Immunobiology of IgE and IgE receptors Presented by Pornsiri Sae-lim, MD. May7, 2021

1. Immunobiology of IgE and
IgE Receptors
Pornsiri sae-lim , MD
Pediatric Allergy and Immunology Department
King Chulalongkorn Memorial Hospital

2. Overview
 Introduction
 History
 Immunobiology of IgE and IgE Receptors
 IgE Structure & Mechanisms of IgE Isotype Switching
 IgE Receptor ( FcεRI, CD23)
 Relationships with Other Systems
 Clinical Significance of Immunoglobulin E
 Normal Immunoglobulin E Production
 Immunoglobulin E in Allergic Disease
 Immunoglobulin E in Infectious and Parasitic Disease
 Immunoglobulin E in Nonatopic Diseases
 Environmental Exposures and Immunoglobulin E,

3. Introduction
 Normal serum concentrations of IgE are typically low (average, 25 kU/L [60 ng/mL])
 The smallest quantities, contributing only 0.002% of circulating immunoglobulins
 The shortest half-life: 2 to 3 days in humans
 The highest affinity for antigens and for IgE receptors
 IgE-mediated immunity and inflammatory reactions
 primarily in terms of immediate or type I allergic reactions
 Defense against parasitic diseases, especially caused by helminths and some protozoa
 highly conserved and appears to have evolved to provide a means for rapidly
responding to certain types of stimuli
Scott P,Middleton’s Allergy,9th. Ed; 2019: 1087-1095

4. James T,Middleton’s Allergy,9th. Ed; 2019: 30-43

5. Role IgE antibody
 Immunomodulatory functions including
Regulation of IgE-receptor density
Promotion of mast cell survival
Suppression of innate antiviral immune responses
Enhancement of Th2 responses to allergens
Han C ,Middleton’s Allergy,9th. Ed; 2019:362-373

6. History
In 1921, Carl Prausnitz and Heinz Küstner
 Küstner’s serum ( who had been highly allergic to fish ) was injected
into Prausnitz’s skin >> the immediate sensitivity to fish was transferred to the site.
 a serum component was responsible for transferring the specific sensitivity
 the Prausnitz-Küstner (PK) reaction or test
 The substance that transferred the sensitivity was called the regain
 Sera containing reagins were called reaginic.
Han C ,Middleton’s Allergy,9th. Ed; 2019:362-373

7.  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
Han C ,Middleton’s Allergy,9th. Ed; 2019:362-373
History

8. Han C ,Middleton’s Allergy,9th. Ed; 2019:362-373

9. T/B cell interactions leading to IgE isotype switching
Han C ,Middleton’s Allergy,9th. Ed; 2019:362-373

10. Molecular events in IgE isotype switching
Han C ,Middleton’s Allergy,9th. Ed; 2019:362-373

11. Structure of the receptors for IL-4 and IL-13
Han C ,Middleton’s Allergy,9th. Ed; 2019:362-373

12. Site of IgE production
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 Han C ,Middleton’s Allergy,9th. Ed; 2019:362-373

13. Site of IgE production
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
Han C ,Middleton’s Allergy,9th. Ed; 2019:362-373

14. 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)
Han C ,Middleton’s Allergy,9th. Ed; 2019:362-373

15. Figure : IgE structure and interaction with FcεRI Han C ,Middleton’s Allergy,9th. Ed; 2019:362-373
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

16. Early events in FcεRI signaling
Han C ,Middleton’s Allergy,9th. Ed; 2019:362-373

17. 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
Han C ,Middleton’s Allergy,9th. Ed; 2019:362-373

18. 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”
Han C ,Middleton’s Allergy,9th. Ed; 2019:362-373

19. FcεRII [CD23]
 monomeric form binds to IgE with a Ka of about 106 to 107 M-1
 not a member of the Ig superfamily
Structure
 member of the C-type lectin family of proteins
 type II transmembrane protein with an intracellular N-terminus
 expressed as an oligomer of coiled stalks bearing lectin domain heads
 bind to the Cε3 and Cε4 domains of IgE
Han C ,Middleton’s Allergy,9th. Ed; 2019:362-373

20. FcεRII [CD23]
Protease sites in the stalks
 can be accessed by both endogenous (ADAM - 8, -10, and -33 ) and allergen
(Der p 1) proteases to give rise to soluble CD23
 fragments (sCD23), which retain their IgE-binding properties

