The Quest for Antibodies and Other Acquired Immune Receptors: A Historical Perspective

The diversity of antibody molecules has for decades been an unsolved enigma that has attracted wide interest among biologists. Parallel to the accumulation of experimental evidence, progress in antibody research was also driven by the theoretical debate that played a particularly prominent role, at least until the entry of molecular biology into this field of investigation. Several publications have examined this topic from a historical perspective. In this article, we aim to examine the history of research into the mechanisms underlying antibody diversity from a partly new standpoint. In jawed vertebrates (gnathostomes), progressively more distant on the evolutionary scale from humans and mice-in non-model mammals, birds, amphibians, bony and cartilaginous fish-certain mechanisms for the diversity of acquired immunity receptors (B-cell receptors [BCR]/immunoglobulins [Ig] and T-cell receptors [TCR]) have been described that are quite unexpected on the basis of what has emerged from biomedical immunology studies. What is more, in Agnatha vertebrates, in several invertebrate phyla and even in bacteria, forms of adaptive immunity have been discovered, based on the ability to finely tune the host defence response to the infectious threats. These defence systems show some similarities with the acquired immunity of jawed vertebrates, although they are based on mechanisms and receptors totally different from BCR/Ig and TCR. Therefore, our aim is to investigate how the theoretical debate on antibody diversity, which developed in the 20th century, partly anticipated some of the central themes in the current research on adaptive immunity systems discovered in the previously mentioned non-model systems. With this aim, we have reformulated, in the language of modern biology, some of the hypotheses advanced in the first decades of antibody diversity research.