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The Discovery of IgE

S. G. 0. Johansson, MD

Department of Clinical Immunology and Transfusion Medicine, Karolínska Hospital, Stockholm, Sweden.

In 1919, a case of asthma caused by allergy to horse dander passively transferred by blood transfusion was reported.' and Prausnitz and Küstner performed their famous passive transfer of a positive skin test, later called the PK test, in 1921.'There seemed to exist a key plasma factor, later called reagin. However, despite efforts during the next: 40 years, little progress was achieved with regard to isolation and characterization of the reagin. The extremely low concentration of the allergy-mediating factor, and its great liability as far as cell surface binding is concerned, obscured most experimental data.

In a textbook on immunological diseases printed in 1965, it was speculated that the reaginic activity "is not a single, indivisible molecular species but is present in allergic sera in the form of labile complexes" and that it "differs radically from immune antibodies."

The underestimation of the extreme sensitivity of a reagin-mediated histamine-release reaction is the most likely explanation for the report in 1964 by Ishizaka et al in which they proved that the reagin was an antibody, and this antibody belonged to the gA immunoglobulin class.

A NEW IMMUNOGLOBULIN

The Ishizaka group in Denver, Colorado, continued their experiments. In 1966 and 1967, they claimed to have an antiserum that could precipitate the reagin, resulting in a decrease in reaginic activity as well as binding to a mixture of reaginic serum and an allergen trace-labeled with an isotope in autoradiography.

Independent of this work and for quite other reasons, our group in 1965 detected an atypical myeloma protein that was found to share the physicochemical properties characteristic of the reagin. Using at that time highly sophisticated radioimmunoassays, it was found that patients with allergic asthma had on average a 6-fold higher concentration of immunoglobulin ND (IgND) than did normals or patients with non-allergic: asthma. A radioimmunoassay, the radioallergosorbent test (RAST), was capable of detecting IgND antibodies to alergen that correlated well with skin testing. It also was shown that the PK reaction in humans could be blocked in a dose-dependent way with isolated IgND" or Fc fragments of the ND protein.

In 1967, reagents were exchanged between the two laboratories, and it was found that antiserum to yE-globulin reacted with isolated ND protein and that purified ND protein could block the reaction of anti-'yE-globulin in a biological test system for reaginic activity. These results, as well as immunological reagent, including purified ND protein, were submitted to the World Health Organization Immunoglobulin Reference Centre in Lausanne, Switzerland. At a workshop in Lausanne in February 1968, in which the main researchers from the two groups participated, it was agreed that there were enough data available on the structure and antigenicity of the material to allow the declaration of a new immunoglobulin, which was called IgE." In addition, its relation to the reaginic: activity was confirmed.

THE CLINICAL IMPACT OF IgE

Despite excellent work at many centers in the world, allergology in the mid-1960s was still a clinical specialty with a questionable reputation. In the absence of solid facts about mechanisms, the field was open for speculation. Allergy diagnosis was most1y based on intradermal skin tests, and the allergen extracts used at that time were far from standardized. In this situation, arguments between clinical centers or active research groups on reported data were strong and wild. It was almost a regular phenomenon that findings reported from one place could not be reproduced in another. The solution to the more than 40-year-o1d riddle of the nature of reaginic: activity was a solid piece of science that improved the standard and reputation of allergology.

Access to IgE allowed experimental, immunochemical studies in vitro. The research activity in this field increased enormously, and scientists from areas other than classical allergy became interested in the field and fed into it knowledge of importance. One example is the characterization of one of those mediators, SRS-A, as leukotrienes, which was presented by biochemists initially without any interest in allergy. Today, we are knowledgeable on the various steps in the allergic reaction, starting with contact with a protein allergen in the environment, leading to an allergic inflammation causing sustained symptoms from mucosal membranes and skin. Each step in this chain of reactions is under genetic control and, therefore, the search for a single allergy gene seems a dead-end.

The improved understanding of allergy seems to allow the common use of one nomenclature. The term hypersensitivity is used for any unexpected reaction from mucosal membranes and the skin. Not until immunological mechanisms can be documented should the term a11ergy be used. Other clinically reproducible reactions can be called non-allergic hypersensitivity.

