clinical significance of immunoglobulin e

CLINICAL SIGNIFICANCE OF IMMUNOGLOBULIN E

Yoavanit Srivaro M.D.

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

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

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


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

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


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

INTRODUCTION

Prausnitz-Kustner reactionTechnique 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


NORMAL IMMUNOGLOBUBULIN E PRODUCTION

IgE ab production is normally highly regulated,resulting in minimal IgE concentration in body fluidsMost 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



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


• 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

NORMAL IMMUNOGLOBULIN E PRODUCTION

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


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


NORMAL SERUM IMMUNOGLOBULINE E CONCENTRATION


NORMAL SERUM IMMUNOGLOBULIN E CONCENTRATION

Immune status

Age

Race

Medication

Disease process

Season of the year

GeneticSerum IgE Level are also influence by

Philip H. Smith .et al .Middleton’s allergy ; 8th edition 2013:1108118


Grundbacher FJ.et al,J ALLergy Clin Immunol 1985;75:651-8

Found Consistently higher IgE serum level in black all age group

Grundbacher FJ.et al,J ALLergy Clin Immunol 1985;75:651-8


• 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



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


Todd A. et al,Ann Allergy Asthma Immunol 2006;97:650-2


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.



3.4% were found to have IgE levels less than 2.0 IU/mL


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


IMMUNOGLOBULIN E IN ALLERGIC DISEASE

• 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

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

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.

http://www.ncbi.nlm.nih.gov.cuml1.md.chula.ac.th/pubmed/?term=Marsh+DG+,Genetic+control+of+basal+immunoglobulin+G+level









IMMUNOGLOBULIN E AND RISK OF ASTHMA

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

• 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.

• 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.


Diagnose of asthma was strongly relate to Serum IgE

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


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


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

Allergic Bronchopulmonary Aspergillosis


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

IMMUNOGLOBULIN E &RISK OF ASTHMA

Tropical Pulmonary Eosinophilia

Gross elevation of serum IgE


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


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


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

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


• 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


• 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


• 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

INDICATIONS FOR MEASURING SPECIFIC IMMUNOGLOBULIN E ANTIBODIES

• 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

• 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


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

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

IMMUNOGLOBULIN E IN INFECTIOUS & PARASITIC DISEASE

Viral infections

Bacterial infections

Yeast & Fungi

Parasitic disease


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

-

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

VIRAL INFECTIONS

MeaslesChildren who developed measles

encephalitis had highest mean levels IgE Ab(540 IU/ml ) in the 1st week after

onset of rash &slower decline

VIRAL INFECTIONS

Rhinovirus InfectionSkoner & 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

VIRAL INFECTIONS

HIVIncreased serum IgE conc. have been reported in HIV-

1 PtAIDS Pt have remarkably high incidence of allergic

reaction to drugs & environmental allergensThe factors associsted with elevated IgE levels in

HIV-1 disease are not completely understoodThe 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

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.

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

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

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


IMMUNOGLOBULIN E IN NONATOPIC DISEASES

Neoplastic disease

Transplantation

Renal & Liver disease


NEOPLASTIC DISEASE

IgE MyelomaHodgkin diseaseBronchial carcinomaBreast cancer


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


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


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


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)

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


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


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

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

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


THANK YOU

clinical significance of immunoglobulin e

Health & Medicine

wks ige

middletons allergy

chain of ige

introductiontotal serum

higher ige serum level

important in1 ige

major ige function

detected allergen specific