21. FcεRII [CD23]
Function
 Facilitate transepithelial allergen transport in gastrointestinal and respiratory
epithelium
 CD23 on B cells and APCs can mediate antigen uptake for more efficient
processing and presentation of antigenic peptides complexed to MHC class II
molecules to the TCR of specific T 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
Han C ,Middleton’s Allergy,9th. Ed; 2019:362-373

22. Figure: CD23 structure and function
Han C ,Middleton’s Allergy,9th. Ed; 2019:362-373

23. Clinical Significance of
Immunoglobulin E

24. Clinical Significance of Immunoglobulin E
 IgE concentrations can be altered by disease processes through four mechanisms
 Total serum IgE levels can reflect nonspecific changes in protein production or
catabolism.
 Total serum IgE concentrations can reflect the balance or overall regulation of the
immune system
 In some diseases, factors specifically stimulate IgE production
 Some diseases may result directly from the production of IgE antibodies specific for
certain allergens.

25. NORMAL IgE PRODUCTION
 Ontogeny of Immunoglobulin E Production
 Normal Serum Immunoglobulin E Concentrations
 Immunoglobulin E in Other Body Fluids

26. Ontogeny of Immunoglobulin E
Production
IgE is not believed to cross the placenta
>> woman’s allergen sensitivities are not passed on directly to her offspring through
IgE transfer
Allergens can be passed transplacentally >> the fetus can produce allergen-specific IgE
 GA 7-10 weeks : Germline transcripts for the ε chain of IgE are detectable
 GA 11 weeks : IgE production observed in human fetal tissue cultures
Less than 1% of cord serum samples contain detectable IgE antibodies to common
allergens
Limited IgE production apparently correlates with limited fetal antigenic exposure

27. Serum IgE concentrations
gradually increase after birth
reach maximum values between the ages of 10 and 15 years

28. Normal Serum Immunoglobulin E
Concentrations
 Factors associated with higher levels of total IgE include
 Male gender, African-American race, obesity, higher serum cotinine
(reflecting tobacco smoke exposure), less than a 12th grade education, and
poverty
 Studies of other racial and ethnic groups suggest that normal total serum IgE
levels vary widely, presumably because of genetic differences and
differences in environmental exposures
 Serum IgE levels are also influenced by genetics
 polymorphisms of CCL11 (i.e., eotaxin-1) also appear to be associated with
total IgE
one nucleotide eotaxin-1 polymorphism variant associated with increases
in African-American families total IgE level

29. Normal Serum Immunoglobulin E
Concentrations
 In atopic individuals, total serum IgE levels may fluctuate over time
 pollen-sensitized individuals, serum IgE levels peak 4 to 6 weeks after the
height of pollen season and subsequently decline until the next pollen season
 “Undetectable” or “absent” serum IgE levels
 Concentrations of less than 2 IU/mL are reported as undetectable
 Might be related to autoimmune disease or recurrent infections.

32. Immunoglobulin E 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 less than 1% of the serum
concentration
 Human breast milk, specifically, has negligible amounts of IgE but may contain
allergen
 Local production of IgE in tissues has been shown in individuals in whom
circulating IgE of the same specificity could not be demonstrated, the clinical
significance of local production has not been well established

33. IMMUNOGLOBULIN E IN ALLERGIC DISEASE
 Total serum IgE levels are 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
 The diagnostic value of total serum IgE concentrations is limited
 Measurement of total serum IgE concentrations is of limited value as a screening
test for allergic disease

34. Immunoglobulin E and Risk of Asthma
 Burrows (1987 ) The 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 (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 the association
between IgE levels of 100 IU/mL or higher and asthma persisted, with an odds
ratio of 18

35. Immunoglobulin E and Risk of Asthma
 Sears (1991)
 Diagnosed asthma was strongly related to serum IgE levels (P < .0001 for trend)
 Airway hyperresponsiveness to methacholine was also highly correlated with
serum IgE levels (P < .0001), and the correlation persisted even after excluding
children with asthma (P < .0001) or all children with histories of wheezing, rhinitis,
or eczema (P < .0001)
 Allergic bronchopulmonary aspergillosis (ABPA)
 Elevated serum IgE level (more than 416 IU/mL [1000 ng/mL]) is one of the
diagnostic criteria
 The level of IgE can be used to follow the course of the disease
 Association between disease activity and levels of anti-Aspergillus IgE antibodies

36. Immunoglobulin E and Risk of Asthma
 A gross elevation of serum IgE may also be helpful in distinguishing tropical
pulmonary eosinophilia from some other causes of pulmonary symptoms
associated with eosinophilia, such as
 Eosinophilic granulomatosis with polyangiitis (EGPA, formerly known as Churg-
Strauss syndrome)
 Granulomatosis with polyangiitis (GPA, formerly known as Wegener’s
granulomatosis)

