Identification of IgE
Authors: Kimishige Ishizaka, Teruko Ishizaka
Journal: Journal of Allergy and Clinical Immunology (2016)

Progress in protein chemistry in the 1950s revealed that the biologic activities of proteins, such as hemoglobin and enzymes, are based on partial structures in the protein molecules. This principle suggested to us the possibility that the human antibodies responsible for induction of reaginic hypersensitivity reactions might have unique structures that are lacking in the antibody molecules involved in immunity and that the differences in the structures of human antibody molecules can be recognized by the immune systems of experimental animals. Our studies were based on the hypothesis that reaginic antibody activity is associated with a unique immunoglobulin isotype, which is now called IgE. As expected, identification of IgE facilitated the analysis of immunologic mechanisms of reaginic hypersensitivity. Subsequent studies revealed that IgE specifically bound to basophilic granulocytes and mast cells through the Fc portion of the molecules and that cross-linking of the cell-bound IgE antibody molecules by allergen induced the release of bioactive mediators, such as histamine and leukotrienes, which initiate allergic reactions. Progress in protein chemistry in the 1950s revealed that the biologic activities of proteins, such as hemoglobin and enzymes, are based on partial structures in the protein molecules. This principle suggested to us the possibility that the human antibodies responsible for induction of reaginic hypersensitivity reactions might have unique structures that are lacking in the antibody molecules involved in immunity and that the differences in the structures of human antibody molecules can be recognized by the immune systems of experimental animals. Our studies were based on the hypothesis that reaginic antibody activity is associated with a unique immunoglobulin isotype, which is now called IgE. As expected, identification of IgE facilitated the analysis of immunologic mechanisms of reaginic hypersensitivity. Subsequent studies revealed that IgE specifically bound to basophilic granulocytes and mast cells through the Fc portion of the molecules and that cross-linking of the cell-bound IgE antibody molecules by allergen induced the release of bioactive mediators, such as histamine and leukotrienes, which initiate allergic reactions. Discuss this article on the JACI Journal Club blog: www.jaci-online.blogspot.com. The reaginic antibody was discovered by Prausnitz and Küstner in 1921. They found that an intracutaneous injection of serum from an allergic patient into a healthy subject followed by next-day challenge of the skin site with the allergen to which the serum donor is sensitive resulted in induction of an erythema-wheal reaction. Because the antibody specific for the allergen was not detectable in donor serum at that time, the antibody-like substance responsible for induction of the erythema-wheal reaction was called "reagin." In the 1950s, the physicochemical properties of reagin in sera of patients with hay fever were studied by using various fractionation methods, such as zone electrophoresis, ion exchange column chromatography, and ultracentrifugation. The results clearly showed that the physicochemical properties of reagin were different from the properties of IgG or IgM. After the third immunoglobulin, IgA, was isolated and characterized, Heremans and Vaerman1Heremans J.F. Vaerman J.P. β2A globulin as a possible carrier of reaginic activity.Nature. 1962; 193: 1091-1092Crossref PubMed Scopus (14) Google Scholar reported that the apparently pure IgA preparations obtained from the sera of patients with hay fever had the skin-sensitizing activity, and their results were confirmed by several other investigators. By the end of 1964, most immunologists and allergists believed that reagin is the IgA antibody specific for allergen. Because our main interest at that time was the structural basis of the biologic activities of rabbit IgG antibody molecules to induce allergic reactions in the guinea pig,2Ishizaka K. Ishizaka T. Sugahara T. Biologic activities of soluble antigen-antibody complex. VII Role of an antibody fragment in the induction of biological activities.J Immunol. 1962; 88: 690-701Google Scholar we wondered whether the principles obtained in animal experiments could be applied for elucidation of the mechanisms of "IgA-dependent" reaginic hypersensitivity in human subjects. Thus we immunized blood group type O subjects with blood group A substance, isolated IgA in their sera, and examined the immunologic properties of the IgA antibodies specific for the blood group substance. To our great surprise, none of the IgA, IgG, and IgM antibodies against the blood group substance sensitized human skin for the Prausnitz-Küstner (PK) reaction.3Ishizaka K. Ishizaka T. Lee E.H. Fudenberg M. Immunochemical properties of human γA isoagglutinin. I. Comparisons with γG and γM globulin antibodies.J Immunol. 