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Lymphocyte Activation in the Development of Immune Tolerance in Women with Recurrent Pregnancy Loss

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Abstract

Association between lymphocyte activation and formation of immune tolerance, as well as pregnancy outcome, in the case of immunocytotherapy (ICT) was studied in women with idiopathic recurrent pregnancy loss (IRPL). The content and phenotypic characteristics of activated T lymphocytes and NK cells were investigated in the peripheral blood of IRPL patients with different pregnancy outcomes (pregnancy prolongation to the full term and habitual miscarriage). The fraction of activated cells in the subpopulation of cytotoxic T lymphocytes (CD3+CD8+/CD3+CD8+CD69+) before ICT was significantly lower in women who lost the pregnancy. After ICT, the fraction of these cells during weeks 5-6 of pregnancy in woman with miscarriage was higher than in women with pregnancy prolonged to the full-term. Excessive content of activated cytotoxic lymphocytes can be a mechanism underlying impaired maternal immunotolerance to fetal alloantigens, which is a leading factor of early pregnancy loss. The obtained data confirm the involvement of activated Th17 cells and FOXP3+ Treg cells in the formation of tolerance to paternal antigens of the fetus. Comparison of the decrease in the fraction of CD4+CD25highRORt+ lymphocytes at the early gestation period (5-6 weeks) and significant upregulation of the IL-17 production by in vitro stimulated whole blood cells in women with miscarriage with the same parameters in women with prolonged pregnancy suggested an imbalance between pro-inflammatory Th17 cells and Treg cells. No such imbalance in the content effector T lymphocytes was observed in women with the full-term pregnancy. Taken together, our data indicate an important role of gestational activation of lymphocytes in the formation of maternal immune response to fetal alloantigens necessary for the prolongation of pregnancy.

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Abbreviations

AHR:

aromatic hydrocarbon receptor

ICT:

immunocytotherapy

IRPL:

idiopathic recurrent pregnancy loss

FOXP3:

forkhead box p3 protein (transcription factor regulating cell differentiation and expression of cytokine participating in immune response suppression)

NK cell:

natural killer cell

RORt:

retinoid-related orphan receptor (transcription factor regulating differentiation of T lymphocytes to Th17 cells)

Th1:

type 1 T helper

Th17:

type 17 T helper

Treg cell:

regulatory T cel

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Funding

The work was performed within a framework of the State Task AAAA-A18-118053190024-2.

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Authors and Affiliations

  1. National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Healthcare of the Russian Federation, 117997, Moscow, Russia

    L. V. Krechetova, L. V. Vanko, V. V. Vtorushina, M. A. Nikolaeva, E. V. Inviyaeva & N. K. Tetruashvili

Authors
  1. L. V. Krechetova
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  2. L. V. Vanko
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  3. V. V. Vtorushina
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  4. M. A. Nikolaeva
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  5. E. V. Inviyaeva
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  6. N. K. Tetruashvili
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Corresponding author

Correspondence to E. V. Inviyaeva.

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The study was approved by the Ethics Committee of the National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Healthcare of Russian Federation. All participants signed an informed consent about inclusion in the study. The authors declare no conflict of interests.

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Krechetova, L., Vanko, L., Vtorushina, V. et al. Lymphocyte Activation in the Development of Immune Tolerance in Women with Recurrent Pregnancy Loss. Biochemistry Moscow 85, 583–593 (2020). https://doi.org/10.1134/S0006297920050077

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