37. Immunoglobulin E and Lung Function
 Complicated by the associations between asthma and IgE concentrations and
between cigarette smoking and IgE concentrations
 Evidence that passive exposure to environmental tobacco smoke was
associated with increased IgE levels in women who were first-degree relatives of
asthmatics

38. Detection of Allergen-Specific
Immunoglobulin E
• Specific IgE concentrations vary according to:
• Age
• Highest in school-age children & young adults
• Very low IgE concentrations in infant
• The degree and duration of the most recent allergen exposure
• Usually rise as a result of pollen exposure
• peak approximately 4 weeks after a seasonal pollen exposure → gradually fall to a nadir
before the next pollen season
• The degree and duration of exposure to cross-reactive allergens (both inhalant and food)
• Immunotherapy
• IgE levels also tend to decline during allergen immunotherapy, but part of the decline
observed in some studies might have been the result of IgG antibody formation blocking
the detection of IgE antibodies

39. Indications for Measuring Specific
Immunoglobulin E Antibodies
 The association between the detectable allergen specific IgE with
allergic symptoms is inconsistent
positive skin-prick test results for grass pollen
68% had nasal symptoms with grass pollen challenge
64% had symptoms correlating with pollen counts

40. Detection of Allergen-Specific
Immunoglobulin E
 Because of the inconsistent relationship between allergic sensitization
determined by the presence of detectable allergen-specific IgE and symptoms
 the results of tests for allergen specific IgE are clinically valuable only when
considered in the context of a patient’s history
 In Vivo VS In Vitro
 infant
 younger than 12 month not fully reflect
their allergic sensitivities immunoassays are valid
 young as six weeks of age and can be
performed on capillary blood samples

41. IMMUNOGLOBULIN E IN INFECTIOUS
 Viral Infections
 Bacterial Infections
 Yeasts and Fungi
 Parasitic Diseases

42. IMMUNOGLOBULIN E IN INFECTIOUS :
Viral Infections
 IgE antibodies are formed in some individuals after viral infections and immunizations
 The role of these IgE antibodies in relation to vaccine effectiveness and adverse reactions needs
further investigation
 Welliver and colleague (1986) :
 highly IgE - RSV during primary RSV infections in children
 Associated with wheezing and other signs of lower respiratory tract involvement
 Peak IgE-RSV titers during acute infection
 Significantly associated with the risk of recurrent wheezing episodes during a 4-year follow-up study

43. IMMUNOGLOBULIN E IN INFECTIOUS :
Viral Infections
 Changes in serum IgE concentrations during viral infections have produced variable results.
 mononucleosis related to Epstein-Barr virus infection
 initial rise in IgE concentration for 7 to 10 days
 decline and then a return to baseline levels over a course of weeks to months
 Measle infection
 initial presentation of measles was 258 IU/mL
 Without complication
 82.5 IU/mL during the second week after the appearance of the skin rash in children
 Complication
 measles-related pneumonia were similar to those with uncomplicated disease
 measles encephalitis had the highest mean levels (540 IU/ mL) in the first week after the onset
of rash and a slower decline in their IgE levels.

44. IMMUNOGLOBULIN E IN INFECTIOUS :
Viral Infections
 Skoner and coworkers: rhinovirus infections in adults with allergic rhinitis acutely produced
a highly significant increase in total serum IgE levels (P < .000008 com- pared with baseline,
and P < .0001 compared with convalescent samples)
 Elevated serum IgE concentrations have been reported in patients with human
immunodeficiency virus type 1 (HIV-1) infections
 High incidence of allergic reactions to drugs and to environmental allergens
 The factors associ- ated with elevated IgE levels in HIV-1 disease are not completely
understood

45. IMMUNOGLOBULIN E IN INFECTIOUS :
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
 Recent work has called this conclusion into question, and longitudinal studies will assess for effects
on persistence of immunization titers

46. IMMUNOGLOBULIN E IN INFECTIOUS :
Yeasts and Fungi
 Some individuals form IgE antibodies specific for yeasts or fungi
 Candida albicans : the levels of antibodies may be increased in individuals with atopic
dermatitis.
 Pityrosporum ovale : Report in antibodies people with atopic dermatitis of the head,
face, and neck
 Trichophyton :
 Associated with asthma in patients
 The mechanism remains to be elucidated
 Asthma symptoms were reduced after treating cutaneous infection