1965; 95: 197-208PubMed Google Scholar Because I believed that the biological activities of antibodies are determined by the structures in the Fc portion of the molecules,2Ishizaka K. Ishizaka T. Sugahara T. Biologic activities of soluble antigen-antibody complex. VII Role of an antibody fragment in the induction of biological activities.J Immunol. 1962; 88: 690-701Google Scholar I could not accept that the anti-ragweed IgA antibody in the sera of patients with hay fever had skin-sensitizing activity but the IgA antibody against blood group substance did not. I wondered whether the reaginic activity in the IgA fraction of sera of patients with hay fever might be associated with a very minor component that was present in the IgA fraction as an impurity. To test this possibility, the rabbit antibody specific for human IgA was added to the IgA fraction of the sera of patients with hay fever to precipitate all IgA in the fraction, and the supernatant was tested for the presence of reagin by using the PK reaction. The results clearly showed that all reaginic activity in the IgA preparation remained in the supernatant, indicating that the activity is associated with an impurity that is undetectable by using the usual immunochemical methods.4Ishizaka K. Ishizaka T. Physicochemical properties of reaginic antibody. III. Further studies on the reaginic antibody in γA globulin preparations.J Allergy. 1966; 38: 108-119Abstract Full Text PDF PubMed Scopus (24) Google Scholar However, this finding brought up another difficult problem. Because the reaginic activity (PK titer) of the supernatant was comparable with the activity of the original serum from which the IgA fraction was obtained, our results suggested that the concentration of the carrier protein of the reaginic activity in the original serum was less than 1 μg/mL. At that time, the requirements for identification of a new protein were to isolate the protein and prove that the physicochemical properties of the pure protein are different from those of the known proteins. However, such approaches are impossible for identification of a minor serum component. Thus I changed our strategy to prepare rabbit antibodies specific for reagin and to identify the reagin in vitro by using the rabbit antibodies. For this purpose, we immunized rabbits repeatedly with the reagin-rich fraction of the sera of patients with hay fever together with complete Freund adjuvant and absorbed the antiserum with normal human IgG, IgA myeloma proteins, and IgD myeloma proteins to remove all antibodies reacting to the known human immunoglobulin isotypes.5Ishizaka K. Ishizaka T. Hornbrook M.M. Physicochemical properties of reaginic antibody. IV. Presence of a unique immunoglobulin as a carrier of reaginic activity.J Immunol. 1966; 97: 75-85PubMed Google Scholar The antiserum was added to the serum of a patient with ragweed sensitivity to test the presence of antibodies specific for reagin in the absorbed rabbit antiserum. After incubation for 24 hours at 4°C, the mixture was centrifuged to remove a trace amount of the precipitate, and 100 to 800 two-fold dilutions of the supernatant were injected intracutaneously into the left side of my back (Fig 1). The right side received the same dilutions of the mixture of the patient's serum with normal rabbit serum. The next day, all of the skin sites were challenged with the purified ragweed antigen E, which was supplied by Drs Merrill Chase and T. P. King (Rockefeller Institute for Medical Research). As shown in Fig 1, no erythema-wheal reaction appeared at the left injection sites, indicating that the rabbit antiserum contained the antibody specific for human reagin and that the rabbit antibody specifically removed reagin in the patient's serum.5Ishizaka K. Ishizaka T. Hornbrook M.M. Physicochemical properties of reaginic antibody. IV. Presence of a unique immunoglobulin as a carrier of reaginic activity.J Immunol. 