Allergy and immunology: history to modern practice

IgE: from its discovery to modern allergy testing and treatment

Immunoglobulin E is present in the blood in tiny quantities, yet its discovery transformed the diagnosis and treatment of allergy. This article follows the scientific roadmap from the mysterious “reagin” of the early twentieth century to specific IgE testing, molecular allergy diagnostics and anti-IgE biological treatment—and explains what raised or reduced IgE can mean today.

IgE discovery, an IgE antibody interacting with a mast cell and modern allergy testing.

The journey of IgE from its historical discovery to modern allergy diagnostics and anti-IgE treatment.

Key clinical message: an IgE result must always be interpreted alongside the patient’s symptoms, timing of reactions, exposure history and, where appropriate, examination and supervised challenge testing. A raised total IgE does not by itself diagnose allergy, while detectable allergen-specific IgE demonstrates sensitisation, not necessarily clinical allergy.

What is IgE?

Immunoglobulin E, usually abbreviated to IgE, is one of the five major classes of human antibody: IgG, IgA, IgM, IgD and IgE. It is produced by plasma cells after B lymphocytes undergo class switching, usually under the influence of type 2 immune signals including interleukin-4 and interleukin-13. Compared with IgG, circulating IgE is extremely scarce and has a short life in serum. Its biological influence is nevertheless powerful because IgE binds with high affinity to FcεRI receptors on mast cells and basophils.

When an allergen cross-links adjacent allergen-specific IgE molecules on these cells, it can trigger rapid release of histamine, tryptase, lipid mediators and cytokines. Depending on the organ involved, the result may include itching, urticaria, swelling, sneezing, wheeze, vomiting or anaphylaxis. IgE also participates in defence against certain parasites and may have evolved as part of a broader system for detecting and responding to potentially harmful environmental substances.

Before IgE had a name: the search for “reagin”

At the beginning of the twentieth century, clinicians could observe immediate allergic reactions but did not know which blood factor caused them. In 1921, Carl Prausnitz and Heinz Küstner carried out the experiment that became known as the Prausnitz–Küstner reaction. Küstner, who was allergic to fish, supplied serum that was injected into Prausnitz’s skin. Subsequent exposure of that skin site to fish allergen produced a local wheal-and-flare response. The experiment showed that immediate hypersensitivity could be transferred by a factor in serum. That factor became known as reagin.

The passive-transfer test was historically important but inherently unsafe because injecting one person’s serum into another could transmit infection. It was eventually abandoned. More importantly, scientists still had to determine the molecular identity of reagin. For decades it resisted classification: it behaved differently from the antibody classes then known and was present at concentrations too low for conventional protein methods to detect easily.

The discovery of IgE: two research paths converge

1966–1967: the Ishizakas identify γE

Working in Denver, Kimishige Ishizaka and Teruko Ishizaka, with colleagues, studied serum from people with ragweed allergy. Using painstaking immunochemical techniques, they showed that reaginic activity belonged to a previously unrecognised immunoglobulin rather than to IgA, as some had suspected. They called it γE-globulin. Their experiments linked this new antibody to immediate hypersensitivity and showed that antibodies directed against it could provoke histamine release from human leucocytes.

1967: Johansson and Bennich characterise an unusual myeloma protein

At Uppsala University in Sweden, Gunnar Johansson and Hans Bennich independently investigated an atypical immunoglobulin produced in very large quantities by a patient with multiple myeloma. The protein, initially called IgND after the patient, did not belong to IgG, IgA, IgM or IgD. Because the myeloma protein was abundant, it gave researchers enough material to analyse the new antibody class and to develop reagents capable of detecting related antibodies in allergic patients.

1968: the fifth immunoglobulin class is formally named IgE

The American and Swedish findings were shown to concern the same immunoglobulin. In 1968, the World Health Organization formally recognised immunoglobulin E as a new human immunoglobulin class. The letter “E” retained the nomenclature of γE and is often associated with the erythema produced in allergic skin reactions. Collaboration between the groups helped establish that IgE carried human reaginic activity.

The discovery is best understood as convergent science rather than a single isolated moment. The Ishizakas identified the antibody responsible for reaginic activity through allergy research; Johansson and Bennich provided an abundant, structurally unusual myeloma immunoglobulin that enabled detailed characterisation. Together, these findings turned an invisible biological activity into a measurable molecule.

Roadmap: from discovery to modern clinical use

1921 — Passive transfer demonstrates a serum factor.
Prausnitz and Küstner show that immediate sensitivity can be transferred through serum, establishing the concept of reagin.

1966–1968 — IgE is identified and formally recognised.
The Ishizakas connect γE to reaginic allergy; Johansson and Bennich characterise IgND; international agreement establishes IgE as the fifth immunoglobulin class.

