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Abstract: In this short remembrance paper, I survey (what I believe are) key events in the evolution of the concepts of preeclampsia from the first workshop in 1998 to the 2012 one, and from Tahiti to Reunion island, via Mauritius and Tioman Island. [Copyright &y& Elsevier]

Citation Chaouat G, Petitbarat M, Dubanchet S, Rahmati M, Ledée N. Tolerance to the Foetal Allograft? Am J Reprod Immunol 2010 In this review, we will detail the concept of tolerance and its history in reproductive immunology. We will then consider whether it applies to the foetal–maternal relationship and discuss the mechanisms involved in non-rejection of the foeto-placental unit. [ABSTRACT FROM AUTHOR]

Abstract: The Fourth International Workshop on ‘Reproductive Immunology, Immunological Tolerance and Immunology of Pre-eclampsia’ was held in the Island of La Reunion in December 2004. Besides intense sharing of immunological data, it included also epidemiological studies from South Africa, USA and Australia, as well as genetic studies from South Africa and Mauritius, discussions on the future of graft transplant tolerance, implications of inositol-phosphoglycans in the pathogenesis of pre-eclampsia (PE), pathways to the inflammatory syndrome and other topics. Participants shared the belief that we may be witnessing significant steps forward in our comprehension of PE as an immunological event, with a prominent role for deregulation of the innate immune system, probably controlled by T cells and cytokine networks at the feto-placental interface. There was a growing consensus for an NK cell (KIR)-dependent event, with regulation exerted by T cells, as well as an important role for HLA-C presentation/recognition and HLA-G in mediating inflammatory cytokine imbalance, with an emphasis on IL-12 and IL-16 It is hoped that the next Workshop in 2006 will prove the immune involvement by dissecting the NK/Treg/Ts cell and HLA-CI HLA-G circuits leading to cytokine and vascular dysfunction. [Copyright &y& Elsevier]

PROBLEM: In the human, lymphocyte alloimmunization immunotherapy (IT)has been proposed as a treatment for recurrent spontaneous abortion (RSA). This treatment has been the subject of debate for a long period of time. Recently, it has been proposed to extend such a treatment for implantation failure in humans, and I was asked to express my opinion on this topic. METHODS: I reviewed the evolution and theories and current paradigms in reproductive Immunology and rationales proposed for IT. New discoveries show the complexity of implantation as a step by step developmental event, in mice and humans, and as such led me to re-examine paradigms currently evoked for extension of IT to implantation. Such a re-examination obviously leads me to re-question the basis of IT for SA itself. CONCLUSIONS: I conclude that the Th1/Th2 paradigm, evoked as the current basis for IT, and as useful as it has been to explain pregnancy, is no longer sufficient. It is especially insufficient to explain the process of implantation, which involves inflammatory molecules and cannot fit in such a scheme. It ensues that alloimmunization has no scientific rationale for the treatment of human implantation as a whole, and should not be applied broadly at such a stage of pregnancy. Furthermore, its use in RSA should be re-examined. [ABSTRACT FROM AUTHOR]

The introduction to this review discusses briefly why immunology, perceived as difficult by assisted reproduction technology clinicians, need nevertheless be envisaged as a central actor in the reproduction process, and how the maternal immune system, initially perceived as a threat to the fetoplacantal unit, is in fact utterly necessary for successful pregnancy. The key cells in such a process are uterine natural killer cells, which can act as friend or foe to the fetus, but are now known to play a key role in local vasculoganesis. As an ultimate consequence in cases of dysfunction/dysregulation, these factors result in implantation failure, abortion or pre-eclampsia. [ABSTRACT FROM AUTHOR]

The 11th workshop on Immunology of preeclampsia in Reunion 2018 celebrated its 20th candle In this paper we try to summarize the main tracks of reflections during these two decades. First, of course, the advances in immunology of reproduction in the field of preeclampsia, which was poorly developed 2 decades ago when we first started in 1998. But, this workshop has not been dedicated only to immunology. Second, one of the main reflections has always been, workshop after workshop: "why does preeclampsia exists in humans?" in an evolutionary view, as we have no established natural animal models in the other some 4500 other mammal species. Third, besides the reflections on the biological plausibility of preeclampsia-disease-of-first-pregnancies-at-a-level-of-a-couple (primipaternity rather than primigravidity), i.e. immunology, paternal-maternal conflict, we had to face an apparent conundrum: the human species should have disappeared (almost 40–50% incidence of hypertensive disorders of pregnancy in couples conceiving within the first 4 months of sexual cohabitation). We report then the dialogues we were obliged to have with zoologists who themselves had no clues on our apparent "extravagant sexuality" and strange reproduction (ridiculous low fertility rate of the human female: 25%). Fourth, debates on the main difference between early onset ("rather immunological") and late onset PE ("rather maternal vascular predispositions"). Further, the debate of why high income countries report 90% of their PE being LOP, while other countries describe epidemiologically very high incidences of EOP. Finally, and always present at all workshops, the physiopathology of the reversible systemic maternal vascular inflammation. [ABSTRACT FROM AUTHOR]