1966; 97: 75-85PubMed Google Scholar Since the rabbit antibody specific for reagin became available, attempts have been made to identify reagin in vitro by using the rabbit antibody and to determine the physicochemical properties of reagin. For this purpose, the globulin fraction of sera of patients with ragweed sensitivity was fractionated by using DEAE cellulose column chromatography, and distribution of reagin in the chromatographic fractions was determined by using the rabbit anti-reagin antibody. In the agarose plate shown in Fig 2, the peripheral wells were filled with the original patient's serum and the chromatographic fractions, and the center well was filled with the anti-reagin antiserum, followed by 131I-labeled ragweed antigen E. Autoradiography of the plate indicated that the precipitin band formed by Fraction II contained the highest anti-ragweed antibody activity. Determination of the anti-ragweed reaginic activity of each fraction by using the P-K test also showed that Fraction II had the highest skin-sensitizing activity.5Ishizaka K. Ishizaka T. Hornbrook M.M. Physicochemical properties of reaginic antibody. IV. Presence of a unique immunoglobulin as a carrier of reaginic activity.J Immunol. 1966; 97: 75-85PubMed Google Scholar, 6Ishizaka K. Ishizaka T. Hornbrook M.M. Physicochemical properties of reaginic antibody. V. Correlation of reaginic activity with γE globulin antibody.J Immunol. 1966; 97: 840-853PubMed Google Scholar Because the protein forming the precipitin band did not belong to any of the known immunoglobulin isotypes but contained the antibodies specific for antigen E, we tentatively called this protein γE because I believed that the human anti-ragweed antibody detected by the rabbit antiserum was responsible for induction of erythema-wheal reactions.5Ishizaka K. Ishizaka T. Hornbrook M.M. Physicochemical properties of reaginic antibody. IV. Presence of a unique immunoglobulin as a carrier of reaginic activity.J Immunol. 1966; 97: 75-85PubMed Google Scholar In the experiment shown in Fig 3, the reagin-rich fraction of the sera of patients with ragweed sensitivity was analyzed by using radioimmunoelectrophoresis. The fraction was placed in the well of the agarose plate, and after electrophoresis, the trough was filled with rabbit anti-γE antiserum, followed by radiolabeled ragweed antigen E. A visible precipitin band was barely seen in the stained slide, but the autoradiograph of the slide clearly showed a fast-moving γ-globulin band, indicating that the electrophoretic mobility of γE is in the fast γ-globulin region.6Ishizaka K. Ishizaka T. Hornbrook M.M. Physicochemical properties of reaginic antibody. V. Correlation of reaginic activity with γE globulin antibody.J Immunol. 1966; 97: 840-853PubMed Google Scholar In a similar manner the molecular weight of γE was determined by using sucrose density gradient ultracentrifugation and gel filtration. The results showed that the sedimentation coefficient of γE is 8.0S, and the molecular weight of the protein is approximately 190,000, indicating that the physiochemical properties of γE are different from the properties of the known immunoglobulin isotypes, such as IgG, IgM, IgA, or IgD. It was also found that γE molecules contained κ and λ light chains, which are common for all the other immunoglobulin isotypes.6Ishizaka K. Ishizaka T. Hornbrook M.M. Physicochemical properties of reaginic antibody. V. Correlation of reaginic activity with γE globulin antibody.J Immunol. 1966; 97: 840-853PubMed Google Scholar In addition, γE had the antigenic determinant, which was not shared by any of the immunoglobulins of known isotypes. The unique antigenic structure of γE together with the presence of antibody activity associated with γE was sufficient for the conclusion that γE represents a distinct immunoglobulin isotype.7Ishizaka K. Ishizaka T. Terry W.D. Antigenic structure of γE globulin and reaginic antibody.J Immunol. 1967; 99: 849-858PubMed Google Scholar The definitive evidence that convinced us of the relationship between γE and reagin was provided by measurement of the antigen-binding activities of the γG, γA, and γE antibodies specific for antigen E in the serum of ragweed-sensitive patients using radioimmunoassays.8Ishizaka K. Ishizaka T. Hornbrook M.M. Allergen-binding activity of γE, γG and γA antibodies in sera from atopic patients. In vitro measurement of reaginic antibody.J Immunol. 1967; 98: 490-501PubMed Google Scholar As shown in Table I, the maximal dilution of the serum, providing positive PK reactions (PK titer), correlated with the allergen-binding activity of γE antibody but not with the activity of γG or γA antibodies in serum. The results indicated that the intensity of the skin-sensitizing activity of the patient's serum is decided by the concentration of γE antibodies specific for the allergen in the serum. On average, the minimal concentration of γE antibody required for a positive PK reaction in sera from 6 patients was 0.25 ng/mL.8Ishizaka K. Ishizaka T. Hornbrook M.M. Allergen-binding activity of γE, γG and γA antibodies in sera from atopic patients. In vitro measurement of reaginic antibody.J Immunol. 