Discovery of IgE: The Forty-Five-Year Hunt for a Ghost
In 1921, two German researchers performed one of the most elegant — and unsettling — experiments in medicine: they took blood serum from a fish-allergic patient, injected it into the skin of a non-allergic volunteer, and showed that the allergy itself had been transferred. Something in the blood carried the reaction. For the next forty-five years, that something had no name but a placeholder — "reagin" — no structure, no photograph, no agreed existence beyond the wheals it raised. The discovery of IgE is the story of how that ghost was finally caught: not by one laboratory but by two, on two continents, working from opposite ends of the problem, in a three-year convergence that ended with a molecule, a name, and a new era for everyone who sneezes. As the fiftieth-anniversary history in the Annals of Allergy, Asthma & Immunology tells it, the strangest part is that both teams were right at the same time.
Key takeaways
- The 1921 Prausnitz–Küstner experiment proved that something in a patient's blood serum could transfer the allergy itself — a factor that carried the placeholder name "reagin" for the next forty-five years.
- In 1966, Kimishige and Teruko Ishizaka in Denver tracked the reaginic activity through fraction after fraction and announced a new immunoglobulin class, present only in trace amounts.
- In Uppsala, Johansson and Bennich's study of a myeloma patient's unmatched protein, IgND, appeared in 1967; a reagent exchange that year showed the two groups had the same molecule.
- In 1968 the class was officially named immunoglobulin E — IgE, the E chosen, as the discoverers recounted, for erythema, the red flare of the skin test.
The Ghost: Reagin and the Prausnitz–Küstner Reaction
The 1921 experiment — Heinz Küstner's serum, Otto Prausnitz's arm — became the field's standard tool, the P-K reaction, and its standard frustration. The factor acquired its placeholder name in the mid-1920s, when Arthur Coca and his collaborators grouped these transferrable sensitivities under the heading of "atopy" and called the blood factor itself reagin. It was an honest label for a mystery: a name that meant "the thing that reacts," coined by scientists who could describe everything about its behaviour except what it was. Researchers could move reagin from person to person; they could measure its activity in skin tests; they could not isolate it. It was fantastically scarce, it clung to skin for weeks in a way ordinary antibodies didn't, and every attempt to purify it from serum dragged along the abundant immunoglobulins — IgG, IgA, IgM — that drowned it out. A history in the Cleveland Clinic Journal of Medicine puts the drought plainly: "It would take 45 years to discover what was being transferred from person to person, well after IgG, IgA, IgD, and IgM were identified." Four of the five antibody classes were catalogued while the allergy factor stayed invisible. The hunt needed either a vastly better purification — or a patient whose body made the stuff in bulk.
The Discovery of IgE, Part One — Denver, 1966: Purifying the Invisible
Kimishige and Teruko Ishizaka, at the Children's Asthma Research Institute and Hospital in Denver, took the purification road. Working with serum from ragweed-sensitive patients, and using their own skin as assay — Kimishige Ishizaka famously let colleagues inject test fractions into his back, reading the wheals as data — the Ishizakas tracked the reaginic activity through fraction after fraction until, in 1966, they could announce a new immunoglobulin: the activity lived in a class of its own, present in trace amounts, distinct from every known antibody. They had caught the ghost in a bottle, barely — there was almost none of it to study. What the field needed to confirm the catch, and to build tests around it, was quantity.
The Discovery of IgE, Part Two — Uppsala, 1967: A Patient Named ND
Quantity arrived from Sweden, wearing a tragedy. In Uppsala, S. Gunnar Johansson and Hans Bennich were studying the blood of a myeloma patient — a man whose cancerous plasma cells produced one protein in industrial amounts. The protein matched no known immunoglobulin. They called it IgND, after the patient's initials, and their structural study appeared in Immunology in 1967. Then came the move that turned two puzzles into one solution: in that same year, the Denver and Uppsala groups exchanged reagents — and the determinants matched. The Ishizakas' painstakingly purified reagin and the ND myeloma protein were the same molecule. In 1968, the two groups jointly presented their evidence to the World Health Organization, and the new class was officially named: immunoglobulin E — IgE.
The letter itself carries the hunt's fingerprint: E was chosen, as the discoverers recounted, for erythema — the red flare of the skin test, the one visible signature reagin had shown the world for forty-five years, now attached to the molecule itself.
