Foreword

For an immunologist, pregnancy remains an enigma although an enormous accumulation of knowledge was achieved during the past decades. Why is the foetus not rejected? In this eBook are described the most recent findings that could possibly answer to this crucial question, as well as the consequences of such discoveries for some important pregnancy associated pathologies, such as preeclampsia and of course recurrent pregnancy loss.

New molecular and cellular networks are now integrated in a rational way in order to propose satisfying models that explain how normal foetus develops and how it avoids an immune attack.

However, we still do not have the whole story that leads the immune tolerance. Interestingly, when I started my research training late 70’s with my mentor Jean Dausset at Saint Louis Hospital in Paris, he was collecting sera from multiparous women for his studies on HLA polymorphism whereas I was trying to isolate T lymphocytes with suppressive activity.

Concerning his work on polymorphism most is now done thanks to the molecular biology approaches. As for the one bearing on suppressor T cells, the concept was there but unfortunately neither the tools nor the knowledge, which allowed Sakaguchi and colleagues to describe for the first time in the mid 90’s the T regulatory cells (Tregs). Nevertheless, are these cells playing a tolerogenic role during pregnancy? More studies are needed to give a final answer to this question since Tregs exhibit distinct mechanisms to exert their function at the steady state and during inflammatory events.

Similarly, what about NK lymphocytes which were initially described as cells exhibiting spontaneous killer activity without previous immunization and were initially proposed to have deleterious action for the foetus? Meanwhile, were described several activating and inhibitory receptors that control NK lymphocyte effector function as well as were identified two distinct functional subsets that have permitted to consider them as potentially benefic for normal pregnancy by secreting cytokines such as VEGF or Angiopoietin 2.

For a “mainstream immunologist”, once we will have discovered the cellular and molecular basis of immune tolerance during pregnancy, which could be the end result of different mechanisms that are used over distinct period of time, then we might be close to manipulate the immune system for avoiding graft rejection and possibly conversely to stimulate immunity for malignancies eradication. Hence, this ebook brings me remembrances of my early years with my mentor in Saint Louis hospital while describing what has evolved since then and paving the way for the future….

Armand Bensussan
Director of Inserm laboratory
Hospital Saint-Louis and University Paris Diderot
France

“Immunology of Pregnancy 2013” is a major achievement.

Edited by Gérard Chaouat, a life long expert in the field, this eBook involves some 65 contributors, all renown in their respective specialties. The 14 chapters cover the field of reproductive immunology in a very comprehensive fashion.

Immunology of pregnancy occupies a very special place in immunology. It has played a major role in setting some of the initial major concepts of immunology. Then, it has somehow become isolated. This may result from the specific status of human pregnancy as a major issued of high personal and social relevance. Reproduction defects in humans affect large numbers of women and men, and profoundly affect their lives, without being truly considered as “real” diseases. Rather, they were felt to be confined to private life. They had in addition to cope with the many cultural and religious traits that guide individual and social behaviour. This situation has undoubtedly impacted the Science in many indirect ways. For example, there have been many attempts to treat reproductive deficiencies in rather empirical ways that had little to do with basic Science, and were less stringently controlled than standard clinical trials.

To some extent, immunology of pregnancy might be the only field of immunology in which research, for several decades, has been more focused on humans than on animals, especially mouse models. In other areas of immunology mouse, work has largely dominated over human immunology. The recognition of human immunology as a stand-alone area of immunology is a recent phenomenon. It was largely triggered by the emergence of new technologies that allow performing more extensive and profound even basic research on humans directly, without relying on the conclusions derived from mouse models. This shift of balance between research on mice and men is of major importance, because it is now clear that the mouse and human immune systems are significantly different, to the extent that mouse is too often non predictive of what happens in humans. The broad phenotypic diversity of human beings is an other incentive to promote human immunology. It may thus be possible that reproductive immunology was ahead of its time in working extensively on humans –perhaps too much in advance to conquer enough basic scientific knowledge.

On top of this, the main stream of basic immunology has focused for quite some time –and rightly so – on a number of specific immune phenomena and mechanisms such as the generation of diversity (antibodies and TCRs), or more recently the Toll Like Receptors involvement in innate responses. On the contrary, immunology of pregnancy is by essence systemic, with much defined outputs, the prediction of which requires a holistic approach. We all know, however, that the latter requires an extensive understanding of the elements that constitute the system and of their interactions. More Science is obviously needed before a system biology approach of pregnancy can actually be productive. As a matter of fact, the phenomenon of pregnancy is even more complicated and comprehensive than an immune phenomenon such as an immune response. Pregnancy and the reproductive immunology associated with it, involve a broad variety of physiological issues of all kinds. It has to cope with development biology, the endocrine system metabolism, etc. and not only immunology per se. This point can be made for immunology at large. Immunologists too often forget that the immune system is embedded within the entire organism to the extent that it is hardly possible –and actually impossible– to define the borders of the immune system. Immunology of pregnancy thus recapitulates many of the issues that deal with immunology in the broad sense of this word.

This eBook is not only comprehensive. It is also written in a somewhat unusual way, because it calls on history and reports a few anecdotes. This is associated with the unique character of the editor, Gérard Chaouat, as man who has invested his entire scientific life in the discipline. Together with a large number of scientific achievements, he has experienced all sorts of special situations, some of which are indeed worth being reported. On my side, I wish to share one anecdote. Twenty years ago or so, we collaborated and made a nice piece of work in a murine model of abortion. My co-workers had mutated all the aminoacid residues sitting on the surface of the alpha helices of the H-2 K^d molecule. We could thus analyse which MHC residues where involved in the immune reaction leading to abortion. This paper was accepted in a good immunology journal, but at the same time, Gérard was writing a general paper on pregnancy for a book dedicated to the general public. He received the galley proofs at the same time and mixed them up. His general paper was rejected by the immunology journal. Nevertheless the immunology paper was immediately sent to print and published in the book for the general public, because the editors did not notice the substitution. Once published, the paper could not be re-published as such, and this is how a good piece of Science has passed completely unnoticed.

Immunology of pregnancy is a fascinating field. As a few other fields, such as that of vaccination, it is directly rooted into the life of people. This gives a special taste to the science and endows it with a human dimension that imprints the field very significantly –some times, I must say to the expense of scientific rigour in developing human applications, but other times by providing completely new approaches. This eBook is a lively illustration of this combination of high-level advanced science with the more pragmatic questions coming from the people. The eBook includes a huge amount of scientific knowledge and perfectly reflects the past and current state of this particularly complex, essential and fascinating field. It is highly recommendable.

Philippe Kourilsky
Member of the French Académie des Sciences
France