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Clinical significance of immunoglobulin E

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Clinical significance of immunoglobulin E

Presented by Yoavanit Srivaro, MD.

August14, 2014

Published in: Health & Medicine
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Clinical significance of immunoglobulin E

  1. 1. CLINICAL SIGNIFICANCE OF IMMUNOGLOBULIN E Yoavanit Srivaro M.D.
  2. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 12. NORMAL IMMUNOGLOBULIN E PRODUCTION
  13. 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. 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. 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. 16. NORMAL SERUM IMMUNOGLOBULINE E CONCENTRATION Philip H. Smith .et al .Middleton’s allergy ; 8th edition 2013:1108-18
  17. 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. 18. NORMAL SERUM IMMUNOGLOBULIN E CONCENTRATION Grundbacher FJ.et al,J ALLergy Clin Immunol 1985;75:651-8
  19. 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. 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. 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. 22. NORMAL SERUM IMMUNOGLOBULIN E CONCENTRATION  Todd A. et al,Ann Allergy Asthma Immunol 2006;97:650-2
  23. 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. 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. 25. Philip H. Smith .et al .Middleton’s allergy ; 8th edition 2013:1108-18
  26. 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. 27. IMMUNOGLOBULIN E IN ALLERGIC DISEASE
  28. 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. 29. Heinz J et al. J Allergy Clin Immunol. 1980 Oct;66(4):305-13
  30. 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. 31. IMMUNOGLOBULIN E AND RISK OF ASTHMA
  32. 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. 33. M.R.Sears.et al ,N Engl J Med 1992;325:1067-71
  34. 34. M.R.Sears.et al ,N Engl J Med 1992;325:1067-71
  35. 35. Diagnose of asthma was strongly relate to Serum IgE M.R.Sears.et al ,N Engl J Med 1992;325:1067-71
  36. 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. 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. 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. 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. 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. 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. 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. 43. Philip H. Smith .et al .Middleton’s allergy ; 8th edition 2013:1108-18
  44. 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. 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. 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. 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. 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. 49. INDICATIONS FOR MEASURING SPECIFIC IMMUNOGLOBULIN E ANTIBODIES
  50. 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. 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. 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. 53. INDICATIONS FOR MEASURING SPECIFIC IMMUNOGLOBULIN E ANTIBODIES
  54. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 77. THANK YOU

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