Clinical significance of immunoglobulin E Presented by Yoavanit Srivaro, MD. August14, 2014

1. CLINICAL SIGNIFICANCE OF
IMMUNOGLOBULIN E
Yoavanit Srivaro M.D.

2. OUTLINE
Introduction
Normal Immunoglobulin E Production
Immunoglobulin E in Allergic disease
Immunoglobulin E in Infectious disease and Parasitic disease
Immunoglobulin E in Nonatopic Disease
Environmental Exposure and Immunoglobulin E

3. INTRODUCTION
Ig E is present in the smallest quantities
Contributing only 0.02% of circulating Ig
Concentration of IgE are typically report as nanograms
or international unit per volume of serum
• 1 IU is equal 2.4 ng of protien
Philip H. Smith .et al .Middleton’s allergy ; 8th edition 2013:1108-18

4. INTRODUCTION
IgE found in all mammals ,including monotremes
Off all immunoglobulin Isotype,IgE has the highest affinity for antigens and for its
receptors
The tremendous biologic amplification link to to IgE & Its receptor is shown the fact that
low concentrations of cell surface IgE can cause life threatening reaction with in minute
Immediate or Type I allergic reaction
Philip H. Smith .et al .Middleton’s allergy ; 8th edition 2013:1108-18

5. INTRODUCTION
Total serum IgE levels
reflect non specific
changes in protein
production or
catabolism
Total serum IgE levels
reflect the balance or
overall regulation of
the immune system
In some diseases,
factors specifically
stimulate IgE
production
Some disease may
result directly from the
production of IgE
antibodies specific for
certain allergen

6. INTRODUCTION
In 1921 the collaboration of Otto Prausnitz& Heinz
Kustner produce discovery
Kustner,who
had been
highly allergic
to fish since
childhood
Prausnitz,who
sufferd from
grass pollen
hay fever
Kustner ‘s
serum was
inject into
Prausnitz’s skin
Philip H. Smith .et al .Middleton’s allergy ; 8th edition 2013:1108-18

7. INTRODUCTION
In 1921 the collaboration of Otto Prausnitz& Heinz
Kustner produce discovery
the immediate sensitivity
to the fish was transfer to
the site
conclude that a serum
component was
responsible for
transferring the specific
sensitivity

8. INTRODUCTION
Prausnitz-Kustner reaction
Technique of passively transferring allergic sensitivity
Substance that transferred the sensitivity was called the
reagin
Sera containing reagins were call reaginic
1966 Two groups of investigators identified reagin as a unique
immunoglobulin isotype IgE
Philip H. Smith .et al .Middleton’s allergy ; 8th edition 2013:1108-18

9. NORMAL IMMUNOGLOBUBULIN E
PRODUCTION
IgE ab production is normally highly regulated,resulting
in minimal IgE concentration in body fluids
Most of the IgE producing plasma cells are found in the
lymphoid tissue(GI tract & Respiratory tract)
The highest concentration of IgE producing plasma cells
have been found in tonsils and adenoids
Philip H. Smith .et al .Middleton’s allergy ; 8th edition 2013:1108-18

10. NORMAL IMMUNOGLOBUBULIN E
PRODUCTION
 Production of IgE Ab is regulated by Th2 cells.
 Activated Th2 cells trigger IgE production in a combination B cells through a
combination of signal including
1) Cytokine:IL-4,IL-13
2)Cell surface:CD40L
• The process class switch recombination occur somatic gene arrangements
leading to a gene encoding the ε heavy chain
HANS C. Oettgen .et al .Middleton’s allergy ; 8th edition 2013:364-377

11. NORMAL IMMUNOGLOBUBULIN E
PRODUCTION
• The major IgE function mediated by two receptors
1) FcER1 :high affinity IgE receptors
2)CD23:low affinity receptors
• Aggregation of FcεRI-bound on mast cells & Basophils -- Immediate
hypersensitivity reaction
• IgE bound to CD23 is important in
1) IgE-facilitated Ag uptake by APC & transcellular allergen transport in GI & Respiratory
epithelium
2)Regulation of IgE production
HANS C. Oettgen .et al .Middleton’s allergy ; 8th edition 2013:364-377

