Discovering anaphylaxis: Elucidation of a shocking phenomenon
2009; Elsevier BV; Volume: 124; Issue: 4 Linguagem: Inglês
10.1016/j.jaci.2009.08.032
ISSN1097-6825
AutoresSheldon G. Cohen, Joy C. Mazzullo,
Tópico(s)Food Allergy and Anaphylaxis Research
ResumoSystemic reactions in experimental animals given small doses of otherwise well tolerated foreign species-derived substances were first noted in Magendie's nutritional studies in which rabbits after repeat injections of egg albumin developed immediate fatal collapse.1Magendie F. Lectures on the blood. Aswell, Barrington, and Haswell, Philadelphia1839Google Scholar Subsequently, Magendie's experience was duplicated by Behring in 1893 with diphtheria toxins,E2Behring E. Infektion and Desinfektion. Thomas, Leipaig1894Google Scholar Flexner with dog serum in rabbits in 1894,E3Flexner S. The pathological changes caused by certain so-called tox-albumines.Med News. 1894; 65: 116Google Scholar and Héricort and Richet with eel serum in dogsE4Héricourt J. Richet C. Effets lointains des injections de sérum d'anguille.Compt rend Soc de biol. 1898; 5: 137Google Scholar in 1898. Regardless of species differences or sources of foreign materials, laboratory animals developed systemic manifestations and fatalities to second doses too small to effect adverse reactions a few weeks earlier. In each instance, the cause was attributed to increased susceptibility to previously unrecognized, toxic properties of causative agents, for which Behring coined the term hypersensitivity. Despite the commonality of outcomes in heterogeneous protocols, the possibility of a newly revealed phenomenon escaped recognition. Viewed as only incidental and unrelated to the subject of study, these unusual developments evoked little if any scientific interest or reason for analysis. The identical experience in Richet's later investigations with Portier led to methodical exploration that uncovered a previously unappreciated immune phenomenon.In 1902, Portier and Richet's research began with studies of the painful and neurotoxic tentacle sting of Physalia, known as Portuguese man-of-war, indigenous to coastal Mediterranean waters. After identifying and isolating the causative toxin, Portier and Richet designed a follow-up to develop attempted protective and therapeutic antitoxin. Immunizing injections with related sea anemone–derived “actinotoxin” engendered surprising, unforeseen outcomes.Dogs considered protected from previous injections collapsed and died within minutes after repeat administration of weaker, immunizing doses. Not only were the animals not rendered immune to the toxin, they had become “sensitized” to its action.5Portier P. Richet C. De l'action anaphylactique de certains venins.Compt rend Soc de biol. 1902; 54: 170-172Google Scholar For this reproducible exception to induced immunity, Richet proposed the name aphlaxis (derived from the Greek for “contrary to protection”) subsequently modified for the sake of euphony to anaphylaxis. With a transformation of a chance incident to discovery, a flow of observations of anaphylaxis and experimental studies followed to define model systems, explore triggers, and describe pathophysiologic mechanisms.In the first variant, within the next year, Arthus described production of a presumed local counterpart of systemic anaphylaxis. After initial subcutaneous or intravenous injections of horse serum antitoxin followed by repeated low doses, rabbits developed sterile, hemorrhagic, edematous, infiltrated tissue lesions progressing to gangerenous plaques. Interpretation of the “Arthus reaction” as “local anaphylaxis”E6Arthus N. Injections répétées de sérum de cheval chez le lapin.Compt rend Soc de biol (Paris). 