It is hard to overstate what the molecule explained. IgE turned out to be the scarcest antibody in human blood — the Cleveland Clinic history gives its share as roughly 0.05% of circulating immunoglobulin, against about 75% for IgG — which is precisely why it hid for 45 years. Getting enough of it to study remained a saga of its own: the same history records that progress depended on the generosity of the second patient ever described with an IgE myeloma, who donated plasma weekly for a year so researchers could accumulate the molecule. Scarcity shaped the whole discovery, at both ends — too dilute to find in ordinary serum, available in bulk only from two of the rarest patients in medicine.
The molecule also had an extra domain in its heavy chain, and a fateful talent: it latches onto mast cells and waits, sometimes for years, so that a later meeting with its allergen triggers the histamine flood whose blockade we recount in the history of antihistamines. And the discovery paid out almost immediately in practice. In 1967 — the hinge year — Johansson, Bennich and Leif Wide published in The Lancet an in-vitro assay using the new antibody to measure allergen-specific IgE in a blood sample, correlating it against challenge tests. It became famous as RAST, the radioallergosorbent test: the first time an allergy could be read off a blood draw instead of a patient's skin. Every IgE blood panel ordered today descends from that assay. An entire diagnostic industry stands on a Denver purification and a Swedish patient's protein.
| Year | Step in the hunt |
|---|---|
| 1921 | The Prausnitz–Küstner experiment: allergy transferred from patient to volunteer by serum |
| Mid-1920s | Coca and his collaborators group the sensitivities under "atopy"; the blood factor is named reagin |
| 1966 | The Ishizakas in Denver announce the reaginic activity is a new immunoglobulin class |
| 1967 | Johansson and Bennich describe the IgND myeloma protein; the reagent exchange shows it is the same molecule; RAST is published in The Lancet |
| 1968 | The two groups present jointly to the WHO; the class is named immunoglobulin E |
What the Ghost's Name Changed
Every modern allergy conversation runs through 1966–68. The counting stations described in how pollen counts are measured quantify the trigger; IgE is the mechanism that makes the trigger matter. The seasonal numbers on the Denver pollen page — Denver, of all cities, the discovery's hometown — land on immune systems built around this one scarce antibody, as do the seasons in New York and Chicago and everywhere on the heatmap. And the practical end of the story is unchanged: if you want to know which IgE your own system has written, the allergy specialists in our directory run the tests the discovery made possible. This article is general information only and is not medical advice.
The discovery kept compounding for half a century. Once the molecule had a name and a blood test, researchers mapped the high-affinity IgE receptor on mast cells, traced the inherited threads of atopy, and eventually turned the antibody into a target in its own right — by the 2000s, therapies existed designed to intercept IgE itself rather than mop up what it releases. Every step descends in a straight line from 1966–68: from a Denver purification, a Swedish patient's abnormal protein, and a shared reagent crossing the Atlantic. The ghost had become the most productive molecule in allergy.
Frequently Asked Questions
What was "reagin"?
The placeholder name given in the mid-1920s to the transferable factor in allergic patients' blood — an honest label meaning "the thing that reacts." Arthur Coca and his collaborators grouped these sensitivities under the heading of "atopy," and researchers could move reagin from person to person and measure its activity in skin tests, but for forty-five years they could not isolate it.
Who discovered IgE?
Two teams, converging. Kimishige and Teruko Ishizaka purified the reaginic activity from ragweed-sensitive patients' serum in Denver and announced a new immunoglobulin in 1966. In Uppsala, S. Gunnar Johansson and Hans Bennich were studying a myeloma patient's unmatched protein, IgND; a 1967 reagent exchange showed the two were the same molecule.
Why did IgE hide for forty-five years?
Scarcity. IgE is the scarcest antibody in human blood — roughly 0.05% of circulating immunoglobulin, against about 75% for IgG — and every attempt to purify it from ordinary serum dragged along the abundant classes that drowned it out. In bulk, it was available only from the rarest of patients: those whose myeloma produced it in industrial amounts.
What did the discovery make possible?
Almost immediately, a blood test: in 1967 Johansson, Bennich and Leif Wide published an in-vitro assay in The Lancet measuring allergen-specific IgE in a blood sample — RAST, the first time an allergy could be read off a blood draw instead of a patient's skin. Every IgE blood panel ordered today descends from that assay.
The discovery of IgE is a reminder that science's hardest problems are sometimes not hidden but dilute — present in every allergic person's blood, in quantities too small to see, waiting for two teams stubborn enough to purify from one end and lucky enough to find abundance at the other. The ghost had a name by 1968. Allergy has had a mechanism ever since.
**The mechanism is IgE; the trigger is the count. See yours before the season does — free pollen counts and 5-day forecasts for cities worldwide at PollenAtlas.com.**