1967; 98: 490-501PubMed Google ScholarTable IAllergen-binding activity of antibodies in patients' sera∗Numerals in the table indicate micrograms of antigen E bound by immunoglobulins in 1 mL of serum.Adapted from Table II in Ishizaka et al.8Ishizaka K. Ishizaka T. Hornbrook M.M. Allergen-binding activity of γE, γG and γA antibodies in sera from atopic patients. In vitro measurement of reaginic antibody.J Immunol. 1967; 98: 490-501PubMed Google ScholarSerumAllergen-binding activityP-K titerγGγAγEIG†Measured by precipitation of all immunoglobulins with anti-light chain antibodies.IG cal‡Values of allergen-binding activity of γG, γA, and γE antibodies were summed.EK0.4000.230.620.631600B0.2600.380.660.643200Fic§Untreated patients (all other patients were treated).0.160.0820.140.330.38800F§Untreated patients (all other patients were treated).0.140.0160.0970.250.27600A10.2300.100.340.33800W0.610.0330.0990.790.74600P1.800.071.91.9400I1.9001.91.90∗ Numerals in the table indicate micrograms of antigen E bound by immunoglobulins in 1 mL of serum.† Measured by precipitation of all immunoglobulins with anti-light chain antibodies.‡ Values of allergen-binding activity of γG, γA, and γE antibodies were summed.§ Untreated patients (all other patients were treated). Open table in a new tab On the basis of these findings, we purified γE in sera of ragweed-sensitive patients with hay fever by combining several fractionation methods, and a trace amount of IgG and IgA remaining in the purified γE fraction was removed by using homemade anti-IgG and anti-IgA immunosorbents. The final preparation, which produced positive P-K reactions up to a dilution of 1:80,000, was analyzed by means of radioimmunodiffusion (Fig 4). In the Ouchterlony plate the center well was filled with purified γE, and the peripheral wells were filled with rabbit antibodies specific for each immunoglobulin isotype, followed by the radiolabeled ragweed antigen E. As shown in Fig 4, only anti-γE formed a visible precipitin band, and the radiolabeled antigen E bound to the precipitin band. None of the known immunoglobulins (ie, IgG, IgA, IgD, and IgM) was detected in the purified γE preparation. Thus we concluded that reagin is the γE antibody specific for allergen.9Ishizaka K. Ishizaka T. Identification of γE antibodies as a carrier of reaginic activity.J Immunol. 1967; 99: 1187-1198PubMed Google Scholar Association of reaginic activity with γE is not restricted to the ragweed antigen system. Reaginic activity against the other allergens, such as house dust and ovalbumin, was also associated with γE.10Ishizaka K. Ishizaka T. Human reaginic antibodies and immunoglobulin E.J Allergy. 1968; 42: 330-363Abstract Full Text PDF PubMed Scopus (126) Google Scholar Rabbit anti-γE antibodies were also useful for identification of patients with E myeloma. At that time, Johansson and Bennich11Johansson S.G. Bennich H. Immunological studies of an atypical (myeloma) immunoglobulin.Immunology. 1967; 13: 381-394PubMed Google Scholar in Sweden isolated atypical myeloma protein (protein ND). After they submitted their article for publication, they recognized that the physicochemical properties of the myeloma protein were almost identical to the properties of γE described in our previous publication.6Ishizaka K. Ishizaka T. Hornbrook M.M. Physicochemical properties of reaginic antibody. V. Correlation of reaginic activity with γE globulin antibody.J Immunol. 1966; 97: 840-853PubMed Google Scholar Thus they contacted us, and we exchanged our rabbit anti-γE and their sheep antiserum specific for the myeloma protein ND. In the experiment shown in Fig 5, we tested whether the antibodies specific for the myeloma protein ND bind to γE. In the agarose plate the center well was filled with the purified γE preparation obtained from serum from a ragweed-sensitive patient with hay fever. Peripheral wells were filled with sheep antiserum specific for the myeloma protein and rabbit antibodies specific for each immunoglobulin isotype, followed by radiolabeled ragweed antigen E. Autoradiography of the plate clearly showed that the antibodies specific for the myeloma protein ND and our anti-γE formed a single precipitin band of identical specificity with γE, indicating that the myeloma protein ND possesses the γE-specific antigenic determinants and therefore that the ND protein is the E myeloma protein.12Bennich H. Ishizaka K. Ishizaka T. Johansson S.G. A comparable antigenic study of γE globulin and myeloma IgND.J Immunol. 