Eclampsia (together with epilepsy) being the first disease ever written down since the beginning of writings in mankind 5000 years ago, we will make a brief presentation of the different major steps in comprehension of Pre -eclampsia. 1) 1840. Rayer, description of proteinuria in eclampsia, 2) 1897 Vaquez, discovery of gestational hypertension in eclamptic women, 3) In the 1970′s, description of the “double” trophoblastic invasion existing only in humans (Brosens & Pijnenborg,), 4) between the 1970′s and the 1990′s, description of preeclampsia being a couple disease. The “paternity problem” (and therefore irruption of immunology), 5) at the end of the 1980′s, a major step forward: Preeclampsia being a global endothelial cell disease (glomeruloendotheliosis, hepatic or cerebral endotheliosis, HELLP, eclampsia), inflammation (J.Roberts. C Redman, R Taylor), 6) End of the 1990′s: Consensus for a distinction between early onset preeclampsia EOP and late onset LOP (34 weeks gestation), EOP being rather a problem of implantation of the trophoblast (and the placenta), LOP being rather a pre-existing maternal problem (obesity, diabetes, coagulopathies etc…). LOP is predominant everywhere on this planet, but enormously predominant in developed countries: 90% of cases. This feature is very different in countries where women have their first child very young (88% of world births), where the fatal EOP (early onset) occurs in more than 30% of cases. 7) What could be the common factor which could explain the maternal global endotheliosis in EOP and LOP? Discussion about the inositol phospho glycans P type. [ABSTRACT FROM AUTHOR]

Abstract: This paper depicts an overview of debates that have taken place during the 14 years of the International Workshops on Reproductive Immunology/Immunological Tolerance and Immunology of Preeclampsia. This 8th event in 2012 (Reunion island, overseas department of France in the Indian Ocean) witnessed a consensus among immunologists on the key role of regulatory T-cells in the orchestration of trophoblastic invasion at the maternal–fetal interface, while they represent some 10% of the immunological cellular repertoire at the site of implantation (NK cells representing 70%). On the vascular side, the upregulation of carbon monoxide CO, metabolite of heme oxygenase-1 (HO-1; by inhibiting soluble Flt-1, SFlt-1, and soluble endoglin, SEng, release), explains the very promising protective and potentially therapeutic effect of pravastatin in preeclampsia and the paradoxical strong protective effect of cigarette smoking on preeclampsia. Finally, there was, through a study performed on Mauritius island a great interest in the inositol phosphoglycans P-type (IPG-P) as a reliable, cheap, and predictive urinary test in preeclamptic women (a few weeks before the clinical onset of the disease). Besides the interest of a specific test, IPG-P may also partially explain the global endothelial cell disease encountered in preeclampsia. Furthermore, the Appendix of this paper lists the programs of all the workshops that have taken place since 1998. [Copyright &y& Elsevier]

Abstract: Hypertensive disorders of pregnancy (HDP) represent 10% of human births globally and the major complication preeclampsia has a 3–5% prevalence. The etiology of HDP remains uncertain; however, major advances have been made over the last 25 years. The Seventh International Workshop on Reproductive Immunology, Immunological Tolerance and Immunology of Preeclampsia 2010 celebrated its 12th Anniversary in Tioman Island in 2010. Over this period, these seven workshops have contributed extensively to immunological, epidemiological, anthropological, and even vascular debates. The defect of trophoblastic invasion encountered in preeclampsia, intra-uterine growth restriction, and to some extent preterm labor, was understood only at the end of the 1970s. On the other hand, clinical and epidemiological findings at the end of the 20th century permitted us to apprehend that “preeclampsia, the disease of primiparae” may well be a disease of first pregnancy for a couple. Among the important advances, reproductive immunology is certainly the topic where knowledge has exploded in the last decade. This paper relates some major steps in the comprehension of this disease and provides a review of epidemiological studies on the “primipaternity paradigm”. It focuses on the relevance of new developments and new concepts in immunology. At the beginning of the 21st century we are possibly closer than ever to understanding the etiology of this obstetrical enigma and also the pathophysiology of global endothelial inflammation in preeclamptic women. In this quest, reproductive immunology will certainly emerge as one of the main players. [Copyright &y& Elsevier]

Abstract: Developed countries represent 20% of the population in the world, but only 12% of human births annually, while 98% of medical publications are issued from these areas. What we can read on preeclampsia is correct, but only for 12% of human pregnancies! In addition, reproductive patterns in the developed world, but only for the last three decades, are different from elsewhere and during the first 70 years of the 20th century. A major difference is in the number of children in families but also, and mainly, in the ages at first pregnancies in primiparae (approaching now 30 years in many developed countries). This is probably why current epidemiological data seem different than that of the 20th century. The purpose of this article is to analyse to what extent the ‘primipaternity model’ may give clues for the comprehension of epidemiological descriptions past and present—and, indeed, it works in many respects. However, it is evident also that a proportion of preeclampsia cases cannot be explained by paternity patterns, and vascular disease predisposition in women (diabetes, obesity, thrombophilias, etc.) evidently comes into play. For these latter, maternal age is also strongly associated with these complications. Here, we reflect on what can be respective parts of the disease in preeclamptic couples, and on preeclampsia as a marker of subjects susceptible to vascular disease. [Copyright &y& Elsevier]

This workshop had four main objectives: (A) Trying to look at the preeclampsia (PE) problem “from the Space Shuttle”: why preeclampsia has emerged in humans (a specific human reproductive feature among 4300 mammal species)? (B) Epidemiology : there are major geographical differences concerning early onset PE and late onset PE throughout the world. (C) Vascular : The very promising use of pravastatin in the treatment of the vascular maternal syndrome (based on the metabolism of carbon monoxide (CO), the role of inositol phosphate glycans P-type (IPG-P), a major role in comprehending the insulin resistance phenotype in preeclampsia. (D) Immunology : the specialty of these workshops since their start in 1998; our understanding of the role of the immune system and the regulation of the deep implantation of the human trophoblast (and the obligatory compromises between the fetal/placental unit and the mother) have reached a kind of “maturity,” following the pivotal studies exploring the biology of repetitive sperm exposure in the female genital tract. The meeting of people who never meet each other in the course of their normal professional lives (obstetricians, evolutionists, geneticists, immunologists, fundamentalist vascular biologists, epidemiologists, anthropologists, neonatologists, etc.) permitted some fruitful reflections to be made again this year. [ABSTRACT FROM AUTHOR]