10-workshops-on-Immunology-of-preeclamp 2017 Journal-of-Reproductive-Immunol

Journal of Reproductive Immunology 123 (2017) 94–99
Contents lists available at ScienceDirect
Journal of Reproductive Immunology
journal homepage: www.elsevier.com/locate/jri
10 workshops on Immunology of preeclampsia
MARK
Chaouat Gerard
976 INSERM Hôpital Saint Louis, Pavillon Bazin, Avenue Claude Vellefaux 75010 Paris, France
A R T I C L E I N F O
A B S T R A C T
Keywords:
Eclampsia
Evolution
Concepts
Immunology
For the 10th issue of the « island workshops », now the Reunion Workshops, organised by Pierre Yves Robillard
since the first one in Tahiti challenging the “vascular disease only” theory of pre eclampsia and introducing the
primipaternity concept, we examined the reasons for considering an Immunological approach to the disease.
This (brief) overview thus examines several important topics in an Immunological framework. I have chosen to
present here the evolution of the main themes rather than a purely chronological vision.
1. Introduction
2. Why Immunology from the 1994 Lancet paper?
This is the 10th issue of the « island workshops », now the Reunion
Workshops, organised by Pierre Yves Robillard since the first one in
Tahiti in 1998 on the island of Moorea….
This workshop was motivated by discussions arising after the publication of the paper by Pierre Yves, Emile Papiernik and colleagues
(Robillard et al., 1994) which was a real “pavé dans la mare” as we say
in French …(incidentally, private jokes about pavés, the workshop
ended may the 2nd, just for the 30th anniversary of May 68, and I was
thus interviewed by French radio from there..).
Why was this paper important?
Because of the by then prevalence of the “vascular disease only”
theory of pre eclampsia.
It should be recalled first here that the prevailing theory was that
preeclampsia was ONLY a vascular disease and ONLY occurring in the
first pregnancy.
It was even written that for any work speaking or even (mildly)
invoking the existence (and even simply the possibility) of PE in a
second pregnancy: “I would suggest that Editors reject any study of
preeclampsia that includes multiparous unless they are analyzed separately” (Chesley, 2000). » (this “very scientific” approach, close to
dictatorial censorship, IS unfortunately a quotation).
The workshop examined the reasons for considering an
Immunological approach after the publication of this paper.
Afterwards, as we will see, it examined several important topics in
an Immunological framework. I have chosen to present here the evolution of the main themes rather than a purely chronological vision.
Of course, not all the communications are discussed, but this does
NOT mean that they were useless (nor bad!). In fact, they all contributed to the progress of our understanding of the disease.
The most salient point of the Lancet paper and, thus, the first
workshop was the introduction of primipaternity, as a replacement of
the primiparity concept.
The authors reported first that there were in French West Indies
(Martinique and Guadeloupe) frequent occurrence of a 2nd preeclampsia in a multiparous woman. This was strongly correlated with
the fact that the biological father had changed and that the affected
pregnancy was in fact the first one with this specific individual. As Bob
Marley would sing about West Indies behaviours, “shame and scandal
in the family”, except the fact that multi partner is rather commonly
accepted in French West Indies. Further explanation is needed: in what
we may call the “slavery belt” (Brazil, Central America, the Caribbean’s,
North America…), masters had strictly forbidden marriages between
slaves during some 3 centuries. These people have then integrated in
their specific reproductive culture a special scheme, and demographers
had to invent the term of “women Family Structure” for these areas.
Also what Jamaican health workers call “visiting sexuality”. Then,
there, it is absolutely not reprehensible to have 4 children with 3 different fathers, everybody is aware (including the siblings, who have
different family names), and, in Guadeloupe, all these families go every
Sunday at the Catholic church together. This made the interviews, and
thus the epidemiological investigations, much easier than in some
Northern European countries where the search for a “non legal” father
was much more difficult, if not almost impossible). Apart from that, a
first occurrence of preeclampsia with that father was still protective in
case of a 2nd pregnancy with the same individual.
Primipaternity if confirmed would imply…. This implied specificity,
while, on the other hand, the protective effect per se was highly suggestive of a memory phenomenon.
E-mail addresses: [email protected], [email protected].