1969; 102: 826-831PubMed Google Scholar Association of antibody activities with γE, together with the presence of the myeloma protein with the antigenic determinant specific for γE, were sufficient for the conclusion that γE represents a unique immunoglobulin isotype. Thus the World Health Organization (WHO) officially named this protein IgE in 1968. Our anti-IgE antibodies were useful for identification of the second case of E myeloma as well. The patient (patient PS) visited Dartmouth Medical School Hospital in 1968. Because the blood test revealed that 65% of his leukocytes were plasma cells, his disease was diagnosed as plasma cell leukemia, and his serum was sent to Mount Sinai Hospital, New York, for identification of the isotype of the myeloma protein. However, the M protein did not produce a precipitin band with any of the antiserum specific for IgG, IgA, or IgD. Considering the possibility that the myeloma protein might belong to IgE isotype, Dr Kochwa at Mount Sinai Hospital sent the serum specimen to us in Denver, Colorado. Indeed, the M protein obtained by using block electrophoresis produced a strong precipitin band with our anti-IgE but not with any of the antibodies specific for the other isotypes. Examination of peripheral blood and bone marrow smears of the patient by means of immunofluorescence revealed that nearly all plasma cells and some lymphoblasts were IgE-producing cells, and the M protein in the serum of the patient was identified as λ type E myeloma protein.13Ogawa M. Kochwa S. Smith C. Ishizaka K. McIntire O.R. Clinical aspects of IgE myeloma.N Engl J Med. 1969; 281: 1217-1220Crossref PubMed Scopus (86) Google Scholar The concentration of E myeloma protein in the plasma of patient PS was 30 to 40 mg/mL. Because he received plasmapheresis once every week for therapeutic purpose, more than 30 L of his plasma was obtained until his death. Thus we isolated E myeloma protein from the patient's plasma using ion-exchange chromatography followed by gel filtration, prepared the Fc fragment of the myeloma protein by means of papain digestion,14Ishizaka K. Ishizaka T. Lee E.H. Biologic function of the Fc fragments of E myeloma protein.Immunochemistry. 1970; 7: 687-702Crossref PubMed Scopus (117) Google Scholar and immunized rabbits and a goat with the Fc fragment. Immunodiffusion analysis in the Ouchterlony plate showed that the antiserum against the Fc fragment formed a single precipitin band of identical specificity with the PS protein, ND protein, and IgE-rich fraction of the sera of patients with hay fever, but no visible precipitin band with normal serum, which contained less than 0.2 μg/mL IgE. At that time, many allergists and immunologists were interested in the IgE system, but they could not prepare monospecific anti-IgE. Thus we have sent purified PS protein and/or the antiserum specific for the Fc fragment of PS protein to many investigators in the United States and Europe on request. Looking to the past, the number of shipments of PS protein/anti-IgE to our colleagues for the next 10 years was close to 100. We believe that the PS protein and the anti-Fcε antibodies facilitated the progress of allergy research in the 1970s. PS protein was quite useful for preparation of commercial anti-IgE antiserum as well. Immediately after our report to the WHO on identification of PS protein as IgE myeloma protein, Dr David Rowe at the WHO selected 3 companies in the United States and 3 companies in Europe and asked us to send purified PS protein to these companies for preparation of commercial anti-IgE antiserum. Because Dartmouth Medical School also supplied the plasma of patient PS to such companies, most of the monospecific anti-IgE used in the world for the next 10 years was prepared by using PS protein. When we initiated our studies on reaginic antibodies in 1963, some allergists told us that reagin is useful for diagnostic purpose but that the cause of allergic diseases, such as hay fever, is idiosyncratic and that reagin is not involved in the pathogenesis of allergic diseases. However, identification of reagin as IgE antibodies facilitated elucidation of the immunologic mechanisms of allergic reactions and raised the possibility that IgE antibodies are involved in the pathogenesis of allergic diseases. In the course of our studies on IgE, we found that an intracutaneous injection of only 1 to 2 ng/mL anti-IgE to healthy subjects resulted in induction of the erythema-wheal reaction, whereas injection of even 1 μg/mL of the antibodies specific for IgG, IgA, IgM, or IgD did not do so.15Ishizaka K. Ishizaka T. Reversed type allergic skin reactions by anti-γE globulin antibodies in humans and monkeys.J Immunol. 