Tis strange – but true; for truth is always strange

This Byron quotation is taken from the foreword of Selye “Calciphylaxis” 1962 and may help to introduce the followup story on the question who described for the first time vitamin D as cofactor in the allergic sensitization process.

On 552 pages, this book is on the somewhat strange observation that a combination of calcium releasing drugs (as favoured by the author) induces sclerodermia like symptoms in the rat. At least from a modern perspective this does not fully fit into our current understanding while it would take experts from several areas for a critical appraisal. Maybe nobody works anymore with such high doses of vitamin D (p26: DHT/Calcamin 1 mg/0.5 ml, D3/Vi-Dé3 600.000 IU/1.5 ml, D2/Roche 850.000 IU/g). Fortunately I do not want to write about calciphylaxis but on the relation of Selye’s setup with allergy.

Of those many combinations of calcium releasing drugs tried on animals, the most effective combination for “systemic calciphylaxis” was DHT and whole egg. I did not find any other allergen in the long list of substances in table 2 on page 53 (Alizarin or mordant red, the substance with the highest potency in his experiments is a known contact allergen).

The yolk experiment is described on page 203ff – Selye always used a few animals for each substance followed by a brief description what he found (with no statistics at all and renember that IgE was discovered only later), for example

Method 2: Rat (200 g, female sign): DHT (2 mg p.o.) 1st day + yolk (50%, 10 ml. i.p.) 2 d day; killed 6th day.
Results: In these larger rats the syndrome produced by yolk was not markedly different from that just described as characteristic for smaller animals. However, here pulmonary calcinosis was not limited to the calcification of large intravascular lipid particles; it frequently involved the connective tissue of the alveoli in the manner characteristic of most other calciphylactic syndromes (Fig. 167). In addition, we sometimes saw calcification of the uterus with predominant participation of the endometrium, a response similar to that produced under certain conditions in large rats treated with DHT + Fe_Dex i.p. (Plate VI, C).

There are two references that I would like to follow-up (Reed/Struck/Steck: Vitamin D: Chemistry, Physiology, Pharmacology, Pathology, Experimental and Clinical Investigations. U Chicago Press, 1939 and his ref 827 -not 829 as cited in the text- Selye. Calciphylaxie, Allergie und Asthma, 7: 241, 1961). The most interesting part in Selyes’s book is on page 6:

Calciphylaxis resembles certain immunologic hypersensitivity reactions (e.g. the tuberculin reaction, the local and general Shwartzman-Sanarelli phenomenon, classical anaphylaxis in the guinea pig, the Arthus phenomenon) in that it likewise depends on a properly spaced treatment with a sensitizer and a challenger. Infiltration of the target area by eosinophils or plasma cells is also characteristic of both anaphylactic and many calciphylactic reactions.
However, in most other respects the two types of responses are essentially different. Unlike in immunologic hypersensitivity responses, in calciphylaxis (1) there is no evidence of immune-body formation (2) the sensitizer and challenger are essentially different substances, and (3) the response is primarily characterized by the local precipitation of clacium salts.
Furthermore, calciphylaxis can be obtained by sensitizers and challengers of known and comparable simple structure. This fact facilitates the study of the underlying chemical mechanisms, but it does not represent an essential difference between calciphylaxis and immunologic hypersensitivity phenomena, since simple compounds of known structure can act as haptenes.
It would be unjustifiable to disregard a priori as coincidental the many similiarities between calciphylaxis, on the one hand, and such reactions as drug allergies, physical allergies, and nonreaginic allergies, on the other, but at present we have no proof of any connection between these phenomena.

There is nothing to add except that we have now this evidence, yea, yea.

(NB The animal on plate I C certainly looks like having a generalized allergic reaction but I am not sure if I am allowed to reproduce this figure here for copyright reasons).