URLS: http://mailto:[email protected], http://mailto:[email protected].
http://dx.doi.org/10.1016/j.jri.2017.06.002
Received 12 May 2017; Received in revised form 7 June 2017; Accepted 20 June 2017
0165-0378/ © 2017 Published by Elsevier Ireland Ltd.
Journal of Reproductive Immunology 123 (2017) 94–99
C. Gerard
All of the following workshops but one (held in Tiomian) were held
in Réunion island, (where we had the chance to have one during an
eruption of the Volcano, and to fly above it by helicopter) and always in
the same place…., hotel Iloha at Saint Leu, which made interactions
easy.
Specific memory is a feature shared only by the immune and nervous system.
The vascular theory, it was admitted, could explain the apparent
protection (primigravidity), but had more difficulties in explaining the
resurgence of the phenomenon in cases of a second occurrence linked to
a change in biological father in multiparous women.
4. Evolutionary perspective
3. Setting some of the framework
Why preeclampsia in human? And great apes?
In the 1st Mauritius workshop, Jean Chaline suggested that preeclampsia might somehow be the price to pay by the human Homo
Sapiens for a bigger brain…(Chaline, 2003).
He reminded us of the existence of preeclampsia in some big apes
(albeit the experimental work is rather small …. for obvious reasons
when dealing with protected/endangered species, some being moreover
territorially aggressive: gorillas) and insisted on the fact that there is
TWO waves of invasion in human placentation, preeclampsia being
characterised in the 2nd one by a « shallow invasion » – data of
Pijnenborg, see for example Naicker et al. (2003).
A part of the discussion later on, which is not fully settled yet, would
be to establish if preeclampsia starts by then or, much earlier, around
the implantation stage itself (see below).
At this 2nd workshop, Jean Chaline presented his views on the extinction of Neanderthal, and the possible relationship with failure to
develop a large and complex enough brain.
The discussion went on about size of the brain and intelligence in
such mammals as dolphins (an epitheliochorial placentation) and elephants, as well as on the preeclamptic (hemochorial placentation) great
apes.
I must stress that this discussion occurred before the discoveries that
Neanderthal was much more technically and culturally developed than
what was thought in the 90s, and the realisation that there were close
relations between Neanderthal and Sapiens communities, and even
exchange of artefacts (commerce) and, even more, interbreeding,
(Temme et al., 2014; and for a relatively recent general overview,
Gibbons, 2014).
This has lead for example to a recent suggestion that disappearance
of Neandertal would have resulted by “dilution” after a period of interbreeding…., but the ideas of genocides, acute competition, or inferior species as far as technology is concerned are no longer as
dominant as they were by then.
Nevertheless, this evolutionary vision led us also to examine the
very concept that allopregnancy had to be considered as a possible
materno foetal immune conflict.
This lead to assess in depth Polly Matzinger remark “Reproduction
cannot be a danger! it does not make evolutionary sense”. One must
recall that it is precisely discussion about “non rejection of the foetal
allograft” that lead Polly, during her discussions with Robert Schwab, of
UCLA Davis, at a bar when she was then a cocktail waitress, to postulate
that self/non self theory was wrong, and that the immune system was in
fact reacting to the 4ds: danger, (“bad” cell) death (as opposite to
“controlled cell death”, such as apoptosis), damage, and distress
(Matzinger, 1994).
Thus we invited Elisabeth Bonney (Bonney, 2016) and Colin Anderson.
Though the danger model as such did not gain universal acceptance,
their talk did cast further light on the importance of uncontrolled post
implantation inflammation, as indeed seen in many cases of sterility
and a subset of recurrent aborters.
The discussions on evolution lead also later to comparative analysis
of viviparous mammals. Eutherian M. Elliott recently focused on the
relationship between oxidative stress and the evolution of placentation
in eutherian mammals (Elliot, 2016).
For him, epitheliochorial placentation, in which foetal tissues remain separated from maternal blood throughout gestation, has evolved
as a protective mechanism against oxidative stress arising from
3.1. First workshop
Wisely enough, since the “blood transfusion effect ” was known
since 1981 and was less suspicious amongst Immunologists than disquisitions on the now defunct “I-J sub-region”, Pierre Yves and Gus had
invited Paul Terasaki, well known for the blood transfusion effect in
kidney transplantation (Tokunaga and Terasaki, 1986) which lead us to
discuss the role of “suppressor T cells”, and we recalled that since the
work of Loblay, Pritchard Briscoe and Basten “multiple low dose tolerance” – in this seminal paper, to Human Gamma Globulin”, was associated with “suppressor T cell memory” – (Loblay et al., 1978).