1968; 100: 554-562PubMed Google Scholar Because healthy subjects have IgE, mechanisms of the skin reaction were considered to be the result of binding of anti-IgE antibodies to IgE on some normal cells in skin tissues. It was also found that human IgE antibodies sensitize not only human skin but also monkey lung tissue and mediate the antigen-induced release of histamine and leukotrienes from tissue.16Ishizaka T. Ishizaka K. Orange R.P. Austen K.F. The capacity of human immunoglobulin E to mediate the release of histamine and slow reacting substance of anaphylaxis from monkey lung.J Immunol. 1970; 104: 335-343PubMed Google Scholar Sensitization of homologous species with IgE antibodies was observed at the cellular level as well. Since 1964, it has been known that incubation of leukocytes of atopic patients with allergen resulted in histamine release.17Lichtenstein L.M. Osler A.G. Studies on the mechanisms of hypersensitivity phenomena. IX. Histamine release from human leukocytes by ragweed pollen allergen.J Exp Med. 1964; 120: 507-530Crossref PubMed Scopus (547) Google Scholar In this system we found that antibodies specific for IgE induced histamine release from the leukocytes of not only patients with hay fever but also healthy subjects. These results indicated that some human leukocytes bear IgE molecules on their cell surfaces.18Ishizaka T. Ishizaka K. Johansson S.G. Bennich H. Histamine release from human leukocytes by anti-γE antibody.J Immunol. 1969; 102: 884-892PubMed Google Scholar Since the second E myeloma protein (PS protein) became available for our research, anti-IgE antibody was specifically purified by using the myeloma protein, and the purified anti-IgE facilitated identification of target cells for IgE. In the experiment shown in Fig 6, normal human leukocytes were incubated with 125I-labeled anti-IgE in the presence of EDTA, which prevented histamine release. Autoradiography of leukocytes clearly showed that radiolabeled anti-IgE bound to basophilic granulocytes but not to the other leukocytes, such as neutrophils, eosinophils, monocytes, or lymphocytes.19Ishizaka K. Tomioka H. Ishizaka T. Mechanisms of passive sensitization. I. Presence of IgE and IgG molecules on human leukocytes.J Immunol. 1970; 105: 1459-1467PubMed Google Scholar ∗CD23 on lymphocytes was not detected in this experiment because 125I-labeled anti-IgE–treated leukocytes were washed extensively before the smears were made. IgE bound to CD23 should have dissociated by washing. The results indicated that basophils bear IgE on the cell surface and that the allergen-IgE antibody reaction on basophils resulted in release of histamine from the cells. Cells sensitized with IgE were identified in tissues as well. In this experiment the E myeloma protein PS was injected into monkeys, and their tissues were treated with 125I-labeled anti-IgE. Autoradiography of frozen tissue sections clearly showed the selective binding of E myeloma protein to mast cells in the skin, omentum, small intestine, and bronchi, indicating that mast cells have receptors for IgE on their surfaces (Fig 7).20Tomioka H. Ishizaka K. Mechanisms of passive sensitization. II. Presence of receptors for IgE on monkey mast cells.J Immunol. 1971; 107: 971-978Crossref PubMed Google Scholar It was also found that IgE molecules bind to the receptors through the Fc portion of the molecule14Ishizaka K. Ishizaka T. Lee E.H. Biologic function of the Fc fragments of E myeloma protein.Immunochemistry. 1970; 7: 687-702Crossref PubMed Scopus (117) Google Scholar and that cross-linking of cell-bound IgE antibody molecules by antigen is responsible for activation of target cells for mediator release.21Ishizaka K. Ishizaka T. Induction of erythema-wheal reactions by soluble antigen-γE antibody complexes in humans.J Immunol. 1968; 101: 68-78PubMed Google Scholar, 22Ishizaka K. Ishizaka T. Immune mechanisms of reversed type reaginic hypersensitivity.J Immunol. 1969; 103: 588-595PubMed Google ScholarFig 7Selective binding of IgE on monkey mast cells. E myeloma protein PS was injected intracutaneously into a monkey. Twenty-four hours later, the skin tissues were treated with 125I-labeled anti-IgE, and frozen sections of the tissues were examined. Both the stained slide (bottom) and autoradiograph (top) are shown.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Identification of the receptors for IgE on basophils and mast cells led to subsequent research on FcεRI by Dr Henry Metzger and his associates, followed by extensive studies by many investigators on the biochemical pathways for the IgE-mediated release of chemical mediators and the synthesis of cytokines by mast cells and basophils. We are very pleased that the IgE system has been used for elucidation of the immunologic and biochemical mechanisms of allergy and for clinical studies on allergic diseases by many investigators for the past 50 years.