Paper: Immunoglobulin E, a new class of human immunoglobulin
Hans Bennich, Kimishige Ishizaka, Gunnar Johansson, David Rowe, Denis Stanworth, and William Terry
Bulletin of the World Health Organization 1968; 38 (1)
Studies of the nature of the antibodies associated with isologous skin sensitizing activity have indicated the presence of a previously unrecognized immunoglobulin in human serum. The immunoglobulin was identified by virtue of specific antigenic determinants. Independently, a protein with similar antigen characteristics was identified both in the serum of a patient with multiple myeloma and in normal serum. It is proposed that the normal protein and antigenically related myeloma proteins shall be designated IgE or γE, and the heavy polypeptide chains of these molecules be designated ε (epsilon)-chains, in accordance with Nomenclature for Human Immunoglobulins. This replaces the previous usage of γE-globulin and IgND.
How wonderful that we have met with a paradox. Now we have some hope of making progress
Niels Bohr, quoted by Moore 19671
It was the convergence of three separate lines of research that culminated, within the space of a year (1966–7), in the solution to a problem which had long vexed allergologists. Reagin was the name given to the unknown ‘principle’ responsible for the action of serum in inducing wheal-and-flare (allergic) reactions in the skin-prick or Prausnitz–Küstner (P-K) test. This activity was generally taken to imply that reagin was an antibody, but in 1966 the only known antibody classes were IgM, IgD, IgG, and IgA. Ishizaka et al.2 analysed different fractions from the sera of allergic subjects for reaginic activity in the P-K test and inferred that reagin belongs to a new class of immunoglobulins, which they called γE. In 1967 Gunnar Johansson and Hans Bennich reported that the myeloma protein from patient ND (‘myeloma ND’) similarly represented a new class of antibody.3 They also noted that its physical properties resembled those of the Ishizakas’ γE. This perception led directly to the experiment which showed that myeloma ND inhibited the activity of reagin in the P-K reaction.4 At a meeting held in Lausanne by the WHO the principal investigators in these three studies agreed to designate this new antibody class immunoglobulin-E.5 Without the identification of the IgE protein we could not have achieved the basic understanding of allergic disease that we possess today. It led directly to an outburst of research on IgE mechanisms in allergic disease, which continues still, and to therapeutic strategies now being pursued for the treatment of allergy and asthma.
Spurred by curiosity about skin hypersensitivity, and guided by their hypothesis concerning the antibody mechanism, the husband-and-wife team of Teruko and Kimishige Ishizaka set out to place reagin within the scheme of the four antibody classes known at the time. Other groups were also chasing the same goal and, with a few exceptions, identified reagin as a fraction of IgA. However, it was the exceptions that caused the Ishizakas to take a different approach. They developed an antiserum against an enriched fraction of reagin, and absorbed out antisera against the known immunoglobulins with their cognate antigens. Then the residual antiserum allowed them to deplete the serum of allergic subjects of reagin activity; they were further able to demonstrate that allergen would bind to the complex formed on an Ochterlony plate between their purified antiserum and serum fractions enriched in reagin. They showed that reagin contains κ and λ light chains, just like other antibody classes, but that the antigenic specificity resided in the heavy chain (in the Fc portion, as Stanworth et al. later found). The Ishizakas named their antibody γE, after the erythema it engendered in the P-K reaction; this was consistent with the terminology used at the time for the other antibody classes, namely γ M, γ G, γ D, and γA.2
In the course of routine analyses of myeloma proteins, Johansson and Bennich observed an immunoglobulin that was not recognized by antibodies specific for IgM, IgD, IgG, or IgA and called it myeloma ND. It transpired that its physical properties differed from those, and Johansson and Bennich realized that they had discovered a new antibody class, differing only in its heavy chain from the others. Myeloma ND was larger than IgA, but insufficiently so for it to be completely resolved by size-exclusion chromatography. Its high sedimentation coefficient and its appearance in the electron microscope revealed an unusually compact structure.3 Johansson went on to show that a similar constituent occurred at elevated concentration in the sera of patients with asthma and hay fever, suggesting its relationship to reagin. A subsequent collaboration with Denis Stanworth and John Humphrey confirmed this hypothesis.6
The critical experiment to identify reagin as representative of the myeloma ND antibody class was performed by Stanworth et al. with the aid of a P-K test in which the skin of a healthy volunteer (Humphrey) was first injected with myeloma ND and next with serum from a subject with hypersensitivity to horse dander. Horse dander was then injected (or not for the control) into the same site. The P-K reaction caused by reagin in the healthy control was blocked in the presence of myeloma ND.4
The drama of the discovery, which in this short period of time identified the reaginic substance as a new class of antibody, now familiar as IgE, was remarkable in many respects, not least because it serves as a model of what openness and collegiality can achieve, involving researchers of four nationalities, working in two continents. The impact was tremendous, given that an ever-increasing proportion—now one in three—of people in the developed world suffer from allergy. One of the direct consequences of their work is the use of the recombinant anti-IgE, omalizumab, in the treatment of asthma. This was pre-figured in the original paper by the Ishizakas in 1966—long before recombinant DNA technology had been thought of—when they showed that depletion of γE from the serum of allergic subjects eliminated the reaginic response in the P-K reaction.
1 Moore R. Niels Bohr, the Man and the Scientist. London: Hodder and Stoughton, 1967: 140.Find this resource:
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. J Immunol 1966; 97: 75–85.Find this resource:
3 Johansson SGO, Bennich H. Immunological studies of an atypical (myeloma) immunoglobulin. Immunology 1967; 13: 381–94.Find this resource:
4 Stanworth DR, Humphrey J, Bennich H, Johansson SGO. Specific inhibition of the Prausnitz–Küstner reaction by an atypical human myeloma protein. The Lancet 1967; 290 (7511): 330–2.Find this resource:
5 Bennich HH, Ishizaka K, Johansson SGO, Rowe DS, Stanworth DR, Terry WD. Immunoglobulin E, a new class of human immunoglobulin. Immunology 1968; 15: 323–4.Find this resource:
6 Johansson SGO. Raised levels of a new immunoglobulin class (IgND) in asthma. The Lancet 1967; 290: 951–3.Find this resource: