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Jellyfishes and dogs: sleuthing allergies

Watch Andreas J. Bircher explain how at the beginning of the 20th century two scientists accidentally discovered hypersensitivity and anaphylaxis.
In 1901, Prince Albert the First of Monaco invited Charles Richet and Paul Portier to use the laboratory on his yacht, Princess Alice The Second. There, they investigated the possibility to develop a vaccine that should protect against the toxins of the jellyfish Physalia physalis, also known as Portuguese man o’ war. The idea of the experiment was to inject animals repeatedly with low, non-toxic doses to induce immunity. To the surprise of the scientists, the animals became not less responsive, but developed severe symptoms and some of them even died. After this, Richet and Portier continue to work in Paris with dogs using a similar toxin of the easier available Actinia species, Anemonia sulcata.
One of their key experiments involved Neptun, a large, healthy male dog. At day one, he was injected a low, non-toxic dose of actinium toxin that was tolerated without reaction. However, 22 days later, the same small dose resulted in very severe symptoms within seconds, and eventually death after 25 minutes. The concept of protective antibodies had been previously postulated by Paul Ehrlich. Inadvertently, Richet and Portier had discovered an antibody-mediated hypersensitivity. Instead of inducing protective antibodies, Immunoglobulin G, short, igG antibodies, they had sensitised Neptun unknowingly to actinium toxin with the first non-toxic dose. This sensitisation led to the formation of Immunoglobulin E, short, igE antibodies, which can elicit an allergic reaction.
Instead of prophylaxis, that is the protection against the toxin, a new phenomenon, the development of hypersensitivity, had thus been confirmed experimentally.
Richet called this phenomenon etymologically not completely correct, ‘Ana-phylaxis’, derived from the ancient Greek word phylaxis, meaning guardian. The new term, meaning against protection, was not immediately accepted. Other physicians had previously observed hypersensitivity reactions in patients after the repeated injection of foreign sera to treat infections, for instance, diphtheria. Nevertheless, Charles Richet received the Nobel Prize in Medicine in 1913 for his work on anaphylaxis. The term anaphylaxis has prevailed and is nowadays used to describe the most severe immediate hypersensitivity reaction. The symptoms involve urticaria, that is rashes on the skin, colicky pain in the intestines, diarrhoea, and asthma. The patient may show also cardiovascular symptoms resulting in an anaphylactic shock. Anaphylaxis is, therefore, potentially fatal.
Anaphylaxis can occur in response to almost any foreign substance. Common elicitors are venoms, such as the venom of bees or wasps, food, but also medication. The modern, highly purified or synthetically produced vaccines have become very rare causes of anaphylaxis nowadays.
In 1901, two scientists experimented with dogs on a yacht. By injecting them the poison of a jellyfish they tried to find a vaccination against it. But instead of producing protection, they discovered another ground-breaking phenomenon that even brought one of them the Nobel Prize.

It took many steps to arrive at the understanding of allergy we share today. As in every knowledge-driven process, experiments that failed were essential. They helped to uncover assumptions that were too general and needed further discrimination to be exact. With the principles of vaccination understood, the mechanism seemed to offer a remedy against a lot of threats to human health. However, as this video shows, researchers underestimated how complex the mechanisms were. In this sense dogs dying from vaccination that led to the discovery of anaphylaxis and hypersensitivity were further stepping stones to grasp allergy as a concept. For a comprehensive sketch of all the anaphylactic symptoms, please look at this graph.

The term ‘allergy’ was coined only some years later. Clemens von Pirquet, director of the Children’s Hospital in Vienna, used antisera (or ‘antitoxins’) produced in horses to treat diphtheria. For the first time, doctors could administer an effective therapy by passive immunisation and save the lives of many of their young patients. However, in some of them, 5 to 10 days after the first infusion, symptoms distinct of diphtheria occurred: fever, urticarial rashes, joint pain, and swellings. If infused again, the patients reacted again with the same symptoms, this time just after a few minutes or hours. In 1905, Clemens von Pirquet published his observations and called this new phenomenon ‘serum sickness’ – a clinical term that has survived until modern times. One year later, von Pirquet described the altered state of immunity in these patients in a short article. He coined the term ‘allergy’, composed of the ancient Greek words ‘allos’ (= altered) and ‘ergos’ (= activity). It is nowadays established as an umbrella term for all types of hypersensitivity reactions with an immunological background. In this article you can learn more about evolving concepts of allergy. Can you think of further substances causing a hypersensitivity reaction or even an anaphylactic shock? Please leave a comment below.

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Allergies: When the Immune System Backfires

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