1903; 55: 817-820Google Scholar ultimately proved to be semantically incorrect when the reaction was later recognized as necrotizing vasculitis effected by deposition of immune complexes. Although misinterpreted at the time, it negated toxins as the agents of anaphylaxis, pointing to anaphylactic sensitizing properties of proteins represented by horse serum and milk. The spectrum of anaphylactogenic agents was further expanded with demonstrations of sensitization to vegetables and animal source proteinsE7Wells H.G. Studies on the chemistry of anaphylaxis.J Infect Dis. 1908; 5: 449-483Crossref Scopus (8) Google Scholar and azo dye hapenic coupled antigens.E8Landsteiner K. Levine T.H. Van Der Scheer Anaphylactic reactions produced by azodyses in animals sensitized with azoproteins.Proc Soc Exp Med. 1929; 28: 811-812Google ScholarNext the guinea pig joined the dog and rabbit as a laboratory animal species susceptible to anaphylactic sensitization and shock. In retrospect, this segment of new information might have been recognized earlier had Victor Vaughan not waited to publish his recollection of experiences in standardizing diphtheria antitoxin during the late 1880s. Previously used guinea pigs inexplicably and suddenly died when injected with horse serum; having survived one assay, they could not be relied on in a second test.E9Vaughan V.C. Vaughan Jr., V.C. Vaughan J.W. Protein split products in relation to immunity and disease. Lea and Febiger, Philadelphia1913Crossref Google ScholarIn 1906, Rosenau and Anderson, concerned with information coming to the Public Health Service Laboratory on patients reacting to diphtheria antitoxin, reported critically controlled immunologic studies on several aspects of anaphylactic reactions and agents. Using guinea pigs as experimental models, they attributed a causative role to the “strange proteid” in horse serum.10Rosenau M.J. Anderson J.F. A study of the cause of sudden death following the injection of horse serum. Hygienic Laboratory Bulletin no. 29. Public Health and Marine Hospital Service, Washington (DC)1906Google Scholar Concurrently Smith had been similarly engaged at the Massachusetts Board of Health. His records having come to the attention of Paul Ehrlich, were passed to Ehrlich's associate Otto for follow-up. With Otto's 1906 publication of verification, the finding thereafter was referred to as “The Theobold Smith phenomenon.”E11Otto R. Gedenkschr. F.d. verstorb. Gerneralstabsarzt…von Leuthold, Berlin 1906;1:153-72Google ScholarIn a series of subsequent investigations, species differences in manifestations and involved organs were reported despite uniform experimental conditions and regardless of effecting proteins.The guinea pig died of asphyxia caused by bronchospasm, the rabbit from pulmonary vascular obstruction leading to cardiac failure, the dog from visceral engorgement and circulatory failure. Nevertheless, in each, identical pathophysiologic reactions of smooth muscle contraction, capillary dilatation, glandular secretions, decreased blood cogulability, transient leucopenia, and lowering of body temperature12Coca AF. Anaphylaxis. In: Coca AF, Walzer M, Thomen AA. Asthma and hay fever. London: Balliere, Tidall & Cox; 1931. p 7-57.Google Scholar suggested a common mechanism.Of theoretical possibilities, two were considered most plausible. The “humoral” theory, postulating toxicity, evolved from Richet's concept of a toxic component in the causative agent. In 1906, Vaughan and Wheeler hypothesized that slow cleavage of the injected protein liberated a toxic product, but in insufficient amounts. Reinjections induced rapid liberation of larger quantities of toxic split protein, evoking shock. Finding that the anaphylactic syndrome could be replicated by intravenous injection of Witte's peptone exemplified the theoretical toxic anaphylactogen.E13Vaughan V.C. Wheeler S.M. The effects of egg-white and its split products on animals: a study of susceptibility and immunity.J Infect Dis. 1907; 4: 476-508Crossref Scopus (5) Google ScholarThe “cellular” theory proposed by Besredka in 190714Besredka A. Du mecanisme de l'anaphylaxie vis-à-vis du derum de cheval.Compt rend Soc de biol. 1907; 59: 294-296Google Scholar presumed that (1) antibody developed during the sensitizing-shocking interval and (2) the latent period between triggering dose and onset of systemic shock reflected antibody reactivation and uptake by target organ cells. The fact that serum antibody could not be demonstrated in in vitro tests initially presented a deterrent to its hypothetical adoption. However, objections faded after in vivo demonstrations of anaphylactic reactions in homologous species by passive sensitization and challenge: in the guinea pig by Otto,E15Otto R. Zur Frage de Serumüberempfindlichkeit. Münich. Med Wschr 1907;54:1665-70Google Scholar in the dog by Richet,E16Richet C. De las substance anaphlyactisante ou toxogénine.Compt rend Soc de biol. 1908; 60: 846-848Google Scholar and in the rabbit by Nicole.E17Nicolle M. Contribution à l'étude du “phénoméne d'Arthus”.Ann Inst Pasteur. 