Otto Prausnitz and Heinz Küstner show that hyper-sensitivity to allergens can be transferred from one individual to the skin of another non-allergic individual using blood serum. This became a clinical method in allergology called the Prausnitz-Küstner test (P-K test).
Arthur Coca and Ella Grove postulate that allergic hyper-sensitivity is mediated by a special form of sensitizing body present in the blood and different from normal antibodies. They call it “atopic reagin,” which becomes the target of a 40-year investigation.
A Swedish farmer in 1965 is diagnosed with a rare form of blood cancer (multiple myeloma). Gunnar Johansson, a PhD student at Uppsala University Hospital, identifies an atypical myeloma protein in the patient’s blood. Together with another PhD student, biochemist Hans Bennich, he begins researching the protein and together they discover that it is a previously unknown immunoglobulin with unique immunological and physiochemical characteristics and gives it the working name immunoglobulin ND (IgND) after the initials of the farmer.
Kimishige and Teruko Ishizaka led a research group in Denver, Colorado, USA that had been searching for the nature of reagin since the early 1960s. In common with many other scientists at that time, they first presented data indicating that reagins were antibodies belonging to the known IgA class. However, further studies of the team using improved techniques, presented in a series of reports during 1966, indicated that reagin from allergic individuals rather belong to a unique, previously undescribed, immunoglobulin class. They called it γE globulin and showed that it comprised P-K test activity and was present in only tiny amounts in allergic serum; a hurdle for its purification and complete characterization.
Together with the experienced immunoassay specialist Leif Wide, a radioimmunosorbent test for IgND was developed. Johansson, Bennich and Wide could then show that IgND was present in serum of healthy subjects as well as in elevated levels in patients with allergy and asthma. In a collaboration between the Uppsala team (Johansson and Bennich) and the British scientists Denis Stanworth and John Humphrey, it was shown that IgND could block the P-K test, a final proof of the association between IgND and reagin. In parallel, Ishizakas’ team in Denver publish improved evidence of the association between γE globulin and reagin, and that γE globulin also is present in normal sera.
Johansson and Bennich contact the Ishizakas and both teams exchange their reagents for independent comparison. They find that IgND and γE globulin share unique epitopes and thus seem to belong to the same immunoglobulin class.
Wide, Bennich and Johansson develop the first radioallergosorbent test (RAST) for measurement of reagins (IgE antibodies) using allergen-coupled sephadex particles and 125I-labelled anti-IgND antibodies. They show a high correspondence between RAST results and allergen provocation results in allergic patients indicating the value of RAST in clinical diagnosis of allergic diseases.
In February 1968 both the Uppsala and Denver teams were invited to the World Health Organization (WHO) International Reference Centre for Immunoglobulins in Lausanne, Switzerland, to present and discuss their findings. It was finally concluded by WHO that a new (fifth) class of immunoglobulin had been discovered, of which reagins were representative, and that this class should be named immunoglobulin E (IgE).
In 1974, Pharmacia launches the world’s first commercial blood test for specific IgE, called Phadebas® RAST, based on the invention by Wide, Bennich and Johansson. It proves to be very useful in clinical practice together with the two-years earlier launched blood test for total IgE, Phadebas® IgE test.
Phadiatop™ was the first multi-allergen IgE test to quickly screen a panel of common allergens. The carefully composed mixture representing the most prevalent allergens could detect atopic symptoms with a sensitivity and specificity as high as 93%.
A highly prestigious prize in allergy, the Pharmacia Allergy Research Forum Award, was established on the 20th anniversary of IgE to encourage progress in allergy research, especially the contributions from outstanding young researchers.
Pharmacia Diagnostics launched the CAP system by introducing a new solid-phase ImmunoCAP® test that greatly improved sensitivity and enabled comparable reporting across laboratories. A universal method for measuring IgE was born that improved research tools and diagnostics.
The world’s first automated laboratory system for allergen sensitization testing was called UniCAP™ 100 and integrated sample handling, measuring instrumentation, and data evaluation in a single platform. Labs were now able to handle a hundred tests in a single run. Over the years, UniCAP would evolve into the Phadia® systems and form a complete family for every size lab.
We have come to understand that the immune system can react similarly to proteins of different allergen sources, giving rise to cross-reactivity and different immunological response. By developing IgE tests for individual allergenic proteins (now over 100), clinicians have been able to grow increasingly precise in both the diagnosis and treatment considerations of individual patients.
The advances in molecular allergology and biochip technologies have enabled the development of a simultaneous IgE test of over 100 different allergens, ImmunoCAP ISAC. Advancements like this can help clinicians to resolve cases where patient symptoms and medical history are inconsistent e.g., to find the cause of anaphylaxis that has occurred without a clear triggering allergen or to accurately diagnose and manage poly-sensitized patients with severe eczema. The future of IgE still has many discoveries left to uncover.