1967 onward — In-vitro allergen-specific IgE testing becomes possible.
The radioallergosorbent test, or RAST, uses allergen bound to a solid phase and radiolabelled anti-IgE to detect allergen-specific antibodies. It begins replacing hazardous passive-transfer methods.

1970s–1990s — Safer, more sensitive laboratory systems evolve.
Enzyme-labelled and fluorescence-based assays progressively replace radioactive detection. Quantification improves and testing expands to inhalant, food, venom, occupational and drug-related allergens.

1990s–2010s — Recombinant allergens and component-resolved diagnostics emerge.
Testing can increasingly distinguish IgE to individual allergen molecules rather than only whole extracts. This can help separate primary sensitisation from cross-reactivity and, for selected allergens, refine risk assessment.

2000s — IgE becomes a therapeutic target.
Omalizumab, a humanised monoclonal anti-IgE antibody, enters clinical practice. It binds circulating free IgE, limits its interaction with FcεRI and gradually reduces receptor expression on effector cells. Depending on jurisdiction and indication, anti-IgE therapy is used in selected patients with severe allergic asthma, chronic spontaneous urticaria and chronic rhinosinusitis with nasal polyps; evidence and licences continue to evolve.

Today — IgE data are integrated with personalised clinical assessment.
Modern practice combines history, skin testing, quantitative specific IgE, allergen components, basophil activation testing in specialist settings and, when appropriate, supervised provocation or food challenge. No laboratory number replaces clinical reasoning.

Total IgE and specific IgE are different tests

Total IgE measures all IgE antibodies in a blood sample, irrespective of what they recognise. The reference interval varies substantially with age, population, laboratory method, parasitic exposure, smoking and other factors. Total IgE may support a broader assessment and is used in the dosing framework for omalizumab in allergic asthma, but it is a poor stand-alone screening test for allergy. A person with allergy may have total IgE within the laboratory range, while a person with very high total IgE may not have symptoms to the allergen being investigated.

Allergen-specific IgE measures IgE directed against a particular extract or molecule—for example birch pollen, house dust mite, peanut or a defined peanut component. A positive result means that immune sensitisation is present. Clinical allergy is diagnosed only when sensitisation fits a convincing pattern of symptoms following relevant exposure. Test values are not universal “severity scores”, and a result does not by itself predict exactly how severe a future reaction would be.

Why indiscriminate allergy panels can mislead

Testing many allergens without an allergy-focused history increases the chance of finding clinically irrelevant sensitisation. This may lead to unnecessary dietary restriction, anxiety or incorrect labelling. Tests should therefore be selected and interpreted in the context of the suspected trigger and clinical history.

Conditions associated with raised IgE

A raised total IgE is a non-specific finding. The degree of elevation overlaps widely between health and disease, and the differential diagnosis changes with the patient’s age, symptoms, travel, infection exposure and immune history.

Atopic and allergic disease

Total IgE is commonly elevated in atopic dermatitis, allergic asthma, allergic rhinitis, food allergy and some forms of immediate drug or venom hypersensitivity. Atopic dermatitis—particularly extensive or severe disease—can produce strikingly high values. However, neither a normal total IgE excludes these diagnoses nor a raised value confirms the clinical trigger.

Allergic bronchopulmonary aspergillosis and related fungal airway disease

Allergic bronchopulmonary aspergillosis (ABPA) is an immune-mediated lung disease most often considered in people with asthma or cystic fibrosis who have compatible symptoms, imaging and fungal sensitisation. Total IgE is an important part of established diagnostic criteria and is useful for monitoring trends after treatment, but it is never interpreted alone.

Parasitic infection

Helminth infections can drive type 2 immunity, eosinophilia and increased total IgE. The likelihood depends on residence, travel, exposure and symptoms. A raised IgE without an appropriate epidemiological history does not establish parasitic infection, and targeted investigation is preferable to untargeted treatment.

Inborn errors of immunity and immune dysregulation

Very high IgE accompanied by recurrent, unusual or severe infection; viral skin infection; abscesses; candidiasis; skeletal or dental abnormalities; marked eczema; failure to thrive; or a strong family history should prompt consideration of an inborn error of immunity. Examples include STAT3-associated hyper-IgE syndrome, DOCK8 deficiency and several other genetic disorders affecting immune regulation. The IgE value alone cannot distinguish these conditions from severe atopic disease, so specialist immunological assessment is essential.

Eosinophilic and inflammatory disorders

Raised IgE can occur in some hypereosinophilic syndromes, eosinophilic granulomatosis with polyangiitis and other disorders characterised by type 2 inflammation. The result is supportive at most; diagnosis depends on the pattern of organ involvement, eosinophil count and disease-specific investigations.