This was of importance since the observation of the duration of
sexual cohabitation enabled Gus Dekker to suggest the protective role
of sperm exposure, and later on even question the protective effects of
oral sex (Koelman et al., 2000), whereas Chris Redman was already
there, and presented to us his views on inflammation as the cause of
preeclampsia which he will develop all along the time course of the
workshops till now, with adaptation to Immunology (see below).
Both myself and Pierre Yves had the feeling that he was more interested at the start of the workshop by vascular theories but inclined at
the end to discuss Immunological ones.
3.2. The 2nd workshop
The 2nd workshop moved from the South Pacific to the Indian
ocean, in that case Mauritius, due to the appointment of Pierre Yves in
La Reunion, and thus his moving away from Tahiti/Moorea… Many of
us who were there would of course remember the paradise like setting
of the Moorea Lagoon…
Further clues were added: the role of sperm was tackled again by
Satish Gupta, and the first mention of HLA-G was made by Debra Wohl
(down regulation of HLA-G in the placentae of preeclamptic women)
(Goldman-Wohl et al., 2000).
The first PE (artificially induced) animal model was introduced by
Sasaki Hayakawa. It was a transfer of IL-12/IL-4 hyper-activated lymphocytes in pregnant mice and such abnormal activation of the innate
immune system by selected cytokines did lead to a pre eclampsia like
syndrome in mice (Hayakawa et al., 2000). Retrospectively, it is interesting to note that C3 deposits were observed in the kidneys of Il-4
treated animals, but this was not noticed enough at the time.
3.3. The continuation …
From these two first workshops, the main discussion themes of the
sessions to come were established.
These were:
• Evolutionary perspective
• Primiparity/primipaternity sperm exposure
• Diagnosis predictive (and indications for Therapy?): IPG VEGF
• IMMUNOLOGY and the vessels, itself divided into:
○ NK
• Complement
• Induction of « tolerance » to the foetal allograft
• Th1/Th2 cytokine unbalance
• Tregs
• The role of Inflammation, debris, small particles
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An important question arising about the consequences of these
studies was whether the mother is primed to paternal alloantigens, and
whether or not this does occur before, during, of after a 1st pregnancy
and was discussed in the first workshops. In a way, the response was
built in the study of Einarsson (the effects of using barrier prior to
conception).
Interestingly exposure to paternal seminal fluid as a reducing factor
for preeclampsia needs not to be by the vaginal route, since exposure
via the oral route will also confer a reduced risk of preeclampsia.
Incidentally, an humoresque note was that we were told that the papers
from this workshop using “oral sex” as keyword had an unusually high
rate of visits (see the above referenced paper from Koelman et al.).
Anyway, this linking of several anatomic compartments of mucosal
immunity has to be related with, conversely the observations/theory
suggesting that at least a part of recurrent abortions are linked to abnormal development the gut flora, resulting in a disequilibrium in the
mucosal immune response. It may seem somehow funny that at one
workshop oral sensitization by artificial MHC peptides was discussed,
but in fact: why not?
A related question is whether priming affects all or only some of the
lymphocyte subpopulations. A set of data did provide evidence in rodents that a sort of priming occurs at mating, and this was extended by
elegant studies of Sarah Robertson showing that T regs subpopulations
were activated in an antigen specific fashion by the paternal sperm,
with a key role to such cytokines as TGF – beta (Robertson et al., 2009).
The cascade of immunological events elicited by seminal TGF beta may
therefore explain epidemiological observations linking acute and cumulative exposure to semen with successful placental development and
pregnancy outcome. This, of course, is to be linked with T regs (see later
on).
