Reconsidering the Medawar paradigm placental viviparity existed for eons, even in vertebrates; without a "problem": Why are Tregs important for preeclampsia in great apes?

The classic Medawar paradigm sees viviparity in vertebrates as a "problem". Established in 1953, it was then largely determined by a self-non-self view of the immune system. However, there are alternative models of the immune system, such as the danger model. For these models, pregnancy is neither a problem nor a danger. Supporting this view, we recall that placenta or placental-like-dependent(1) (allo) pregnancy has existed for eons. In fact, it appeared as far back as the time of aquatic colony invertebrates, such as some of the Bryozoa.(2) Since then, convergent evolution has seen placentation appear in a large variety of phyla. These placentae did not seem to cause "immunological problems", even in vertebrates possessing a graft rejection potential. The reappearance of placentae in marsupial and eutherian mammals found placentae confronted with a highly developed adaptive immune system. Two strategies were developed, therefore: short-term only placentation (marsupials) or specialised control of T cell-mediated immunity (Tregs). The problem is likely to be most acute in cases of deep invasive placentation. As an alternative to a restricted view of the Medawar paradigm for preeclampsia, an integrated model putting both inflammation and Tregs into perspective is proposed, somehow embedding the questioning of the initial Medawar paradigm.

Inflammation, NK cells and implantation: friend and foe (the good, the bad and the ugly?): replacing placental viviparity in an evolutionary perspective.

This review summarises an invited talk presented at the 2012 ESRI/ASRI meeting in Hamburg, concerning current views of inflammation in pregnancy, which is timely given that the effects of a local injury in the uterus acts to favour implantation. Recalling that inflammation can be good (it is useful and necessary for implantation), bad (in implantation failure, RSA) and ugly (at the extreme, endometriosis is associated with pain and infertility) leads to consideration of its status in pregnancy. Its role in implantation and the fact that pregnancy maintains some aspects of inflammation throughout, leads to revision of not only concepts of immunosuppression and the Th1/Th2 paradigm, but also the feto-maternal relationship as seen since Medawar's hypotheses were advanced. This is examined from an evolutionary perspective, which should lead to further review of our perception of uterine NK cells, and the emergence of Treg cells to control some aspects of adaptive immunity, which appeared long after placentation.

Immune priming: mothering males modulate immunity.

The transfer of immunity from mother to offspring is widespread in animals. The father's contribution to this is usually negligible. However, in a sex-role reversed pipefish where fathers do the mothering, fathers make an important immune priming contribution, too.

A review of the evolution of viviparity in squamate reptiles: the past, present and future role of molecular biology and genomics.

Squamate reptiles (lizards and snakes) offer a unique model system for testing hypotheses about the evolutionary transition from oviparity (egg-laying) to viviparity (live-bearing) in amniote vertebrates. The evolution of squamate viviparity has occurred remarkably frequently (>108 times) and has resulted in major changes in reproductive physiology. Such frequent changes in reproductive strategy pose two questions: (1) what are the molecular mechanisms responsible for the evolution of squamate viviparity? (2) Are these molecular mechanisms the same for separate origins of viviparity? Molecular approaches, such as RT-PCR, in situ hybridisation, Western blotting and immunofluorescence, have been invaluable for identifying genes and proteins that are involved in squamate placental development, materno-foetal immunotolerance, placental transport, placental angiogenesis, hormone synthesis and hormone receptor expression. However, the candidate-gene or -protein approach that has been used until now does not allow for de novo gene/protein discovery; results to date suggest that the reproductive physiologies of mammals and squamate reptiles are very similar, but this conclusion may simply be due to a limited capacity to study the subset of genes and proteins that are unique to reptiles. Progress has also been slowed by the lack of appropriate molecular and genomic resources for squamate reptiles. The advent of next-generation sequencing provides a relatively inexpensive way to conduct rapid high-throughput sequencing of genomes and transcriptomes. We discuss the potential use of next-generation sequencing technologies to analyse differences in gene expression between oviparous and viviparous squamates, provide important sequence information for reptiles, and generate testable hypotheses for the evolution of viviparity.

No cancer in cancers: evolutionary trade-off between successful viviparity and tumor escape from the adaptive immune system.

Some invertebrate species including the king crab and king squid enjoy relatively long lives of up to 20 years. Nevertheless, there are few reports of malignancies among invertebrate animals while there are many such reports in lower vertebrates such as in fishes, amphibians, and reptiles. Viviparity is characteristic of most mammalian species, although it has been observed in both vertebrate and non-vertebrate species. As adaptive immune responses evolved among the cartilaginous fishes by virtue of gene duplication, all viviparous vertebrates cope with specific immune responses to reject the fetal allograft. The escape mechanisms employed by both human and animal malignancies share common properties, which are also employed by feto-placental units, such as the expression of non-classical major histocompatibility antigens (HLA-E, HLA-F, and HLA-G in humans), accumulation of regulatory T cells, Th2-directed immune responses, Fas/FasL- and/or PD-1/PD-L1-induced apoptosis, and the expression of indoleamine 2, 3 dioxygenase which starves the local tryptophan supply that is indispensable for an effective cytotoxic T cells response. In humans, a single cancer cell requires 1-10 years to develop into a clinically remarkable tumor. For cancer cells, the genes encoding the immunoregulatory mechanisms employed by feto-placental units could be of value for escaping the host immune system. Taken together, these observations support the author's hypothesis that the evolution of viviparity resulted in an evolutionary trade-off that may have increased susceptibility to malignancies.