Rare haematological and other associations

Marked monoclonal IgE production is exceptionally rare but may occur in IgE myeloma. Increased IgE has also been reported in some lymphoproliferative disorders and in conditions such as Kimura disease. These are uncommon explanations; the surrounding clinical picture, serum protein studies, blood count, examination and other investigations determine their relevance.

Treatment-related changes

After starting omalizumab, conventional assays may show an increase in measured total IgE because they detect longer-lived omalizumab–IgE complexes. This does not mean that active free IgE has increased; free IgE falls. Total IgE measured during treatment should therefore not be interpreted in the same way as a pretreatment value or used casually to redetermine dosing.

What can a low or undetectable IgE mean?

Low IgE is much less discussed than high IgE. In many people it is simply their normal biological pattern and causes no symptoms. There is no universally accepted threshold across all assays, although research commonly defines very low or “IgE-deficient” results around the lower detection limit, often below approximately 2–2.5 kU/L. A single low value is not, on its own, a diagnosis.

Normal variation and non-atopic phenotype

Some healthy people naturally have little measurable IgE. If there are no recurrent infections, autoimmune features, unexplained systemic symptoms or concerns about other immunoglobulins, no disease may be present.

Predominantly antibody deficiencies

Very low IgE is frequently found alongside broader antibody deficiency, including common variable immunodeficiency (CVID) and agammaglobulinaemia. It can act as a clue when a patient also has recurrent sinopulmonary infection, poor vaccine responses, bronchiectasis, persistent gastrointestinal infection, autoimmunity or low IgG, IgA or IgM. Assessment may include quantitative immunoglobulins and functional antibody responses, guided by an immunologist.

Selective IgE deficiency

Selective IgE deficiency describes very low IgE despite otherwise normal major immunoglobulin classes. Research cohorts have reported associations with recurrent respiratory infection, autoimmunity and other immune abnormalities, but definitions vary and causation is not established. It is not yet as clearly standardised as better-known antibody deficiencies. Clinical context should determine whether further assessment is useful.

A low total IgE does not absolutely exclude allergy

A person can have clinically important allergen-specific IgE even when total IgE is low, although interpretation near an assay’s detection limit requires care. Conversely, some immediate reactions are not IgE-mediated at all. If the history strongly suggests allergy, a specialist may consider targeted skin testing, carefully selected specific IgE testing, a basophil activation test in selected circumstances or a supervised challenge.

How IgE is used in a modern allergy clinic

The most valuable use of IgE begins with an allergy-focused history: the suspected exposure, amount, route, reproducibility, interval before symptoms, organs involved, treatment required and relevant cofactors such as exercise, alcohol, infection or medicines. This generates a pre-test probability. Testing is then selected to answer a defined clinical question rather than to search indiscriminately.

Skin-prick testing provides rapid evidence of cutaneous mast-cell sensitisation. Serum specific IgE can be particularly useful when skin testing is impractical, when extensive skin disease is present, when medicines interfere with skin responses or when the history calls for molecular allergen analysis. Component-resolved testing may clarify cross-reactivity—for example between pollens and plant foods—or identify sensitisation to molecules associated with more persistent allergy. Its usefulness varies by allergen and it does not replace clinical assessment.

For food allergy, a medically supervised oral food challenge remains the reference standard when diagnosis remains uncertain and the balance of benefit and risk supports it. For drug allergy and venom allergy, pathways differ and may require validated skin tests, specific IgE where informative and controlled challenge or provocation in an appropriate clinical environment.

Frequently asked questions about IgE

Does a high total IgE mean I have an allergy?

Not necessarily. Allergy is one common explanation, but eczema, parasitic infection, ABPA, certain immune disorders and other uncommon conditions can also raise total IgE. The result needs clinical interpretation.

Can normal total IgE rule out allergy?

No. A patient may have clinically relevant IgE to one or more allergens while their overall total IgE remains within the laboratory reference interval.

Does a higher specific IgE result predict a more severe reaction?

Not reliably. For some foods, increasing values can increase the probability of clinical reactivity within a defined population, but values do not accurately predict the severity of an individual future reaction.

Is “RAST” still the correct term?

RAST refers to the original radioallergosorbent method. Modern laboratories generally use non-radioactive enzyme or fluorescence immunoassays, although “RAST” is still sometimes used informally to mean a specific IgE blood test.

Should total IgE be repeated?

Only when the result will help answer a clinical question—for example, monitoring ABPA or contributing to a defined specialist assessment. Repeating it routinely without a clinical purpose may not be informative.

