Braverman Reproductive Immunology research team attended the 38th ASRI meeting in Shanghai, China

Pre-eclampsia has been the most discussed pregnancy complication during this meeting. Affecting up to 7% of pregnancies in the United States and characterized by hypertension and proteinuria, pre-eclampsia is also associated with an increased secretion of pro-inflammatory cytokines and oxidative stress that injures the placenta and leads to placental ischemia during pregnancy. Many talks focused on the key role of protein misfolding and aggregation, detectable in maternal serum, in the development of pre-eclampsia. While protein aggregations have been detected in women with PE, scientists are now assessing if this can be used as a predictive marker for PE (early detection in maternal serum before symptoms occurrence). Protein aggregates are normally cleared up by a process called autophagy that maintains homeostasis.

In PE, autophagy is altered which leads to poor placentation, exacerbated with toxic protein aggregates. Dr Sharma (Women and infants Hospital, Brown University, Providence, RI) showed how a protein called cis pin tau (involved in microtubules organization) is involved in hypoxia inducing protein aggregates. More interestingly, using a disaccharide named trehalose, they can destroy protein aggregates and restore normal parameter in mice (blood pressure, proteinuria) preventing the onset of PE-like features. The role of pyroptosis, a cell -death program (caspase I dependent mechanism) has been highlighted in PE where hypoxia induces unfold protein aggregation leading to massive inflammatory response through a pyroptosis process (Dr Cheng, Women and infants Hospital, Brown University, Providence, RI).

Preterm birth has been proposed to find its roots prior to pregnancy with a genetic predisposition shaping maternal risk for this obstetrical complication (Dr Muglia, Cincinnati Children’s hospital Medical Center, Cincinnati, OH). There are genetic variants associated with PTL that are present in higher incidence in patients more prone to this complication. As an example, African American women have a 4-fold increase in PTL risk as compared to Caucasian. Among these genetic variants, EB1 (involved in blood pressure and childhood obesity), Wnt 4 (associated with endometriosis) and EEFSEC (involved in selenium metabolism) were found to be associated with preterm birth. Interestingly, selenium, an essential nutrient for human health, has been found in lower concentration in maternal serum of women experiencing a miscarriage as compared to successful pregnancy. These findings don’t come as a surprise knowing that selenium contributes to the balance between pro-oxidants and anti-oxidants. Indeed, selenium is a key component of several selanoproteins, of which the best known is the antioxidant glutathione peroxidase. Lower selenium levels may reflect a disruption in the pro/anti-oxidant balance pointing towards oxidative stress.

Dr Muglia suggests a systematic screening for selenium levels with adequate supplementation when required (just like folic acid supplementation to prevent neural tube defects).

A novel protein FGL2 (fibrinogen like protein), secreted by regulatory T cells was found to be increased in the peritoneal fluid as well as in the endometrium (lesions and unaffected endometrium) in ENDO women versus controls. As a result, this factor promotes cell proliferation and cell invasion. Further, FGL2 is also increased by pro-inflammatory cytokines so once the lesions are formed, there is an amplification loop where FGL2 amplifies lesions formation and growth and in return the pro-inflammatory cytokines environment increases FGL2 level (Dr Hou, FuDan University, Shanghai, China). An interesting concept has been presented by Dr Guo (FuDan University, Shanghai, China) who defined endometriotic lesions as wounds undergoing repeated tissue injury and repair (ReTIAR). As a result, platelets are recruited which induce:

These activated platelets reduce NK cell cytotoxic activity, enabling lesions formation. Besides inflammation and estrogen dependency, coagulation is also a driven force for endometriosis.

Research has put into light a novel molecule, identified as T cell immunoglobulin and mucin domain (Tim)-3. The binding of Tim-3 present on many immune cells with its ligand, galectin-9 (Gal-9) could induce the apoptosis of effector T cells such as Th1 and Th17 cells, and thus might regulate the tolerance during pregnancy. Tim-3 pathway also participates in regulating the activities of CD4+ regulatory T cells, monocyte-macrophages, dendritic cells and natural killer cells. Recent work presented at the meeting has defined the role on Tim-3/Gal-9 pathway on decidual macrophages whose activation can alleviate the preeclampsia-like symptoms in a mice model (Dr Li, Tongji Medical College, Wuhan, China).

Further, other previous studies have shown much reduced levels of Tim-3 expression on pNK cell of patients suffering from reccurent miscarriage, altering their immunosuppressive activity. In addition, animal studies have shown that when Tim-3 is blocked, this leads to reduced levels of Th2 cells and increased fetal loss rate in mice. This is certainly a potential biomarker for RPL diagnosis.

Macrophages represent one of the major leukocyte subsets in the endometrium. They act as primary mediators of tissue remodeling and are involved in the maternal immunotolerance. Decidual macrophages display a balance between anti-inflammatory and proinflammatory phenotypes. Several talks focused on factors able to mediate a M2-polarization such as M-CSF and glycodelin A thus promoting angiogenesis and trophoblast invasion. Another factor TIM3 (a mucin) induces also a M2 macrophage polarization required for the maintenance of maternal fetal tolerance.

Many of these talks are in keeping with our thinking that pregnancy complications are a large spectrum whose causes occur early on, before or during the peri-implantation period requiring an early diagnosis and adequate therapies to allow an optimal implantation and prevent later obstetrical complications.