12. NORMAL IMMUNOGLOBULIN E
PRODUCTION

13. ONTOGENY OF IMMUNOGLOBULINE E
PRODUCTION
GA 7-10 wks
• Germ line transcripts for the ε chain of IgE are detectable
GA 11 wks
• IgE has been observe in human placental tissue
GA 20 wks
• B cells primed to undergo class switching for IgE production can produce IgE
Philip H. Smith .et al .Middleton’s allergy ; 8th edition 2013:1108-18

14. ONTOGENY OF IMMUNOGLOBULIN E
PRODUCTION
In developed countries less than 1% of cord serum samples contain
detectable IgE to common allergens
Some of the detected allergen –Specific IgE may be of maternal origin
But allergen-Specific IgE rarely has been demonstrated in cord serum
when IgE Ab to the same allergen were not detectable in mother’s serum
Philip H. Smith .et al .Middleton’s allergy ; 8th edition 2013:1108-18

15. Philip H. Smith .et al .Middleton’s allergy ; 8th edition
2013:1108-1118
Philip H. Smith .et al .Middleton’s allergy ; 8th edition 2013:1108-18

16. NORMAL SERUM IMMUNOGLOBULINE E
CONCENTRATION
Philip H. Smith .et al .Middleton’s allergy ; 8th edition 2013:1108-18

17. NORMAL SERUM IMMUNOGLOBULIN E
CONCENTRATION
Age
Immune
status
Race
Medicati
on
Disease
process
Serum IgE Genetic
Level are also
influence by
Season
of the
year
Philip H. Smith .et al .Middleton’s allergy ; 8th edition 2013:1108118

18. NORMAL SERUM IMMUNOGLOBULIN E
CONCENTRATION
Grundbacher FJ.et al,J ALLergy Clin Immunol 1985;75:651-8

19. Found Consistently higher IgE serum level in black all age group
Grundbacher FJ.et al,J ALLergy Clin Immunol 1985;75:651-8

20. NORMAL SERUM IMMUNOGLOBULIN E
CONCENTRATION
• Total serum IgE levels may vary two
fold to fourfold annually sensitive
patient in response to pollen seasons
• The maximum IgE levels are usually
reached 4 to 6 weeks after peak of the
pollen seasons
Philip H. Smith .et al .Middleton’s allergy ; 8th edition 2013:1108-18

21. NORMAL SERUM IMMUNOGLOBULIN E
CONCENTRATION
 Questions have arisen about
-Undetectable
-Absent
 Most clinical assays for total IgE have a lower limit of
detection of 2-5 IU/mL.
 Conc. of less than 2 IU/mL are reported as undetectable
 Some have speculated that undetectable conc. IgE might be
related to autoimmune dis. & recurrent infections

22. NORMAL SERUM IMMUNOGLOBULIN E
CONCENTRATION

Todd A. et al,Ann Allergy Asthma Immunol 2006;97:650-2

23. NORMAL SERUM IMMUNOGLOBULIN E
CONCENTRATION
In a geographically based cohort of 626 pregnant women
Total serum IgE levels were measured using a standard
assay with a lower limit of detection of 2.0 IU/mL.
Sera with IgE levels less than 2.0 IU/mL were assayed again
using a low IgE protocol with a detection limit of 1.2 IU/mL.
Todd A. et al,Ann Allergy Asthma Immunol 2006;97:650-2

24. NORMAL SERUM IMMUNOGLOBULIN E
CONCENTRATION
3.4% were found to have IgE levels less than 2.0 IU/mL
Todd A. et al,Ann Allergy Asthma Immunol 2006;97:650-2

25. Philip H. Smith .et al .Middleton’s allergy ; 8th edition 2013:1108-18

26. IMMUNOGLOBULIN E IN OTHER BODY
FLUID
Nasal washing
Bronchial washing
Nasal polyp tissue
Intestinal fluid
Feces
Saliva
Breast milk
Urine
Tears
Middle ear effusion
Aqueous humor
CSF
Philip H. Smith .et al .Middleton’s allergy ; 8th edition 2013:1108-18

