P-512 Cell-mediated immunity as a biomarker of predisposition in recurrent miscarriage.
Authors: Alarcón A , Alonso R , Mejía M A , Gallego A , Carbone J 
Published: June 2023

Abstract

Study question
Are alterations in the peripheral cellular immune system a potential risk factor for recurrent miscarriage?

Summary answer
Percentage alteration of some circulating immune cell subpopulations could be used as biomarkers or potential therapeutic targets in recurrent miscarriage.

What is known already
About 50% of patients with recurrent miscarriage (RM) have no known cause of the disease. The maternal immune system plays an important role in maternal-fetal tolerance, so an imbalance in the maternal immune system could trigger reproductive failure in women. Antiphospholipid syndrome is the only immunological alteration with sufficient evidence of association with RM, however, there are many other immunological parameters under investigation that appear to mediate the maternal-fetal relationship such as KIR receptors and HLA-C. Other authors are focusing their studies on reproductive immunology at the cellular level, looking at the role of different lymphocyte subpopulations in RM.

Study design, size, duration
Prospective observational analytical study (cases and controls) conducted in the Immunology Department of the Hospital General Universitario Gregorio Marañón (Madrid, Spain) from 2019 to 2022. It included a group of 49 non-pregnant women with a clinical history of recurrent miscarriages of unknown cause, and two control groups, one with 40 women of childbearing age who had at least one live newborn and another with 60 women of childbearing age who had no history of pregnancy.

Participants/materials, setting, methods
The inclusion criteria for the study were: two or more gestational losses (&lt; 22 weeks of pregnancy). Patients with severe uterine pathologies, genetic disorders, thrombophilias, obesity, infections, coeliac disease without gluten restriction, uncontrolled endocrine disorders, immunomodulatory treatment, autoimmune disorders and documented RM were excluded from the study.
An immunophenotypic study of T, B, NK and NKT lymphocyte subpopulations and monocytic series was performed. Cell characterization was carried out by 6-colour flow cytometry in peripheral blood.

Main results and the role of chance
When comparing the cellular profile of RM patients with the profile of both control groups, we observed alterations in the percentage levels of CD3+ T cells, CD8+ T cells, NKT cells and non-switch and class switch memory B cells in the patient group, suggesting the presence of a predominantly pro-inflammatory peripheral cellular immune profile in RM patients. In contrast to previous studies by our research group, we did not observe significant differences between the percentage levels of NK cells and activated CD8+ T cells (HLA DR+) in the patient and control groups, which may be explained by the high and exhaustive patient selection in this study.
After association study of these alterations with RM, we identified levels of NKT cells &gt; 5%, CD8+ T cells &gt; 26.50%, non-switch memory B cells &gt; 22% and class switch memory B cells &gt; 32% as new biomarkers of RM risk. In addition, the combination of at least two of these new biomarkers was found to significantly increase the likelihood of developing the disease, suggesting that RM is a complex pathology in which multiple factors may influence the pathogenesis of the disease.

Limitations, reasons for caution
Among the limitations of our study, we can highlight the collection of control group variables from databases developed in previous studies, in addition to a small sample size.

Wider implications of the findings
The determination of these immunological biomarkers in RM allows us to evaluate the role of immunomodulatory therapies on these biomarkers in order to evaluate possible new treatments to help prevent immune-mediated reproductive failure, thus contributing to a more personalized medicine.

Trial registration number
Not applicable