Professor S.G.O. (Gunnar) Johansson (born 1938) was a medical student at the Uppsala University Hospital in Sweden, when in 1965 he discovered an atypical myeloma protein in the serum of a patient which was shown to represent a new immunoglobulin class involved in allergic diseases known as IgE. Along with his colleague Hans Bennich, he described the immunological and physiochemical characteristics of IgE and its association with reaginic activity. Together with Bennich and Leif Wide, he developed the first blood tests for IgE (RIST) and allergen-specific IgE antibodies (RAST).
S.G.O. Johansson in 1980 was appointed Professor of Clinical Immunology (Allergology) at Karolinska Institutet, Stockholm and he has made considerable scientific contributions in the field of allergology. He was elected President of the European Academy of Allergy and Clinical Immunology, 1995-1998, and President of the World Allergy Organization, 1997-2000.
Professor S.G.O. Johansson is recognized internationally by more than 25 national and international societies of Allergology and Clinical Immunology and recipient of numerous national and international awards.
S.G.O. Johansson in 2015 is an Honorary Doctor in Medicine in Universidad San Pablo, Madrid, and in 2017 is appointed Honorary Doctor at Uppsala University’s Faculty of Pharmacy for his contribution in the discovery of IgE and the development of modern IgE antibody diagnostics.
Professor Hans Bennich (born 1930) was a biochemist and PhD student at Uppsala University when he, together with Gunnar Johansson, isolated, analyzed and described an atypical myeloma protein from the serum of a multiple myeloma patient and showed that it represented a new immunoglobulin class involved in allergy (immunoglobulin E). Bennich and Johansson began working together with immunoglobulin research in 1962, and formed a close collaboration that would continue for more than 20 years.
After the discovery of IgE, Hans Bennich continued his research about the IgE molecule for more than a decade but then he changed focus. He was appointed Professor in Molecular Immunology in 1986 and leader of a research group at Uppsala University studying insect immunity until his retirement.
Besides his great achievements in immunoglobulin research and insect immunity, Hans Bennich is recognized for his contribution in development of protein chromatography methods. Hans Bennich was appointed in 1989 as a member of the Royal Swedish Academy of Sciences.
Professor Leif Wide (born 1934) developed the first IgE test and allergen-specific IgE test in 1967 together with S.G.O. Johansson and Hans Bennich. With the IgE test it was possible to show that IgE (at that time called IgND) was present in serum of both healthy and allergic individuals, a prerequisite for the acceptance of IgE as a new unique immunoglobulin class in 1968. The specific IgE test was known as the radioallergosorbent test (RAST) and was commercialized by Pharmacia in 1974.
Leif Wide was a young student when in 1960 he developed the world's first pregnancy test based on immunoassay technology. In 1965-1969, he made a series of discoveries concerning immunoassay techniques that included the competitive solid-phase assay and the two-site, non-competitive sandwich assay. Wide convinced Pharmacia to start with in vitro diagnostics and to develop hormone assays based on his inventions using sephadex particles as solid phase, as well as tests for diagnosis of allergy.
Leif Wide was appointed Professor in Biochemical Endocrinology at Uppsala University and has in the past few years made discoveries concerning improved immunoassay techniques to measure different protein glycoforms. He has been awarded a number of prestigious scientific prizes for his life-long work.
Professor Kimishige Ishizaka (born 1925) and his wife Professor Teruko Ishizaka (born 1926) led a research team at the University of Colorado Medical School in Denver that in 1966-67 showed that reagin, the antibody in serum involved in allergic reactions, belonged to a unique, previously undescribed, immunoglobulin class known as IgE.
In 1970 they moved to Johns Hopkins University School of Medicine in Baltimore where they continued their efforts to identify the biological processes of allergic diseases. They worked there until 1989, when Kimishige Ishizaka became Scientific Director and President of the new La Jolla Institute for Allergy and Immunology where they stayed until retirement.
Kimishige Ishizaka has been awarded a number of prestigious awards for his work in allergy and immunology including the Gairdner Foundation International Award and the 2000 Japan Prize. He has been a member of the United States National Academy of Sciences since 1983.
The history of diagnostic allergen sensitization testing has a celebrated lineage that reaches back through Thermo Fisher and Phadia, which developed the first commercially available test for allergen-specific IgE antibodies shortly after the discovery of IgE, and continues to develop some of the most routinely used solutions for immunodiagnostics in the world.
Click the arrows at right to cycle through some of the important technologies and tests that have resulted from discovering IgE.
As a milestone, the 50th anniversary of the discovery of IgE provides an opportunity to look forward towards the future of our field and the promise of further evolving technologies. Thermo Fisher Scientific is committed to seeing this rich history continue to reveal even more exciting developments that will improve diagnosis, treatment, and the quality of life for everyone affected by allergies and asthma.