27. IMMUNOGLOBULIN E IN ALLERGIC
DISEASE

28. • A LARGE STUDY By Wittig & Coworker
• Calculate the diagnostic sensitivity &
specificity of total serum IgE determination
• Using 3 cutoff levels
• For 570 Asthmatic and 244 Rhinitis Pts
Heinz J et al. J Allergy Clin Immunol. 1980 Oct;66(4):305-13

29. Heinz J et al. J Allergy Clin Immunol. 1980 Oct;66(4):305-13

30. IMMUNOGLOBULIN E IN ALLERGIC
DISEASE
• Marsh & colleagues calculated ->the optimal
total serum IgE level for discriminating
between allergic & non allergic adults was
100 IU/ml
• This cutoff misclassified approximately 20%
of each group
Marsh DG et al.Proc Natl Acad Sci U S A. 1974 Sep;71(9):3588-92.

31. IMMUNOGLOBULIN E AND RISK OF
ASTHMA

32. • We studied the relation between the serum total IgE level and airway hyperresponsiveness in the presence
or absence of asthma and other atopic diseases in a birth cohort of children.
M.R.Sears.et al ,N Engl J Med 1992;325:1067-71
• Data from
- a questionnaire regarding respiratory symptoms
-measurements of the serum total IgE level
-airway responsiveness to inhaled methacholine
• Data were obtained for 562 11-year-olds in New Zealand.

33. M.R.Sears.et al ,N Engl J Med 1992;325:1067-71

34. M.R.Sears.et al ,N Engl J Med 1992;325:1067-71

35. Diagnose of asthma was strongly relate to Serum IgE
M.R.Sears.et al ,N Engl J Med 1992;325:1067-71

36. IMMUNOGLOBULIN E & RISK OF ASTHMA
OMALIZUMAB
(anti-human IgE monoclonal ab)
• Approved for tx of allergic asthma in individuals 12 years old and
older
• The package insert indicate that IgE levels cannot be measure
accurately after tx
• In most studies total IgE levels increase for several months after
the initiation of tx & then decline to very low level
Philip H. Smith .et al .Middleton’s allergy ; 8th edition 2013:1108-18

37. IMMUNOGLOBULIN E & RISK OF ASTHMA
Allergic Bronchopulmonary Aspergillosis
 An elevated serum IgE level > 416 Iu/ml is one dx criterior ABPA
 Level of IgE can be used to follow course of disease
 Serum IgE level fall when disease successfully tx with glucocorticoid
 Serum Ig E level increase when disease exacerbation
 There appears to be an association between dis. Activity &level of anti-Aspergillus
antibody
Philip H. Smith .et al .Middleton’s allergy ; 8th edition 2013:1108-18

38. IMMUNOGLOBULIN E & RISK OF ASTHMA
Allergic Bronchopulmonary Aspergillosis
 Several studies have suggested that tx of ABPA with Omalizumab is effective in
controlling the dis while using sig. lower doses of oral glucocorticoid
Philip H. Smith .et al .Middleton’s allergy ; 8th edition 2013:1108-18

39. IMMUNOGLOBULIN E &RISK OF ASTHMA
 Many physician assume they tx allergic Pts with oral
corticosteroids can reduce serum total IgE conc.
 But a study of 1o adults with allergic asthma
demonstrate that 20 mg of oral Prednisolone bid
resulted in increased IgE concentration in all 10
individuals
 The increase in IgE was polyclonal ,as shown by
measurement of IgE specific to different allergens
 Serum IgG levels were unchange
 Philip H. Smith .et al .Middleton’s allergy ; 8th edition 2013:1108-18

40. IMMUNOGLOBULIN E &RISK OF ASTHMA
Tropical Pulmonary Eosinophilia
Gross elevation of serum IgE
Philip H. Smith .et al .Middleton’s allergy ; 8th edition 2013:1108-18