1907; 21: 128-137Google ScholarImmunopathogenic insights followed Otto's observation of tolerance in animals surviving fatal shock.E15Otto R. Zur Frage de Serumüberempfindlichkeit. Münich. Med Wschr 1907;54:1665-70Google Scholar Termed antianaphylaxis by Besredka and Steinhardt, similar refractory states were demonstrated in animals who received injections of small amounts of antigen followed by increments in dosage. “Desensitization” was attributed to complete neutralization of anaphylactic antibodies.E18Besredka A. Steinhardt E. De l'anaphylaxie et de l'antianaphylaxie vis-à-vis du serum da cheval.Ann Inst Pasteur (Paris). 1907; 21: 117-127Google Scholar Residual excess antigen reinduced production of anaphylactic antibodies, leaving only partial tolerance or masked anaphylaxis, following desensitization.E19Wiel R. The nature of anaphylaxis and the relations between anaphylaxis and immunity.J Med Res. 1913; 27: 497-527PubMed Google ScholarTo pioneers Rosenau and Anderson,E11Otto R. Gedenkschr. F.d. verstorb. Gerneralstabsarzt…von Leuthold, Berlin 1906;1:153-72Google Scholar Richet,E20Richet C. De l'anaphylaxie en général et de l'anaphylaxie par la mytilocongestine en particulier.Ann Inst Pasteur. 1907; 21: 497-524Google Scholar Arthus, E21Arthus M. “In all antitoxic immunity there is an element of anaphylaxis.” (Translated) inscription on photographic portrait, from the National Library of Medicine, Bret Ratner collection.Google Scholar Hektoen,E22Hektoen L. Allergy on anaphylaxis in experiment or disease.JAMA. 1912; 58: 1081-1088Crossref Scopus (7) Google Scholar and Bordet,E23Bordet J. Le mechanisme de l'anaphylaxie.Compt rend Soc de Biol. 1913; 68: 225-227Google Scholar viewing anaphylaxis and immunity as outcomes of the same antibody-mediated mechanism was not incongruous. In one or another manner of expression, they suggested that hypersensitivity occurred as a first step during the early stage of immunization-induced defense. In a contrasting Darwinian evaluation, anaphylaxis represented evolutionary loss of adaptation of natural defense mechanisms.E24Eccles R.G. A Darwinian interpretation of anaphylaxis.Med Rec. 1911; 80: 109-118Google ScholarIn retrospect, Schultz in 1909 provided the first clue to pathophysiology of anaphylactic shock, finding that isolated strips of ileum from sensitized guinea pigs, suspended in physiologic saline, contracted when challenged by the corresponding antigen.25Schultz W.H. Physiological studies in anaphylaxis, I: the reaction of smooth muscle of the guinea-pig sensitized with horse serum.J Pharmacol Exp Ther. 1909; 1: 549-567Google Scholar The following year, the comprehensive account by Auer and Lewis of fatal anaphylaxis in the whole shocked guinea pig demonstrated bronchoconstriction with air trapping and distention of the lungs.E26Auer J. Lewis A. The physiology of the immediate reaction of anaphylaxis in the guinea pig.J Exp Med. 1910; 12: 151-175Crossref PubMed Scopus (40) Google Scholar With target tissue identified, Simonds explained species differences in anaphylactic manifestations in relation to target organs' composition of contractile smooth muscle: guinea pig bronchi, rabbit pulmonary arterioles, dog hepatic veins.27Simonds J.P. The fundamental physiological reaction in anaphylactic and peptone shock.JAMA. 1919; 73: 1437Crossref Scopus (2) Google ScholarAn additional dimension to the cellular theory followed with the first indication of a biochemical mediator of shock. Dale and Laidlaw, in a variation of Schultz's model—henceforth known as the Schultz-Dale phenomenon—using a strip of guinea pig uterus challenged with preformed tissue component β-iminazolylethylamine (histamine), demonstrated identical muscle contraction.E28Dale H.H. Laidlaw P.P. Further observations on the physiological action of βiminapolylethylamine.J Physiol. 