When to seek specialist advice

An allergy or immunology assessment may be helpful when symptoms suggest an immediate allergic reaction, the trigger is uncertain, existing test results conflict with the history, avoidance is significantly affecting nutrition or quality of life, or IgE is markedly abnormal alongside recurrent infection, severe eczema, eosinophilia or systemic features.

Urgent symptoms: difficulty breathing, throat tightness, collapse or rapidly progressive symptoms after an exposure may represent anaphylaxis and require immediate emergency treatment. Laboratory testing should never delay emergency care.

This article is for general education and does not replace individual medical advice, diagnosis or treatment. Reference intervals, test availability and licensed treatment indications may differ between laboratories and jurisdictions.

References

  1. Platts-Mills TAE. The discovery of IgE 50 years on. Clinical & Experimental Allergy. 2017;47:868–871.
  2. Ishizaka K, Ishizaka T, Hornbrook MM. Physico-chemical properties of human reaginic antibody. IV. Presence of a unique immunoglobulin as a carrier of reaginic activity. Journal of Immunology. 1966;97:75–85.
  3. Ishizaka K, Ishizaka T, Terry WD. Antigenic structure of γE-globulin and reaginic antibody. Journal of Immunology. 1967;99:849–858.
  4. Johansson SGO, Bennich H. Immunological studies of an atypical (myeloma) immunoglobulin. Immunology. 1967;13:381–394.
  5. Bennich HH, Ishizaka K, Johansson SGO, Rowe DS, Stanworth DR, Terry WD. Immunoglobulin E, a new class of human immunoglobulin. Bulletin of the World Health Organization. 1968;38:151–152.
  6. Wide L, Bennich H, Johansson SGO. Diagnosis of allergy by an in-vitro test for allergen antibodies. The Lancet. 1967;2:1105–1107.
  7. Gould HJ, Sutton BJ. IgE in allergy and asthma today. Nature Reviews Immunology. 2008;8:205–217. doi:10.1038/nri2273.
  8. Galli SJ, Tsai M. IgE and mast cells in allergic disease. Nature Medicine. 2012;18:693–704. doi:10.1038/nm.2755.
  9. Hamilton RG, Matsson PNJ, Hovanec-Burns DL, et al. Analytical performance characteristics, quality assurance and clinical utility of immunological assays for human IgE antibodies of defined allergen specificities. Clinical Chemistry. 2015;61:133–147.
  10. Dramburg S, Hilger C, Santos AF, et al. EAACI Molecular Allergology User’s Guide 2.0. Pediatric Allergy and Immunology. 2023;34(Suppl 28):e13854.
  11. Santos AF, Riggioni C, Agache I, et al. EAACI guidelines on the diagnosis of IgE-mediated food allergy. Allergy. 2023;78:3057–3076. doi:10.1111/all.15902.
  12. Ansotegui IJ, Melioli G, Canonica GW, et al. IgE allergy diagnostics and other relevant tests in allergy: a World Allergy Organization position paper. World Allergy Organization Journal. 2020;13:100080.
  13. Homburger HA. Human immunoglobulins. In: Henry’s Clinical Diagnosis and Management by Laboratory Methods. 23rd ed. Elsevier; 2017.
  14. Holland SM, DeLeo FR, Elloumi HZ, et al. STAT3 mutations in the hyper-IgE syndrome. New England Journal of Medicine. 2007;357:1608–1619. doi:10.1056/NEJMoa073687.
  15. Freeman AF, Holland SM. The hyper-IgE syndromes. Immunology and Allergy Clinics of North America. 2008;28:277–291.
  16. Agarwal R, Sehgal IS, Dhooria S, et al. Revised ISHAM-ABPA working group clinical practice guidelines for diagnosing, classifying and treating allergic bronchopulmonary aspergillosis/mycoses. European Respiratory Journal. 2024;63:2400061.
  17. Elkuch M, Greiff V, Berger CT, et al. Low immunoglobulin E flags two distinct types of immune dysregulation. Clinical & Experimental Immunology. 2017;187:345–352.
  18. Lawrence MG, Palacios-Kibler TV, Workman LJ, et al. Low serum IgE is a sensitive and specific marker for common variable immunodeficiency. Journal of Clinical Immunology. 2018;38:225–233.
  19. Gon Y, Maruoka S, Mizumura K. Omalizumab and IgE in the control of severe allergic asthma. Frontiers in Pharmacology. 2022;13:839011.
  20. Davies AM, Allan EG, Keeble AH, et al. Allosteric mechanism of action of the therapeutic anti-IgE antibody omalizumab. Journal of Biological Chemistry. 2017;292:9975–9987.