Peculiarly convincing was the Comparison of Indian and Creole
populations in Mauritius, since the occurrence of preeclampsia is very
different in Indian population, where the women tend to have a single
partner, and the local Creole population, where, as in West Indies, there
exist a high number of 2nd set preeclampsia linked to the frequent
occurrence of multi sexual partnership (Poonyth et al., 2003).
pregnancy, particularly in species with unusually long gestation periods
and unusually large placentas. “Human beings comprise an unusual
species that has the life history characteristics of an epitheliochorial
species, but exhibits hemochorial placentation, in which foetal tissues
come into direct contact with maternal blood. I argue that the risk of
preeclampsia has arisen as a consequence of the failure of human beings
to evolve epitheliochorial placentation”.
This is not so far from the Jean Chaline original paper, and mixed
somehow the deep invasion process and the oxidative stress theories of
the origin of pre eclampsia (see below).
For my part, I did re-examine the 1953 Medwar paradigm: it is
phrased as “”some immunological and endocrinological problems
raised by the evolution of viviparity in vertebrates. (Medawar, 1953). I
found (to my great surprise) that not only did placental pregnancy did
evolve/appear in many VERTEBRATE species (as well as very early in
invertebrate evolution) but that despite the presence of allograft rejection capacity allo pregnancy was proceeding in almost all of them w/
o any apparent immunological confrontation problems (Chaouat,
2016).
“Problems” did appear in eutherian mammals, with apparently (the
literature is rather scarce) a lower intensity in epitheliochorial (be it
diffuse or cotydelonary) and endothelio chorial placentae than in hemochorial ones, albeit the equine pregnancy offers signs of necrosis,
haemorrhages and rejection but nevertheless proceed to term (this,
incidentally, does not fit with the danger theory?) except in the case of
intra species pregnancy such as the donkey in horse one (Allen and
Stewart, 2001).
In fact two evolutionary “bricolages” were used by viviparous
mammals, once diverted frome egg laying ones, the monotremes (see
platypus). For one branch, there is implantation but as soon as paternal
MHC would appear on the placenta, the marsupials “deliver” and the
conceptus moves to the marsupial pouch.
Another strategy (ours) was to tame the immune system by attraction of regulatory T cells (see below). The bricolage used then, in our
branch, the eutherians, was to use a non coding sequence gene as (CNS1) to promote attraction and/or? development of intra uterine regulatory T cells. CNS-1 is expressed ONLY in eutherian mammals, and its
KO results in profound pregnancy wastage (Samstein et al., 2012).
Another consequence of the coexistence of an “allo” conceptus with
the innate immune system as early as Cambrian, the presence of lymphoid aggregates around uterine vessels as early as in viviparous shark
placenta suggests/confirms the that the uterine NK cells were from the
beginning NOT a “danger”.
6. Insulin resistance, inositol phosphoglycans
A second point where there has been regular progress is the field of
Inositol phosphoglycans story. I will only briefly summarize, since there
is a full length review in this issue by the authors.
At the beginning of the workshops, Thomas Rademacher presented
first the measurements of the urinary content of inositol phosphoglycans IPG P-type and IPG A-type, putative insulin second messengers, in
preeclampsia, as well as in the placenta from preeclamptic patients and
from normal pregnancies. Pregnancy was associated with an increase in
urinary IPG-P-type, a much higher level was seen in preeclamptic
women. Later data confirmed the existence of this state of insulin resistance in active preeclampsia, but, moreover, a further step was to
demonstrate that women with clinical evidence of insulin resistance
were at higher risk to develop the syndrome. For a comprehensive
overview, see Scioscia et al. (2011) and of course this issue of this
journal.
The next step was to test the populations in Mauritius on a large
scale assay, and then, again in Mauritius, to test prospectively a kit
permitting detection and measurement of such the development of
preeclampsia. As discussed in the 2016 workshop, and in this issue, the
results demonstrate that an easy, non invasive (urine) testing of women
can allow the detection of these at risk for preeclampsia. Moreover, the
results of this prospective study show that the detection of preeclampsia
can be obtained rather early in pregnancy (Dawonauth et al., 2014).
5. Sperm tolerance, memory
The second important topic was the role of sperm exposure and the
concepts of primiparity vs. primi paternity.
Several presentations dealt with that topic. I will give a few examples.
The concept of primipaternity as well as the shorter the duration of
sexual cohabitation the bigger the risk of PE after being discussed had
of course to be confirmed, since it was a key issue leading to
Immunology as well as the effects of sexual cohabitation, Several studies confirmed the importance of priming, and, moreover, its maintenance.
