As we have seen, natural antibodies first emerged as an experimental phenomenon without a plausible theoretical explanation. They were originally denied the status of antibody; then, adjustments to the side-chain theory transformed them from a curiosity into a foundation of the theory. However, in accommodating natural antibodies, Ehrlich had opened several holes in his mechanism of antibody formation.Thus, by 1905, natural antibodies were clearly established as problematic. From the practical standpoint, it seemed unwise to maintain an identity between normal and (...) immune antibodies, given the therapeutic differences in their avidity. With the decline of Ehrlich's theory of antibody formation and the spread of Landsteiner's hapten technique for the production of antibodies against artificial antigens after World War I, the theoretical possibility of their existence as other than anomaly seemed more remote than ever. However, outside the theory and despite clinical considerations, natural antibodies remained a perplexing experimental phenomenon.49This is a somewhat different picture from that usually offered by historians of immunology. Debra Jan Bibel, for example, has recently written: “Ehrlich had no problem in accepting natural antibodies, since they were even predicted by his side-chain theory of antibody formation.:50 However, we have seen that far from being predicted by Ehrlich's side-chain theory, natural antibodies emerged as an anomaly and caused Ehrlich to significantly modify his theory in order to accommodate them. We have also seen that researchers opposed to Ehrlich's school, such as Bordet, initially accepted the existence of natural antibodies, before realizing what an important tool they would be for Ehrlich. Once natural antibodies came to be seen as a confirmation of Ehrlich's theory, attitudes changed and the very existence of natural antibodies was called into question. Other opponents of Ehrlich, such as Landsteiner, opposed natural antibodies from the beginning, before it came to be believed that there was an “infinity of antibodies,” which would make their existence impossible.51. (shrink)