Problem: Strong evidence suggests that the immune system plays a critical role in the progression and development of endometriosis. This study aims at assessing the endometrial immune profile in patients with endometriosis-associated recurrent implantation failures (RIFs) following in-vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI), in comparison to women with male infertility-associated RIFs. Method of Study: This case-control study compared the endometrial immune profile in women with endometriosis-associated RIFs (case group) versus those with male infertility-associated RIFs (control group). The profile was evaluated using the ratio of IL-18/TWEAK mRNA expression levels (a biomarker for angiogenesis and Th1/Th2 balance), the ratio of IL-15/Fn14 mRNA expression levels (a biomarker for uNK cell activation/maturation), uNK cell counts, and CD56 mRNA expression levels (a marker for uNK cell mobilization). Results: The distribution of immune profiles significantly differed between the case group and the control group. The case group had fewer patients with a regulated profile (18.9% vs. 24.3%, P value 0.01) and more patients with under-activated profiles (34.2% vs. 28.4%, P value < 0.0001). Additionally, the case group had a higher proportion of immature uNK cells (46.2% vs. 39.2%, P value 0.007). The immaturity of uNK cells in endometriosis-associated RIFs appeared to be mediated by decreased IL-15 expression levels. Conclusions: The study highlights unique immune characteristics in the endometrial environment of women with endometriosis-associated RIFs, emphasizing the role of immune dysregulation in the development and progression of endometriosis.
Chez l’homme, le taux d’implantation moyen d’un embryon obtenu apres FIV/ICSI se situe aux alentours de 15 a 20 %. On estime qu’environ la moitie des patientes infertiles traitees sont concernees partiellement ou totalement par un probleme de receptivite uterine conjoint et se trouvent en echec d’implantation malgre le transfert correct d’embryons de qualite. Jusqu’a present, la receptivite uterine au sens d’une evaluation biologique de l’aptitude immunologique maternelle a recevoir un embryon ne fait pas partie de la demarche diagnostique courante pour optimiser les chances d’implantation. L’objectif de cet article va etre de decrire les bases physiologiques et le rationnel de l’approche innovante developpee par la societe de recherche et d’innovation medicale MatriceLAB Innove afin de permettre une optimisation de la receptivite uterine. Au terme de 10 ans de recherche fondamentale, il semble possible de proposer une approche pratique, clinique et innovante issue de la recherche sur la receptivite uterine afin d’optimiser la prise en charge des patientes en fecondation in vitro. La premiere partie de cette revue reprendra les bases physiologiques et immunologiques gouvernant la receptivite uterine et l’implantation embryonnaire : rationnel physiologique et immunologique. Cela introduira le rationnel concernant les biomarqueurs que nous utiliserons au cours de ce diagnostic. La seconde partie sera dediee aux consequences therapeutiques et donc a la personnalisation du soin que nous introduisons en cas de profil immunologique perturbe. Enfin, a partir de ces bases, nous illustrerons les resultats cliniques obtenus en 2012-2013 par le centre d’assistance medicale procreative de l’hopital Pierre-Rouques-Les Bluets (Paris) apres personnalisation du soin dans des cas difficiles d’echecs inexpliques d’implantation embryonnaire.
An important subset of implantation defects/early abortion seems to be linked with a deregulation of the interleukin (IL)-12/IL-15/IL-18 system as well as tumor necrosis factor (TNF)- and natural killer (NK)-controlled/mediated networks at the decidual placental interface, both in case of deficient or excess expression. The presence of TNF in high amounts in the pre/peri-implantation uterus and its pivotal role during pregnancy are difficult to reconcile with its abortive effects in ongoing pregnancy. We therefore searched for regulators of the IL-12/IL-18 family of cytokines as well as for antagonist(s) of TNF with potentially selective effects on implantation.We first used Swiss mice to verify the presence in the murine reproductive tract of 'new members' of the IL-12 family of cytokines, IL-23 and IL-27, as well as of tumor necrosis factor-like WEAK inducer of apoptosis (TWEAK), described as acting with TNF as Yin and Yang of innate immunity in murine placenta/ decidua at days 0-12.5. We then compared expression by RT-PCR in the CBA x DBA/2, and CBA x BALB/c murine mating combinations. Finally, we performed in vivo neutralization experiments of TWEAK and IL-27.Immunohistochemistry (IHC) studies showed that IL-23, IL-27, and TWEAK were expressed at the interface. For RT-PCR, IL-23 expression peaked at day 9.5 in the non-aborting mating combination, a peak absent in the aborting one, and thus difficult to explain except by invoking a feed back on EB13 (Epstein-Barr virus-induced gene 3 cytokine). Most important, an immediate post-mating IL-27 hyper expression was seen in the CBA x DBA/2 mating compared to CBA x BALB/c one. The difference in expression resurged and was statistically very significant by days 6.5-9.5, compatible with an early activation of inflammation on day 0.5 which would then peak again in the 'resorption window' where takes place the early NK/mph activation described by Baines et al. A significant TWEAK expression was present in both strains from days 0.5 to 4.5 peaking in both cases in the first days when it is known that intra uterine TNF also reaches high levels as a component of post-mating inflammation. However, it was lower from day 1.5 in the abortion-prone CBA x DBA/2 mating combination, and almost absent by days 6.5-9.5 when compared to the non-aborting CBA x BALB/c mating combination. In both mating combinations, neutralization of TWEAK-enhanced resorption rates, but surprisingly so did IL-27 neutralization.TWEAK is likely offering protection against the deleterious effects of TNF in implantation explaining embryo survival in a TNF-rich environment, and equal number of implants in both strains. However, there is a clear difference of protection in abortion-prone mating peaking in the abortion/resorption window but starting early, and therefore possible links with the prevention of abortion in CBA x DBA/2 matings by interfering with complement activation as recently described by Girardi et al. are discussed, as well as consequences for our current view of feto-maternal 'seed and soil' interplay. The apparently paradoxical effects of IL-27 neutralization are also discussed.
Infertility affects millions of people of reproductive age. The failure of a blastocyst to implant is a leading cause of psychological distress. It became increasingly evident that an effective immune dialogue occurs at each step in the fluids surrounding the oocyte, the spermatozoa, the embryo, or the endometrium. Exploring and deciphering this dialogue could potentially help understand why 50% of healthy euploid blastocysts fail to implant. Introducing immunology into reproductive medicine requires a change of mindset to bring immune hypothesis to clinical applications. Implantation of an embryo requires a prepared uterus in order to dialogue with the embryo, which is able to express and repair itself. Exploring the uterine immune profile of patients with previous implantation failures (IF) or recurrent miscarriages (RM) has already been developed and is under evaluation as a precision tool to equilibrate the uterine environment before implantation to increase the subsequent live birth rate after the embryo transfer. Immunology may also be fundamental in the future to identify through non-invasive procedure the competence of oocytes or embryos through reliable immune biomarkers quantified in follicular fluids or embryo supernatants during the in vitro fertilization (IVF) process. Non-invasive biomarkers would allow physicians to identify competent oocytes or embryos based on their ability to communicate with the mother and their energetic potential for all the self-repair processes that should occur during the preimplantation and the implantation period. This area of research is only beginning.
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