In this respect, for example, a study by Einarsson and colleagues
monitored the consequences of usage of barrier methods of contraception and indeed fewer than 4 months of cohabitation among users of
barrier methods for contraception is associated with a significantly increased risk for preeclampsia (Einarsson et al., 2003). In addition, a
study by D. Hall presented in 2006 was strongly suggestive that preeclampsia and gestational hypertension are less common in HIV infected women being managed with mono- or triple anti-retroviral
therapy, a fact which they confirmed in 2014 (Hall et al., 2014), albeit
the issue is still controversial (Adams et al., 2016).
7. VEGF
Another marker has been discussed repeatedly, e.g. VEGF s Flt1. It
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has been first introduced together with Angiopoietin in human and
murine immune abortion pathways (see below)and then as such by
Anan Karumanchi in the 2006 workshop (Kopcow and Karumanchi,
2007). It should be recalled here (see below) that the regulation of
angiogenic factors (VEGF, angiopoietin 2) in the regulation of placental
growth was also initially linked to NK cells by Anne Croy (see below),
who was the first to propose a role for such cells in preeclampsia (and
presented that in one of the workshops) (Croy et al., 2000).
In the 2006 edition, Karumanchi has shown that sFlt1 (soluble FMSlike tyrosine kinase1) is upregulated in preeclamptic patients blood,
where it acts as a potent antagonist to VEGF and (PlGF). This (important) increase precedes the established preeclampsia and in fact can
be detected prior to onset of clinical symptoms. Consistent with the
action of the circulating protein to bind PIGF, free (or unbound) PlGF
levels are decreased in preeclamptic women, also well before the onset
of clinical symptoms.
Thus, we dispose of a second predictive test, albeit slightly more
invasive than an urine sampling.
Etiologically speaking dysregulation of other anti-angiogenic agents
such as sFlt-1, e.g. PLGF and sEndoglin was also examined by Foidart,
who nevertheless concluded that such a deregulation was “not the definitive answer” (Foidart et al., 2009).
It should be pointed out that, such a deregulation can be integrated
in a purely vascular theory, where a poor placentation would be leading
to poor uteroplacental perfusion and hypoxia, which would in turn
stimulatessFlt-1 and sEng production causing the maternal syndrome
However, as Foidart pointed, whereas the deregulations are real, this
theory would suggest that, antioxidant therapy could prevent PE, but
the data concerning the effects of such a treatment so far are “at best
conflicting”.
Linked to that, anyway, it was shown that Impaired autophagy of
extravillous trophoblast (EVT) by soluble endoglin may disturb EVT
invasion and vascular remodelling.
uNK KIR interactions (Hiby et al., 2004).
They classified HLA-C in different groups −It should be recalled
here that near onset of the workshops, HLA-C was perceived by several
workers as quasi monomorphic, which it was recalled several times, it is
not.
In fact, Hiby proved that a proper activating signal from maternal
KIR was beneficial if HLA-C Group 2 is present in the fetus. The data
were completed by a study of KIR AA genotype and HLA-C2 frequencies
in different populations in the world, showing a reciprocal relationship
between AA frequency and HLA-C2 frequency.
It must be mentioned, however, that despite the generalisation of
this interaction as important in the pathology of recurrent abortions
and low birth weight by the same group years afterwards. Shigeru Saito
presented data comparing the two types of couples in Japan, and that
“the incidence of pre-eclampsia in these couples consisting of Japanese
women and Caucasian men was similar to that in Japanese women and
Japanese men. Our data do not support that of Hiby et al.” (Saito et al.,
2006), but the authors replied that in their opinion the Japanese study
was statistically flawed (Moffett et al., 2006). See reply by the authors
in Saito and Sakai (Saito and Sakai, 2016).
9. Of mice and men… Complement ….
For years, anyway, the CBA x DBA/2 murine mating combination
was presented solely as an immune abortion model…. and even by me,
that despite a paper pointing “Immunological similarities between implantation and pre-eclampsia » (Chaouat et al., 2005)….: mice were
never tested for albuminuria nor blood pressure…
Guillermina Girardi did that, and nicely showed that symptoms of
preeclampsia were present in first pregnancy of this mating combination.
