reduce serum total serum
IgE concentrations?
• Study of 10 adults with allergic asthma with 20 mg of oral prednisone given twice
daily resulted in increased IgE concentrations in all 10 individuals
• Serum IgG levels were unchanged

• Gross elevation of serum IgE helpful in distinguishing tropical pulmonary eosinophilia
from some other causes of pulmonary symptoms associated with eosinophilia, such as
Churg-Strauss syndrome and Wegener granulomatosis
Tropical Pulmonary Eosinophilia

IgE and Lung Function
• Relationship between total serum IgE levels and lung function complicated by asthma
and cigarette smoking and IgE concentrations
• Several studies have suggested that higher total serum IgE levels are associated with a
more rapid decline in lung function with advancing age
• Significant inverse association was found between IgE levels and lung function

IgE in Cord Blood

IgE in Cord Blood
• Attempt to identify newborns at increased risk for the development of allergic
disease
• Maternal IgE does not normally cross the placenta, although fetal cord blood can be
contaminated by maternal blood during late pregnancy and delivery and must be
carefully collected
Majority of studies suggest that  total IgE in cord blood  indicator of higher risk:
• Newborns with elevated cord IgE levels had an increased risk of developing
urticarial food reactions at 1 year of age, atopic dermatitis by 2 years of age,
allergen sensitization and wheezing at 7 years of age, or allergic rhinitis by 11 and
20 years of age
• However, no relationship was found between cord blood IgE levels and the
development of asthma, allergic rhinitis, or atopic dermatitis by the time the child
was 18 to 21 years of age despite a modest association with total IgE levels at
those ages in another study

Detection of Allergen-Specific IgE
Clinical value
• Predictive value of food-specific IgE antibody levels and positive results for food
challenges
• But relationship between inhalant allergy-specific IgE and symptoms is not as
robust
Specific IgE concentrations vary according to:
• Age
• Degree and duration of the most recent allergen exposure
• Degree and duration of exposure to cross-reactive allergens
• Immunotherapy

Indications for Measuring Specific IgE
• Association between presence of detectable allergen-specific IgE (determined by
positive skin test results or IgE antibody measurements) with allergic symptoms is
inconsistent  results of tests for allergen-specific IgE are clinically valuable only
when considered in the context of a patient’s history
• In vitro tests are not as sensitive as skin tests
• Skin tests have lower time and reagent costs
• Detection of cross-reactive IgE antibodies potential problem with in vitro tests

Viral Infections
• Welliver and colleagues (1986): RSV - Peak IgE-RSV titers during acute infection were also
significantly associated with the risk of recurrent wheezing episodes during a 4-year follow-up
study (difficult to reproduce)
• IgE antibodies formed in some individuals after viral infections and immunizations
• Studies of mononucleosis related to EBV infection - initial rise in IgE concentration for 7-10
days, followed by decline and then a return to baseline levels over a course of weeks to
months
• Skoner and coworkers (1995): rhinovirus infections in adults with allergic rhinitis acutely
produced highly significant increase in total serum IgE levels
• Increased serum IgE reported in patients with human immunodeficiency virus type 1 (HIV-
1) infections and remarkably high incidence of allergic reactions to drugs and environmental
allergens

Bacterial Infections
• IgE specific for S. aureus exotoxins usually found in patients with HIES
• Anti-staphylococcal toxin IgE may be related to various allergic diseases,
especially nasal polyps and chronic rhinosinusitis
• Children develop IgE antibodies specific for pertussis and tetanus toxoids after
immunization but do not have major clinical significance

Yeasts and Fungi
• IgE antibodies specific for Candida albicans infection can be detected, and may
be increased in individuals with atopic dermatitis
• IgE antibodies to yeast Pityrosporum ovale found in people with atopic dermatitis
of the head, face, and neck

Parasitic Diseases
• Increased IgE levels occur during helminth parasitic infections
• Association between increasing levels of tissue invasion and increasing levels of
IgE
• Secretion by parasites of factors that stimulate production of IL-4 or IL-13, or both,
leading to increased IgE levels
• Total serum IgE levels fall after successful treatment

IgE in Nonatopic Disease
Neoplastic Disease
• Most direct relationship between IgE and neoplastic disease occurs with IgE
myeloma
• IgE concentrations at the time of diagnosis ranged from 0.6 to 63 g/L
• Strongest association between allergic sensitization and gliomas
• Hodgkin disease -  serum IgE levels and fall with successful treatment
• Studies of forms of cancer other than Hodgkin disease have not revealed
consistent patterns of IgE elevation associated with the cancer or the response
to therapy

Transplantation
•  serum IgE levels from 7 to 2000-fold in patients after bone marrow
transplantation
•  IgE concentrations do not seem to result from myeloablative or
immunosuppressive therapy used in patients with neoplasia, seen in
immunodeficient children with bone marrow transplanted without myeloablative
therapy
• Many cases of new-onset allergic sensitization and disease after solid organ
(e.g., kidney, liver, lung) transplantation have been reported
• May related to specific immunosuppressive drugs

Renal and Liver Disease
• Total serum IgE levels  in patients with nephrotic syndrome, glomerulonephritis,
minimal change disease, IgM nephropathy, focal glomerulosclerosis, and
membranous glomerulonephritis
• High IgE levels in nephrotic syndrome associated with decreased response to
steroid therapy
•  IgE have also reported in liver disease

Environmental Exposure and IgE
Cigarette Smoking
•  Serum IgE concentrations in smokers compared with nonsmokers and
intermediate concentrations in ex-smokers
• The effect of smoking on serum IgE levels greater in men > women
• Smoking workers are at increased risk for allergic sensitivity to certain
occupational allergens
• Results of various studies on the relationship of passive smoking with allergy
have been conflicting
• Tobacco smoke exposure increased allergen-specific IgE production

Environmental Exposure and IgE
Alcoholic
•Total IgE levels are increased in atopic and nonatopic alcoholics
Diesel Exhuast
• In vivo and in vitro studies showed a direct effect of diesel exhaust particles on
IgE production in mice, particles acted as an adjuvant for IgE production
• Increase in intranasal cytokine production, including IL-4, IL-5, IL-6, and IL-10
• Exposure to diesel exhaust particles and air pollutants may alter local nasal IgE
production
Animal Exposure

Take Home Messages
 Measures of total IgE levels - not useful in diagnosis of allergic diseases because
of wide range of normal concentrations
 With half-life of 2 to 5 days, serum IgE can change in days or weeks from
changes in balance of Th1, Th2, and regulatory T cell
 Changes can result from a wide variety of exposures, including allergens, viral
infections, medications, and tumors
 Measurements of allergen-specific IgE - useful in diagnosis of allergic disease
when interpreted in the context of medical history

Immunoglobulin E: immunobiology and clinical significance

Recommended

Recommended

More Related Content

What's hot

What's hot (20)

Similar to Immunoglobulin E: immunobiology and clinical significance

Similar to Immunoglobulin E: immunobiology and clinical significance (20)

More from Chulalongkorn Allergy and Clinical Immunology Research Group

More from Chulalongkorn Allergy and Clinical Immunology Research Group (20)

Recently uploaded

Recently uploaded (20)

Immunoglobulin E: immunobiology and clinical significance

Editor's Notes