1911; 41: 182-195Google Scholar Twenty-one years later, evidence was added by Dale's suggestion of liberated histamine or a histaminelike product of cellular breakdown as critical in anaphylactic shock. In 1932, Bartosch and associates found a histaminelike smooth muscle contracting substance in the perfusate recovered from anaphylactically sensitized guinea pig lung exposed to the corresponding antigen.29Bartosch R. Feldberg W. Nagel F. Das Freiwerden cincs histaminoholichen Stoffes bei der Anaphylaxic des Meerschweinchens.Pflueger Arch Ges Physiol. 1932; 230: 129-153Crossref Scopus (40) Google Scholar The same year, Dragstedt and Gebauer-Fuebuegg identified histamine in blood and lymph of intact animals during induced anaphylaxis.30Dragstedt C.A. Gebauer-Fuebuegg E. Studies in anaphylaxis, I: the appearance of a physiologically active substance during anaphylactic shock.Am J Physiol. 1932; 102: 512-526Google ScholarHypothesizing a human counterpart lower animal anaphylactic shock, Meltzer in 1910 equated the commonality of airways obstruction and respiratory distress in human asthma and guinea pig anaphylactic shock.E31Meltzer S.J. Bronchial asthma as a phenomenon of anaphylaxis.JAMA. 1910; 55: 1021-1024Crossref Scopus (35) Google Scholar Unlike guinea pig anaphylaxis, however, human asthma could not be induced at will, desensitized, or characterized by smooth muscle contracting antibody. Any lingering doubt about a lesser consequential role for guinea pig–like bronchospasm in human asthma was further dispelled by the detailed histopathologic examinations of Huber and Koessler.E32Huber H.I. Koessler K.L. The pathology of bronchial asthma.Arch Int Med. 1922; 30: 689-760Crossref Scopus (329) Google Scholar In asthma, a disorder in which inaccurate assumptions of the functional aspect had been given priority over physical changes, their classic report of accurate measurements demonstrated luminal narrowing of small and middle sized bronchi and bronchioles by cell wall thickening, hyperemia, cellular infiltration, edema, and hyperactive glandular exudation.The question of a human counterpart of lower animal anaphylactic shock posed a more complex issue for resolution. Instances of human and fatal collapse after a wasp sting dated back to an account of the death of Egyptian Pharaoh Menes (c. 264 B.C.) recorded in hieroglyphics on ivory tablets recovered from his tomb.33Waddel L.A. Egyptian civilization, its Sumerian origin and real chronology. Luzac and Co, London1930Google Scholar Authoritative Egyptologists, however, failed to verify its authenticity with an alternative interpretation that Menes was carried off by a hippopotamus into the Nile. A distinction had not been made between the hieroglyphic hippo and the name of the town with a similar sound and determinative sign of a wasp or bee.E34Chafee F.H. Insect sting allergy, letter to the editor.J Allergy. 1969; 43: 309Abstract Full Text PDF Scopus (6) Google Scholar It is likely that the Pharaoh Menes himself was a mythical figure.E35Krumbbaugh J.W. Kempe S. Keller C.A. Wright P.M. Pharaoh Menes' death after an anaphylactic reaction—the end of a myth.Allergy. 2004; 11: 1234-1235Google Scholar Nevertheless, Hymenoptera venom remains antiquity's earliest awareness of an anaphylactic agent. Aristotle (384-322 B.C.) noted that a bee's sting could cause the death of an animal as large as a horse,E36Aristotle. Historia Animalia. In Tohmpson DW. The works of Aristotle, Smith JA, Ross WD editors. Oxford 1952; Clarendon IV, 15;627.Google Scholar and 2 human instances of fatal bee stings were recorded in the Hebrew Babylonian Talmud (2nd century B.C.-3rd century A.D.)E37Epstein I, trans. The Babylonian Talmus, Seder Mo-ed (English translation). Soncino, London1938Google ScholarSome 15 centuries later, newly evolving immunization procedures for prevention and treatment of infectious diseases evoked instances of iatrogenic simulation of nature's hymenopteras life-threatening stings. In 1896, five years after the introduction of horse serum–derived diphtheria antitoxin into clinical medicine, human fatalities were reported after its administration.E38Gottstein A. Über Toderfaile, welch bei der Anwhidung des Diphtheriaheilserums beobachter warden-sind.Ther Mh. 1896; 10: 269-272Google Scholar In 1905, three years after the discovery of anaphylaxis, von Pirquet and Schick defined human serum sickness, differentiating its symptom diagnosis from exanthematous infectious diseases.39von Pirquet C.F. Schick B. Die Serumkrankheit. Franz