Moreover, and this is important, this was correlated with alterations
in local angiogenesis and local angiogenic factors production.
Even most important, a variety of treatments affecting complement
activation did prevent both pregnancy loss and ‘clinical’ and biological
preeclampsia symptoms. These were ip injection of recombinant CrryIg, or anti-C5 MoAB on days 4 and 6, or a C5aR cyclic antagonist
peptide. Alternative pathway activation was inhibited by administering
anti–factor B mAb (2 mg i.p.) on days 4–10 of pregnancy. All these
treatments resulted in a correction of the CBA x DBA/2 pregnancy
pathologies. (Girardi, 2009; Ahmed et al., 2010)
Moreover, she was able to demonstrate a crucial role for tissue injury and proposed prevastatin treatment in consequence, and indeed
this prevented preeclamptic syndrome in CBA × DBA/2 murine matings (and corrected the associated VEGF deregulations, decreasing sFlt1 levels and increasing VEGF levels). It should be recalled here that
independently a Japanese group reported correction of a preeclamptic
syndrome artificially induced by expression of human sFLT1 (hsFLT1)
specifically in the murine placenta using a pravastatin treatment
(Kumasawa et al., 2011).
Additionally, it was shown that statins induce Hmox1 and suppress
the release of sFlt-1 and sEng.
Thus, statins and Hmox1 activators were seen as potential novel
therapeutic agents for treating preeclampsia, and indeed randomised
control trials were initiated. It should be mentioned in this review that a
very limited (4 women) open study produced apparently positive results. For more data, see this Journal issue.
For our own, we tested in cooperation with Francesco Tedesco very
early the role of MBL as a complement activator initiating pregnancy
loss, or implantation defects, or preeclampsia, in mice and human.
Indeed, blocking MBL, and in case of mice, MBL-A, resulted in
prevention of these syndromes (Petitbarat et al., 2015).
This set of data also offers a link towards abnormal NK activation at
the interface.
Albeit uNK cells are normally non cytotoxic and essentially angiogenic, an abnormal NK activation can occur in the periphery, and the ds
8. NK cells
Whatever the effects, anyway, those data pointed out to a role of
angiogenic mediators. It was in this respect that the role of the uterine
NK cells was tackled. At the onset of the workshops, NK, and hyper
activation of these, were seen mostly, if not exclusively, as a threat
towards the embryo.
The data were clear cut in mice and rat immune abortion models,
much less clear and conflicting in human (especially when regarding
the need to “tame down” (quote) uterine and circulating NK cells,
especially by lymphocyte Immunisation (lymphocyte immunotherapy
protocols in case of either implantation failure or recurrent spontaneous
abortions…).
However, when dealing with implantation, it became evident the
pre and peri implantation uterus was filled with uterine NK cells and
that these cells were somehow activated…
This apparently appeared as a contradiction which was resolved by
Anne Croy who demonstrated that uterine NK cells are not only “normally” non cytotoxic, but, in fact are a main source of angiopoietin 2,
critical itself to destabilisation of uterine arteries and their subsequent
transformation into spiral arteries.
Indeed, NK −/− mice do implant BUT abort around day 9.56 and
that this can be prevented by transferring normal NKs (Croy et al.,
2003).
Further to this major step, in parallel the acronym KIR = Killer
Inhibitoy receptor was replaced in the literature by the use of KIR as an
acronym for Killer Ig like Receptor (this has Created for a time some
confusion…).
The demonstration that activation of the “activating KIRS” on the
uterine NKs leads to the secretion by uNK cells of angiogenic factors
was then linked also to the stimulatory role of the placental paternal
MHC by the important results of Hiby et al., dealing with HLA-C and
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specific activated T regs correct abortion and 1st pregnancy induced
albuminuria in the CBA x DBA/2 system. See for example out work in
cooperation with David Klatmann (Chen et al., 2013).
RNA injection systems (POLY IC, Poly I C14U) are good models to study
such effects.
But it has also been proposed that the effects can be local, and IL-17
and TH-17 cells have been proposed to be one of those activation
pathways. Moreover, it has also been shown that uNK do not exhibit a
“fixed phenotype”.
