Homology Between Immune Responses in Vertebrates and Invertebrates: Does it Exist?

Increasingly larger numbers of immunologists realize that there is more to their discipline than the human body and its animal model, the mouse body, reveal. Many are beginning to appreciate that studying organisms other than humans and mice can not only be rewarding intellectually but may also be relevant to human health. However, as immunologists widen their horizon of interest and include in their experimental menageries creatures as disparate as earthworms, fruit flies, and horseshoe crabs, they often fall into what could best be termed the ’homology trap’. An example will explain. An exchange of tissue patches between genetically dissimilar earthworms of the same species will often have a similar outcome to the exchange of tissue grafts between two mice belonging to different inbred strains [1, 2]. In both instances the grafts at first heal in, only to be destroyed, ‘rejected’, subsequently. Moreover, in both cases the rejection is preceded by an infiltration of the graft by mononuclear cells from the circulating fluid, the haemolymph in earthworms and the blood in the mouse. Also, when a second graft from the same donor is placed on the recipient, it is rejected earlier than the first graft — in the mouse always and in the earthworm sometimes. The striking superficial similarity between the processes taking place in the earthworm and mouse presents a great temptation to consider the two phenomena to be homologous; that is, to have the same evolutionary origin. The temptation is rarely resisted, as is reflected in the frequent use of the term ‘allograft reaction’ for both phenomena, with the implicit or explicit inference that the mechanisms underlying them are similar in principle. Comparative immunology is rife with such inferences of homology between similar phenomena or structures: investigators studying invertebrates speak routinely of ‘second-set reactions’, ‘immunological memory’, ‘antigen presentation’, ‘lymphocytes’, ‘granulocytes’, and ‘interleukins’—all terms borrowed from vertebrate immunology [3]. In all these instances, the basis for the application of these terms to invertebrates is functional similarity with vertebrates, mostly mammals, and particularly humans and mice. Homology is an ill-defined concept [4, 5]. Opinions differ as to what should be considered homologous and the debate, which often has overt or covert philosophical undertones, has not yet yielded any consensus. The one thing all the experts agree on, however, is that implications of homology must not be based on functional similarity. Homology can exist at different levels [6]. Anatomical and morphological comparisons of adult organisms belonging to different species reveal similarities at the level of structure ( 1⁄4 morphological homology ). Comparisons of embryos provide information about similar origin of two structures during development ( 1⁄4 developmental homology ). Correspondence between gene expression patterns brings to light similarity in cascades of transcription factors regulating the formation of similar structures ( 1⁄4 regulatory homology ). Finally, alignments of gene or protein sequences disclose similarities at the DNA or protein level ( 1⁄4 gene homology ). Often a character is homologous at one or more but not all of the levels, giving rise to the question which of the levels is more important in deciding whether a feature is homologous. Functional similarity is excluded from the definition of homology because it so easily and so often arises independently during evolution. A feature shared by two taxa but absent in their common ancestor is analogous but not homologous, and the sets of inferences that can be made from analogous or homologous characters are different. Homologous structures may have different functions and nonhomologous structures often have a similar function. Hence ‘functional homology’ makes the entire concept of homology meaningless [7]. If function cannot be used in defining homology of immune phenomena, which criterion can? Or, somewhat more specifically, how should one go about deciding which immune responses of vertebrates and invertebrates are homologous? Before I attempt to answer these questions, I must introduce two other concepts: the deuterostome–protostome split of the metazoan (animal) phylogenetic tree, and the anticipatory–nonanticipatory schism in the metazoan immune responses.