Deutieke, Leipzig1905Google Scholar Especially pertinent was the description of immediate collapse and potentially fatal shock in highly sensitized patients seconds to minutes after serum administration. In the period that followed, the overlapping symptoms of accelerated-immediate serum reactions with anaphylaxis led to disagreements on pathogenetic interpretations, mechanisms, and nomenclature as hypothetical counterparts. The ultimate comparative evaluation of immune-mediated properties would resolve the questionable issue.In 1929, Wells documented criteria for anaphylactic sensitization: induction, reproducibility, passive sensitization, antibody-induced contraction of virgin guinea pig strips, species-specific differential symptoms, and desensitization after recovery.40Wells H.G. The chemical aspects of immunity.2nd ed. Chemical Catalog, New York1929Google Scholar Meanwhile, Prausnitz and Kustner discovered a key to understanding human sensitization—a passively transferable serum skin sensitizing principle demonstrable only by its in vivo property of inducing immediate whealing on challenge with corresponding antigen (allergen).41Prausnitz C. Kustner H. Stuien uber Uberempfindlichkeit. Centralb Bakteriol 1 Abt Orig 1921;86:160. Translated by Prausnitz C. In: Gell PGH, Coombs RRA, editors. Clinical aspects of immunology. Oxford: Blackwell Scientific Publications; 1962. p. 808-16.Google ScholarAnaphylaxis and systemic reactions occurring within seconds to minutes after injection of foreign antisera had some but not total similarities of acute shock. Immediate serum reactions began with facial suffusion, generalized urticaria, angioedema, and asthmatic wheezing, and where sensitivity was great, progressed to violent shock, decreased blood pressure or acute emphysema and pulmonary edema. Whereas target organ smooth muscle contraction was the hallmark of anaphylactic shock, that of fatal immediate serum reaction was laryngeal edema. Sensitization resulted from previous administration of therapeutic horse-derived antiserum or immunizing diphtheria toxin-antitoxin, or naturally in a hereditarily predisposed subgroup on exposure to horse dander.42Kolmer J.A. Tuft L. Clinical immunology, biotherapy and chemotherapy. Saunders, Philadelphia1943Google Scholar The earliest recorded severe systemic symptoms evoked by experimental immunization with grass pollen extractE43Dunbar W.P. The present state of our knowledge of hay fever.J Hygiene. 1913; 132: 105-148Crossref Scopus (46) Google Scholar and experimental application of a buckwheat grain to scarified skin of a patient misdiagnosed as having buckwheat poisoningE44Smith H.L. Buckwheat poisoning with report of a case in man.Arch Int Med. 1909; 3: 350-359Crossref Scopus (43) Google Scholar brought constitutional hypersensitivity reactions into the immediate serum type category.That anaphylactic shock characterized by smooth muscle contraction in lower animals and human immediate serum (type) reactions resulting from increased vascular permeability were clinically not one and the same was corroborated by immunologic differences. Anaphylactic antibody–induced smooth muscle contraction, diffused throughout the body, sensitized guinea pig and inactivated antigen. Human immediate serum type reactive antibody was skin-sensitizing, quickly attached to body cells, induced enhanced vascular permeability, did not inactivate antigen, could not be desensitized, and often was associated with atopic (hay fever, asthma, food-sensitive) diseases.42Kolmer J.A. Tuft L. Clinical immunology, biotherapy and chemotherapy. Saunders, Philadelphia1943Google ScholarIt is difficult, if not impossible, to make a man demonstrably anaphylactic to horse serum by a series of hypodermic injections of horse serum—e.g. such as were given in the 1914 war in the form of anitetanic serum: often wounded men had four of five heavy shots of such serum on their way down from the front line in France to the Base Hospital in England; but they didn't become anaphylactic, or scarcely so. Quite different is the behaviour of horse-asthmatic patients who have acquired their tendency to violent idiotoxic responses to horse serum, not by artificial injections, but by inheriting this idiotoxic diathesis . . . Such very different hypersensitive states can hardly be the same thing to be lumped together under the name ‘anaphylaxy.’ At present the word is used chiefly by carefree writers as an elegant variant. . . . and barely comes into human medicine at all.—John Freeman, 1950E45Freeman J. Hay fever: a key to the allergic disorders. Heinemann, London1950Google ScholarAs hypersensitivity and atopic diseases began to emerge as a new and separate segment of medicine, early practitioners replaced its name of clinical anaphylaxis with that of allergy (allergie, derived from the Greek for “strange diseaserdquo”), as proposed by von Pirquet in 1905.It is true that the accelerated or immediate serum reactions in the induced or acquired types of allergy, as for example those following serum reinjection into a previously non-sensitized individual, closely resemble animal anaphylactic shock. However since these reactions do not possess all of the necessary criteria of true anaphylaxis (such as the demonstration of an antigen-antibody reaction and successful desensitization) it is better to designate them as secondary serum reactions rather than as acute anaphylactic reactions in the human. It is well to point out, however, that failure to obtain all of the necessary criteria may be because such evidence can be obtained only from clinical experience and not from the deliberate induction of such reactions as in the lower animal.—John Kolmer, Louis Tuft, 194342Kolmer J.A. Tuft L. Clinical immunology, biotherapy and chemotherapy. Saunders, Philadelphia1943Google ScholarWhether one objective was partially met by Ishizakas’ discovery of IgE and reactions with corresponding antigens on mast cell surfaces may still be controversial. Traditional semantics would question deviation from the accepted historical definition of anaphylaxis in 1929.39von Pirquet C.F. Schick B. Die Serumkrankheit. Franz Deutieke, Leipzig1905Google Scholar Criteria yet to be satisfied include demonstrations of typical reactions in the virgin guinea pig strip and desensitization after recovery from anaphylactic shock. Nevertheless, what biomedical research could not establish, arbitrary usage and adaptation of the term accomplished: an expanded and all encompassing definition of anaphylaxis.1. systemic or generalized anaphylaxis; a type 1 hypersensitivity reaction in which exposure of a sensitized individual to a specific antigen or hapten results in urticaria, pruritus, and angioedema, followed by vascular collapse and shock and often accompanied by life-threatening respiratory distress . . . 2. a general term originally applied to the situation in which exposure to a toxin resulted not in development of immunity (prophylaxis) but in hypersensitivity. The term was extended to include all cases of systemic anaphylaxis in response to foreign antigens and also to include a variety of experimental models, e.g., passive cutaneous anaphylaxis. Anaphylaxis has now been subsumed under the more general concept of type I (immediate) hypersensitivity.E46Reproduced from Dorland's illustrated medical dictionary.31st ed. Saunders, Philadelphia2007Google Scholar Systemic reactions in experimental animals given small doses of otherwise well tolerated foreign species-derived substances were first noted in Magendie's nutritional studies in which rabbits after repeat injections of egg albumin developed immediate fatal collapse.1Magendie F. Lectures on the blood. Aswell, Barrington, and Haswell, Philadelphia1839Google Scholar Subsequently, Magendie's experience was duplicated by Behring in 1893 with diphtheria toxins,E2Behring E. Infektion and Desinfektion. Thomas, Leipaig1894Google Scholar Flexner with dog serum in rabbits in 1894,E3Flexner S. The pathological changes caused by certain so-called tox-albumines.Med News. 1894; 65: 116Google Scholar and Héricort and Richet with eel serum in dogsE4Héricourt J. Richet C. Effets lointains des injections de sérum d'anguille.Compt rend Soc de biol. 1898; 5: 137Google Scholar in 1898. Regardless of species differences or sources of foreign materials, laboratory animals developed systemic manifestations and fatalities to second doses too small to effect adverse reactions a few weeks earlier. In each instance, the cause was attributed to increased susceptibility to previously