Le Bouteiller et al. demonstrated in decidual NML cells that the
specific engagement of NKp46-, and to a lesser extent of NKG2C-, but
not of NKp30-activating receptors induced intracellular calcium mobilization, perforin polarization, granule exocytosis and efficient target
cell lysis Thus, uterine NK cells CAN become cytotoxic (El Costa et al.,
2009).
A crucial role for NK/and activated T cell inhibition/destruction by
apoptosis by HLA-G was a regular opic of the workshops, and as stated
down regulation of HLA-G production, and or expression in the placentae of preeclamptic women has been reported by several authors in
these workshops; whereas the mechanisms of action of HLA-G on NK
and T cells has been shown to rely not only on its membrane bound
isoforms, but also, and perhaps more importantly on soluble ones.
Moreover, sHLA-G have been shown to not only play a role in inhibition of local cytotoxic pathways, but, most important, in control of
local angiogenesis, and uterine arteries remodelling and extension (Le
Bouteiller et al., 2007).
An important feature of the complement inhibition data is that a
protection can be offered by a treatment as early as day 4 in mice, e.g.
at the very peri implantation period, and not as late as the initially
thought to be predominant, TNF, gamma INF and activated macrophages classical “resorption window” of the CBA x DBA/2 murine
mating combination.
12. Conclusion
Thus, we come to an integrated scheme, and albeit I disagree partly
with Chris Redman when he says “the reactivity to fetal alloantigens are
not really in cause”, his 2010 abstract merits to be quoted as a conclusion, and the last sentence highlighted:
“Pre-eclampsia develops in stages, only the last being the clinical
illness. This is generated by a non-specific, systemic (vascular), inflammatory response, secondary to placental oxidative stress and
not by reactivity to fetal alloantigens. However, maternal adaptation
to fetal (paternal alloantigens) is crucial in the earlier stages. A preconceptual phase involves maternal tolerization to paternal antigens
by seminal plasma. After conception, regulatory T cells, interacting
with indoleamine 2,3-dioxygenase, together with decidual NK cell
recognition of foetal HLA-C on extravillous trophoblast may facilitate placental growth by immunoregulation. Complete failure of
this mechanism would cause miscarriage, while partial failure
would cause poor placentation and dysfunctional uteroplacental
perfusion. The first pregnancy preponderance and partner specificity of pre-eclampsia can be explained by this model. For the first
time, the pathogenesis of pre-eclampsia can be related to defined
immune mechanisms that are appropriate to the fetomaternal
frontier. Now, the challenge is to prove the detail »”.
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10. “Its all inflammation, stupid !”
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This suggested that the initial events in murine models and human
pathologies of preeclampsia could take place very early.
In this respect, continuous studies of the (hyper) inflammation
process, trophoblast damage, and micro particles shedding by the group
of Redman and Sargent are very important. Besides recalling that “It’s
all inflammation, stupid” (original title of one presentation in 2010)
and the micro-vesicles are to blame” – see (Redman and Sargent, 2007),
the group has proposed that in fact pre eclampsia is a multi stage disorder, starting indeed very early (Redman, 2014).
This conceptual evolution from the Tahiti workshop to the last one
is certainly better tackled by CWG Redman than myself, and I refer to
his paper in this issue.
It does not neglect such factors as complement regulators, etc… as
discussed in this brief overview as “tamers” of such an inflammation,
and amongst such tamers are T regs.
11. T regs
A salient feature of the primipaternity model is the specific protection offered by a first same partner pregnancy to the following
conceptions, as well as the effects of long cohabitation, and eventually
additional effects of oral sex.
The ideal candidates for such a memory effect were proposed as
early as the 1st meeting to be “suppressor T cells”.
Following the “resurrection” of these as regulatory T cells after the
work of S Sakaguchi (Sakaguchi et al., 1985), and especially in view of
their important role in pregnancy as initially demonstrated by Aluvihare and Betz (Aluvihare et al., 2004), these have been extensively
studied in the frame of these workshops, and there seems to be a consensus that they indeed play a cardinal role, albeit possibly not solely,
since it has been shown that “Decidual NK cells remember pregnancy”.
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controlled low dose treatment of Interleukin 2 corrects abortion in
murine abortion models, and we have verified that transfer of paternal
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