One immediate benefit of the availability of IgE and tests for IgE antibody was the ability to analyze and standardize allergen preparations. It was found early on that labeling an allergen extract in w/v or PNU/ml was no guarantee for a given allergen potency In fact, batches of extracts of simple allergen sources, such as pollen, from a single producer regularly varied in potency by a factor of 100; for molds, differences up to 10 000 were reported. Many extracts (eg, bee and wasp allergens) did not contain any detectable allergen.

When specific antisera to IgE became available, it was possible to develop in vitro tests for measurement of IgE antibodies to allergen. Results of the RAST, published in 1967, showed a correlation between the presence of IgE antibody in serum and positive skin and provocation tests, as well as symptoms of allergy.

Today, approximately 400 different allergens are available for RAST-based allergy diagnosis. In addition to classical pollen, dander and food allergens, drugs, occupational chemicals, and recombinant allergens are available. The general availability of the in vitro test to doctors, specialists, or non-specialists in allergology, as well as the high reproducibility of the test results, has greatly improved the quality of allergy diagnosis in general.

CONCLUSIONS

During the 30 years that IgE has been known, knowledge of allergy has improved immensely. Available now are reliable procedures for allergy diagnosis, standardized allergen preparations for diagnosis and treatment, and tests to monitor the efficiency of therapeutic procedures. However, despite these advances, the prevalence of allergic diseases is increasing.

More efforts must be dedicated to the understanding of why an atopic individual is sensitized, how this sensitization can be avoided by primary prevention, and how to interfere and reverse the harmful effect of this sensitization. Allergy is a serious problem for hundreds of millions of people, and no effort should be spared to improve their quality of life.

REFERENCES

1. Ramirez MA. Horse asthma following b1ood transfusion: report of a case. JAAM. 1919J3:984.

2. Prausnitz Q Küstner H. Studien éber die Üeberernfíndlichkeit. Zentralb1 Báteriol 1. Abt Orig. 19210:160.

3. Schon AH, Gyenes L. Immunology of atopic diseases: antibodies in non- treated patients and antibodies developed during treatment. In: Samter M, Alexander HL, cds. Immunological Diswes. London, UK: j & A Churchill; 1965:519-538.

4. Ishizaka K Ishizaka T, Hathom EM. Blocking of Pausnitz-Kiistner sensitization with reagin by "A" chain of human y,,-globulin. Immunochem.

1964; 1: 197.

5. Ishizaka K, Ishizaka T. Identification of yE-antibodies as a carrier of reaginic activity. J Immunol. 1967;999:1187.

6. Bennich H, Johansson SGO. Studies on a new class of human immunoglobulins: 11. Chemical and physical properties. In: IGIlander J, ed. Gammaglobutinp Structure and Control Biosynthesis. Stockhoim, Sweden: Almqvist & Wlksell; 1967:199-205.

7. Johansson SGO, Bennich H. Studies on a new class of human immunoglob- ulins: I. Immunological properties. In: Killander j, ed. Gammaglobulins. Structume and Control of Biosynthesis. Stockholm, Sweden: Almqvist & Wilesell; 1967:193-197.

8. Johansson SGO. Raised levels of a new immunogiobulin class (IgND) in asthma. Lancet. 1967;2:951-953.

9. Wlde L, Bennich H, Johansson SGO. Diagnosis of allergy by an in-vitro test for aliergen antibodies. Lancet. 1967;2:1105-1107.

10. Stanworth DR, Humphrey JH, Bennich H, Johansson SGO. Specific inhibition of the Prausnitz-Kiistner reaction by an atypical human rnyelorna protein. Lancet. 1967;2:330-332.

11. Stanworth DR, Humphrey JH, Bennich H, Johansson SGO. Inhibition of the Prausnitz-Küstner reaction by proteolytic cicavage fragments of a human myeloma protein of immunoglobulin class E. Lancet. 1968;2:17-18.

12. Bennich HH, Ishizaka K, Johansson SGO, Rowe DS, Stanworth DR, Terry VíD. Immunoglobulin E, a new class of human immunoglobulin. Buü WorldHealth Organ. 196838:151-152.