47. IMMUNOGLOBULIN E IN INFECTIOUS :
Parasitic Disease
 Elevated IgE levels typically 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
 Total serum IgE levels typically fall after successful treatment of the parasitized individual

48. IMMUNOGLOBULIN E IN INFECTIOUS :
Parasitic Disease
 Lynch and colleagues (1993) : Inverse relationship between parasitic and allergic
disease
 Examined the effects of antihelminth treatment on IL-4 production, IgE levels, and skin test
reactivity
 Children living in a tropical slum area where infections with Ascaris lumbricoides
(roundworm) and Trichuris trichiura (whipworm) were common
 Compared the results in children who underwent 22 months of treatment to children in the
same area whose parents declined treatment
 Levels of IL-4, total IgE levels, and blood eosinophilia declined in treated children, whereas
levels in untreated children increased
 In contrast to the fall in total serum IgE levels, treated children were more likely to be skin
test positive to house dust extract at the end of the study than at the beginning (17% versus
68%, P < .001)

49. IMMUNOGLOBULIN E IN NONATOPIC DISEASES
Neoplastic Disease
Transplantation
Renal and Liver Disease

50. IMMUNOGLOBULIN E IN NONATOPIC
DISEASES : Neoplastic Disease
 Most direct relationship between IgE and neoplastic disease occurs with IgE myeloma
 rare, only 40 cases reported since the initial description by Johansson and Bennich in 1967
 IgE concentrations at the time of diagnosis ranged from 0.6 to 63 g/L
 Symptoms of IgE myeloma are indistinguishable from those of other myelomas
 average survival time is shorter than with other myelomas

51. IMMUNOGLOBULIN E IN NONATOPIC
DISEASES : Transplantation
 bone marrow transplantation : IgE levels from sevenfold to 2000-fold have been reported
in patient
 do not seem to result from the myeloablative or immunosuppressive therapy
 May increased IgE levels were thought to result from graft-versus-host disease
 Solid organ transplantation (e.g., kidney, liver, lung)
 new-onset allergic sensitization and disease
 may be partially related to the specific immunosuppressive drugs used to prevent
rejection
 Rencent report :
352 pediatric post–liver transplant >> recipients found 30 developed de novo
food allergy or eosinophilic gastrointestinal disease
exposure to tacrolimus alone was insufficient to explain de novo allergic disease
rather, younger age and underlying predisposition to atopic disease may play
larger roles.

52. IMMUNOGLOBULIN E IN NONATOPIC
DISEASES: Renal and Liver Disease
Renal disease
 Elevated total serum IgE : Nephrotic syndrome associated with different forms
of glomerulonephritis, including minimal change disease, IgM nephropathy,
focal glomerulosclerosis, and membranous glomerulonephritis
 Associated nephrotic syndrome are associated with a decreased response to
steroid therapy
Liver Disease
 Also been reported among patients with liver disease
 unclear related to liver disease in general or the particular cause of liver
disease

53. ENVIRONMENTAL EXPOSURES AND
IMMUNOGLOBULIN E

54. ENVIRONMENTAL EXPOSURES AND
IMMUNOGLOBULIN E : Cigarette Smoking
 Higher serum IgE concentrations in smokers compared with nonsmokers and intermediate
concentrations in ex-smoke
 Relationship between the duration of smoking cessation and decline in IgE levels
 Smoking workers are increased risk for allergic sensitivity to certain occupational allergens
 No published reports have yet noted an effect of e-cigarette smoking on IgE or atopy in
humans

55. ENVIRONMENTAL EXPOSURES AND
IMMUNOGLOBULIN E : Diesel Exhaust
 Air pollution, especially airborne concentrations of diesel exhaust particles >>
 In vivo and in vitro studies : direct effect of diesel exhaust particles on IgE production in
mice
 Diaz-Sanchez ….:
 nasal challenges in 11 healthy, nonsmoking adults with various quantities of diesel exhaust
particles
 Diesel exhaust particles acted as an adjuvant for IgE production
 Increased IgE concentrations were associated with an increase in intranasal cytokine production, including
IL-4, IL-5, IL-6, and IL-10

56. ENVIRONMENTAL EXPOSURES AND
IMMUNOGLOBULIN E : ANIMAL EXPOSURE
 Meta-analyses of the data : show a relatively consistent effect of animal
exposure on allergic sensitization , the risk of allergic disease and total serum IgE
levels.
 Exposure to indoor dogs and cats during pregnancy reduces cord blood IgE
levels
 Effect of animal exposure during the first year of life may persist at least until 18
years of age