unrecognized, toxic properties of causative agents, for which Behring coined the term hypersensitivity. Despite the commonality of outcomes in heterogeneous protocols, the possibility of a newly revealed phenomenon escaped recognition. Viewed as only incidental and unrelated to the subject of study, these unusual developments evoked little if any scientific interest or reason for analysis. The identical experience in Richet's later investigations with Portier led to methodical exploration that uncovered a previously unappreciated immune phenomenon. In 1902, Portier and Richet's research began with studies of the painful and neurotoxic tentacle sting of Physalia, known as Portuguese man-of-war, indigenous to coastal Mediterranean waters. After identifying and isolating the causative toxin, Portier and Richet designed a follow-up to develop attempted protective and therapeutic antitoxin. Immunizing injections with related sea anemone–derived “actinotoxin” engendered surprising, unforeseen outcomes. Dogs considered protected from previous injections collapsed and died within minutes after repeat administration of weaker, immunizing doses. Not only were the animals not rendered immune to the toxin, they had become “sensitized” to its action.5Portier P. Richet C. De l'action anaphylactique de certains venins.Compt rend Soc de biol. 1902; 54: 170-172Google Scholar For this reproducible exception to induced immunity, Richet proposed the name aphlaxis (derived from the Greek for “contrary to protection”) subsequently modified for the sake of euphony to anaphylaxis. With a transformation of a chance incident to discovery, a flow of observations of anaphylaxis and experimental studies followed to define model systems, explore triggers, and describe pathophysiologic mechanisms. In the first variant, within the next year, Arthus described production of a presumed local counterpart of systemic anaphylaxis. After initial subcutaneous or intravenous injections of horse serum antitoxin followed by repeated low doses, rabbits developed sterile, hemorrhagic, edematous, infiltrated tissue lesions progressing to gangerenous plaques. Interpretation of the “Arthus reaction” as “local anaphylaxis”E6Arthus N. Injections répétées de sérum de cheval chez le lapin.Compt rend Soc de biol (Paris). 1903; 55: 817-820Google Scholar ultimately proved to be semantically incorrect when the reaction was later recognized as necrotizing vasculitis effected by deposition of immune complexes. Although misinterpreted at the time, it negated toxins as the agents of anaphylaxis, pointing to anaphylactic sensitizing properties of proteins represented by horse serum and milk. The spectrum of anaphylactogenic agents was further expanded with demonstrations of sensitization to vegetables and animal source proteinsE7Wells H.G. Studies on the chemistry of anaphylaxis.J Infect Dis. 1908; 5: 449-483Crossref Scopus (8) Google Scholar and azo dye hapenic coupled antigens.E8Landsteiner K. Levine T.H. Van Der Scheer Anaphylactic reactions produced by azodyses in animals sensitized with azoproteins.Proc Soc Exp Med. 1929; 28: 811-812Google Scholar Next the guinea pig joined the dog and rabbit as a laboratory animal species susceptible to anaphylactic sensitization and shock. In retrospect, this segment of new information might have been recognized earlier had Victor Vaughan not waited to publish his recollection of experiences in standardizing diphtheria antitoxin during the late 1880s. Previously used guinea pigs inexplicably and suddenly died when injected with horse serum; having survived one assay, they could not be relied on in a second test.E9Vaughan V.C. Vaughan Jr., V.C. Vaughan J.W. Protein split products in relation to immunity and disease. Lea and Febiger, Philadelphia1913Crossref Google Scholar In 1906, Rosenau and Anderson, concerned with information coming to the Public Health Service Laboratory on patients reacting to diphtheria antitoxin, reported critically controlled immunologic studies on several aspects of anaphylactic reactions and agents. Using guinea pigs as experimental models, they attributed a causative role to the “strange proteid” in horse serum.10Rosenau M.J. Anderson J.F. A study of the cause of sudden death fo
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