41. IMMUNOGLOBULIN E & LUNG FUNCTION
 Evaluation of the relationship between total serum IgE
levels & Lung function is complicated by
1)Asthma & IgE conc.
2)Cigarette smoking & IgE conc.
 Several studies have suggested that higher total serum
IgE levels are associated with a more rapid decline in
lung function with advancing age
Philip H. Smith .et al .Middleton’s allergy ; 8th edition 2013:1108-18

42. IMMUNOGLOBULIN IN CORD BLOOD
 Because IgE is not normally transferred across the placenta to infant
 IgE concentration in cord blood is thought to indicate an infant’s
Basal predisposition to IgE production
 If this is true ,cord blood IgE concentrations should be useful
indicator of child’s risk of developing allergic disease
 Several early studies suggested that cord blood IgE was usefull
marker of allergic risk
 But subsequent studies have failed to show strong association
between cord blood IgE conc. And allergic risk during childhood
Philip H. Smith .et al .Middleton’s allergy ; 8th edition 2013:1108-18

43. Philip H. Smith .et al .Middleton’s allergy ; 8th edition 2013:1108-18

44. DETECTION OF ALLERGEN-SPECIFIC
IMMUNOGLOBULIN E
 Clinical value of knowing the mass units of allergen
specific igE :Predictive value of food-specific IgE Ab
levels & positive result food challanges
 Information on the relationship between inhalant
allergy specific IgE Ab level & symptoms is not as robust
 The strongest relationships have been found between
the total amount of allergen-specific IgE measured and
the levels of exhaled nitric oxide

45. FACTORS AFFECTING IMMUNOGLOBULIN E
LEVELS
Specific IgE Conc.
Age
Degree and Duration
of recent allergen
exposure
Degree and Duration
of exposure to cross
react allergen &IT

46. FACTORS AFFECTING IMMUNOGLOBULIN E
LEVELS
• The level of Specific IgE typically peak
appox 4 wks after seasonal pollen
exposure
• Then gradually fall to nadir before next
pollen season
• Seasonal changes are not usually of
sufficient magnitude to shift and assay
result from –ve to +ve

47. FACTORS AFFECTING IMMUNOGLOBULIN E
LEVELS
• Ig E Ab levels rise after insect stings in
some individuals
• Irrespective of whether the sting
provoked allergic S/S
• General trend of declining allergen-specific
IgE with time has been
documented with insect venom & drug
specific IgE

48. FACTORS AFFECTING IMMUNOGLOBULIN E
LEVELS
• IgE levels tend to decline
during IT
• But part of decline
observed in some studies
might have been result of
IgG Ab formation blocking
to the detection of IgE Ab

49. INDICATIONS FOR MEASURING SPECIFIC
IMMUNOGLOBULIN E ANTIBODIES

50. • Cross sectional study of 2295 Dutch
• 20- 70 yrs of age
• Who were questioned about nasal s/s
& SPT & in vitro test IgE Ab for 9 common
allergens
Droste JHJ .et al. J Allergy Clin Immunol,1996 Apr97;(4):922-32

51. • Cross sectional study of 2295 Dutch
• 20- 70 yrs of age
• Who were questioned about nasal s/s
& SPT & in vitro test IgE Ab for 9 common
allergens
Droste JHJ .et al. J Allergy Clin Immunol,1996 Apr97;(4):922-32

52. • Cross sectional study of 2295 Dutch
• 20- 70 yrs of age
• Who were questioned about nasal s/s
& SPT & in vitro test IgE Ab for 9 common
allergens
Associations between nasal s/s after indoor &
outdoor allergens exposures& positive test
results for specific Ig E Ab were highly
significant
But far from absolute
Droste JHJ .et al. J Allergy Clin Immunol,1996 Apr97;(4):922-32

53. INDICATIONS FOR MEASURING SPECIFIC
IMMUNOGLOBULIN E ANTIBODIES

54. INDICATIONS FOR MEASURING SPECIFIC
IMMUNOGLOBULIN E ANTIBODIES
Two major concerns limit the use of in vitro tests for
allergen specific IgE inUSA
In most cases,In vitro tests are not as sensitive as skin tests for
detecting allergen-Specific IgE
On per test basis,Skin test have lower time &reagent costs

55. INDICATIONS FOR MEASURING SPECIFIC
IMMUNOGLOBULIN E ANTIBODIES
 Detection of cross-reactive IgE Ab is a potential problem with in vitro tests
 Many individuals allergic to pollens have detectable IgE Ab to foods
 20-30% of those with food specific IgE Ab do not report S/S related to
foods
 Many of the pollen-food cross reaction may result from profilin ,a highly
conserved molecule among plants
 Cross-reactive Ab between food & latex allergens also complicate the
interpretation of in vitro tests for latex specific IgE Ab

56. IMMUNOGLOBULIN E IN INFECTIOUS &
PARASITIC DISEASE
Viral infections
Bacterial infections
Yeast & Fungi
Parasitic disease
Philip H. Smith .et al .Middleton’s allergy ; 8th edition 2013:1108-18

57. VIRAL INFECTIONS
Respiratory syncytial virus
 Williver & colleague were the 1 st report
 Peak IgE-RSV titers during acute infection were sig. asso. with risk of
recurrent wheezing episodes during 4 yrs follow up study
 Later research suggests IgE Ab are formed in some individuals after viral
infection & immunization
 Role of this IgE Ab is relation to vaccine effectiveness & adverse reaction

58. VIRAL INFECTIONS
Epstein-Barr virus infection
Initial rise in IgE concentration for 7-10 days
Follow by a decline
Then a return to baseline levels over a course of wks
to months

59. VIRAL INFECTIONS
Measles
Children who developed measles encephalitis had
highest mean levels IgE Ab(540 IU/ml ) in the 1st
week after onset of rash &slower decline

60. VIRAL INFECTIONS
Rhinovirus Infection
Skoner & coworker
Reported that experimentally induce rhinovirus infection in
adults with AR
Acutely produce a highly sig. increase total serum IgE
No sig. change in IgE levels in non AR

61. VIRAL INFECTIONS
HIV
Increased serum IgE conc. have been reported in HIV-1 Pt
AIDS Pt have remarkably high incidence of allergic reaction to
drugs & environmental allergens
The factors associsted with elevated IgE levels in HIV-1 disease
are not completely understood
The relationship between the progressipon of HIV-1 & IgE levels
has varied among studies
Increase levels of IgE in HIV-1 infection appears to be a poor
prognostic sign

62. BACTERIAL INFECTIONS
 IgE specific for S.aureus exotoxins is usually found in Pts with
hyperimmunoglobulinemia E with recurrent infection syndrome
 Staphylococcal toxin IgE may be related to various allergic
disease
- Nasal polyps
- Chronic rhinosinusitis
 Children develop IgE Ab specific for pertussis & tetanus toxoids
after immunization.

63. YEAST &FUNGI
 IgE Ab specific for individuals Ag in Candida albicans :Atopic
dermatitis
 IgE Ab to Pityrosporum ovale :Atopic dermatitis of
head,face,neck
 Ig Ab to Trichophyton :Asthma

64. IMMUNOGLOBULIN E & PARASITIC
DISEASE
 Increased IgE Levels typically occur during helminth parasitic infections
 There seem to be an association between increasing levels of tissue invasion and
increasing levels of IgE
 The increased IgE conc. are the result of parasitic specific & non specific
polyclonal IgE production
 One mechanism proposed to explain the increase in total IgE levels is the
secretion by parasite factor that stimulate production o IL-4 or IL-13 or both
leading to increase IgE levels
 Total serum IgE levels typically fall after successful tx of the parasite

65. IMMUNOGLOBULIN E & PARASITIC
DISEASE
 The hypothesis that IgE is at least partially protective in parasitic dis. Is
widely debated
 Some studies strongly support a protective role for igE Ab ,other studies
show no protective effect
-Schistosomiasis
-Ascaris
-Malaria
 Philip H. Smith .et al .Middleton’s allergy ; 8th edition 2013:1108-18

66. IMMUNOGLOBULIN E IN NONATOPIC
DISEASES
Neoplastic disease
Transplantation
Renal & Liver disease
Philip H. Smith .et al .Middleton’s allergy ; 8th edition 2013:1108-1118

67. NEOPLASTIC DISEASE
IgE Myeloma
Hodgkin disease
Bronchial carcinoma
Breast cancer
Philip H. Smith .et al .Middleton’s allergy ; 8th edition 2013:1108-18

68. NEOPLASTIC DISEASE
IgE Myelomas
-rare disease
-only 40 case reported
-initial description by Johansson &Bennich in 1967
-the low frequency of igE-myeloma presumably reflects the small No of IgE
producing cells normally presents in the body
Philip H. Smith .et al .Middleton’s allergy ; 8th edition 2013:1108-18

69. NEOPLASTIC DISEASE
IgE Myelomas
-some IgE myeloma might have been missed because
1) the quantity of IgE produced by the myeloma might have been less than that
detectable by routine screening
2)they might have been misclassified as light chain disease
-IgE conc. At the time of Dx 0.6-63 gm/L
-survival time shorter than other myelomas
Philip H. Smith .et al .Middleton’s allergy ; 8th edition 2013:1108-18

70. NEOPLASTIC DISEASE
Hodgkin disease
- Associate with increase serum IgE levels
-High IgE conc. Associate with a nodular sclerotic pattern
-IgE levels usually fall with successful tx
Philip H. Smith .et al .Middleton’s allergy ; 8th edition 2013:1108-18

71. NEOPLASTIC DISEASE
Bronchial carcinoma
-Larger quantities of allergen specific IgE were
associated with poorer prognosis
Breast cancer
-IgE level above the geometric mean for age were
poor prognostic sign (ER +ve)

72. NEOPLASTIC DISEASE
 In some animal tumor models,antitumor Ag IgE Ab have
been protective against tumor growth
 The anticancer effect of tumor Ag-specific IgE & IgE of
other Ag specificities are being evaluated
 In some model systems,the unique properties of
IgE,especially related to ability to attract&activate
eosinophils,appear to have important antitumor effect
Philip H. Smith .et al .Middleton’s allergy ; 8th edition 2013:1108-18

73. TRANSPLANTATION
 Increases in serum IgE levels from 7-fold to 2000-fold have been
reported in pt after BM transplantation
 Initially,the increased IgE levels were thought to result from GVHD
 But subsequence studies showed that igE levels also increase in pt
who did not have GVHD
 Increased IgE conc. do not seem to result from myeloablative or
immunpsuppressive tx use in pt with neoplasia
• Because increased IgE levels have also been observed in
immunodeficient children whom BM with transplant
Philip H. Smith .et al .Middleton’s allergy ; 8th edition 2013:1108-18

74. RENAL AND LIVER DISEASE
Nephrotic syndrome
 Total serum IgE levels are elevated in pt with NS
-Minimal change dis.
- IgM nephropathy
- Focal glomerulosclerosis
- Membranous gromerulonephritis
 High IgE level are associate with decrease response of steroid tx
Liver disease
 Increased levels of igE
Philip H. Smith .et al .Middleton’s allergy ; 8th edition 2013:1108-18

75. ENVIRONMENTAL EXPOSURE AND
IMMUNOGLOBULIN E
 Cigarette smoking
-Most studies have found increase serum IgE conc.
 Alcoholic
-Total IgE levels are increased in atopic & nonatopic
• Diesel exhaust
-Alter nasal local IgE production
Philip H. Smith .et al .Middleton’s allergy ; 8th edition 2013:1108-18

76. SUMMARY
 Measurement of total IgE levels are not useful in the dx of
allergic disease <---------> Because wide range of normal conc.
 Measurement of allergen specific Ig E are useful in the Dx of
allergic disease <---------> When they are interpreted in the
context of an individual’ medical hx
Philip H. Smith .et al .Middleton’s allergy ; 8th edition 2013:1108-18

77. THANK YOU