Endometrial NK cells in repeated implantation failure – quantity and functional markers

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Abstract

BACKGROUND: Alteration in the composition and function of endometrial immune cells, in particular NK cells, are associated with implantation and placentation pathology, which is considered as one of the causes of reproductive losses. However, data regarding abnormalities in the number and activity of NK cells in repeated implantation failures, including depending on the type of infertility, remain ambiguous.

AIM: The aim of this study was to evaluate the number of CD56+ and CD16+ cells and the area of expression of CD107a and NKG2D markers in the endometrium of patients with repeated implantation failure (RIF).

MATERIALS AND METHODS: This prospective comparative study included patients with RIF (main group I, n = 47), who were divided into two subgroups: Ia, patients with primary infertility (n = 29); Ib, patients with secondary infertility (n = 18). Comparison group II included patients with a history of effective ART programs (n = 17). Control group III included healthy fertile women without a history of reproductive loss (n = 12). Endometrial biopsies were obtained on days 19–23 of the menstrual cycle. The expression of CD56+, CD16+, CD107a and NKG2D was assessed by immunohistochemistry.

RESULTS: In the endometrium of patients in groups I and II, as compared to the control group, the number of CD56+ cells was significantly increased (p < 0.001). In patients of subgroup Ia, when compared to the control group, we verified an increase in the number of CD16+ cells (p < 0.05) and a decrease in the expression of CD107a (p < 0.05). In patients in groups I and II, a negative correlation was revealed between the number of CD56+ and CD16+ cells and the number of pregnancies in history (rs = –0.30 and rs = –0.34, p < 0.05), while a positive correlation was found between the expressions of CD56+ and CD107a (rs = 0.66 and rs = 0.75, p < 0.05). In patients in group II, a positive correlation was revealed between the expressions of CD16+ and CD107a (rs = 0.75, p < 0.05). In the endometrial stroma, CD107a expression increased significantly in patients in group I (p < 0.05), while NKG2D expression increased in groups II and III (p < 0.01, p < 0.05) from the early to the middle stage of the secretion phase. In patients of group II, a positive correlation was established between the expressions of CD56+ and NKG2D (rs = 0.68, p < 0.05).

CONCLUSIONS: In the endometrium of patients with primary infertility and RIF, the number of CD56+ and CD16+ cells is increased with a decrease in the expression of their activation marker CD107a, which may be a potential mechanism for impaired implantation. Further studies of the immune profile of the endometrium may help to personalize diagnostic and therapeutic approaches to management of patients with RIF and to increase the chances of pregnancy in ART programs.

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About the authors

Valeria A. Zagaynova

The Research Institute of Obstetrics, Gynecology and Reproductology named after D.O. Ott

Author for correspondence.
Email: zagaynovav.al.52@mail.ru
ORCID iD: 0000-0001-6971-7024
Russian Federation, Saint Petersburg

Olesya N. Bespalova

The Research Institute of Obstetrics, Gynecology and Reproductology named after D.O. Ott

Email: shiggerra@mail.ru
ORCID iD: 0000-0002-6542-5953
SPIN-code: 4732-8089

MD, Dr. Sci. (Med.)

Russian Federation, Saint Petersburg

Inna O. Krikheli

The Research Institute of Obstetrics, Gynecology and Reproductology named after D.O. Ott

Email: ovrt@ott.ru
ORCID iD: 0000-0002-5439-1727
SPIN-code: 7356-6189

MD, Cand. Sci. (Med.)

Russian Federation, Saint Petersburg

Alexander M. Gzgzyan

The Research Institute of Obstetrics, Gynecology and Reproductology named after D.O. Ott

Email: agzgzyan@gmail.com
ORCID iD: 0000-0003-3917-9493
SPIN-code: 6412-4801

MD, Dr. Sci. (Med), Professor

Russian Federation, Saint Petersburg

Tatyana G. Tral

The Research Institute of Obstetrics, Gynecology and Reproductology named after D.O. Ott

Email: ttg.tral@yandex.ru
ORCID iD: 0000-0001-8948-4811
SPIN-code: 1244-9631

MD, Cand. Sci. (Med.)

Russian Federation, Saint Petersburg

Gulrukhsor Kh. Tolibova

The Research Institute of Obstetrics, Gynecology and Reproductology named after D.O. Ott

Email: gulyatonbova@yandex.ru
ORCID iD: 0000-0002-6216-6220
SPIN-code: 7544-4825

MD, Dr. Sci. (Med.)

Russian Federation, Saint Petersburg

Dmitry I. Sokolov

The Research Institute of Obstetrics, Gynecology and Reproductology named after D.O. Ott

Email: falcojugger@yandex.ru
ORCID iD: 0000-0002-5749-2531
SPIN-code: 3746-0000

Dr. Sci. (Biol.)

Russian Federation, Saint Petersburg

Igor Yu. Kogan

The Research Institute of Obstetrics, Gynecology and Reproductology named after D.O. Ott

Email: ovrt@ott.ru
ORCID iD: 0000-0002-7351-6900
SPIN-code: 6572-6450

MD, Dr. Sci. (Med.), Professor, Corresponding Member of the Russian Academy of Sciences

Russian Federation, Saint Petersburg

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2. Fig. 1. CD107a expression in the endometrium, magnification ×400: a, control group III; b, subgroup Ia (with repeated implantation failure); c, subgroups Ia and Ib (with repeated implantation failure), comparison group II and control group III; d, group I (with repeated implantation failure), comparison group II and control group III in the early and middle stage of the secretion phase; * p < 0.05

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3. Fig. 2. NKG2D expression in the endometrium, magnification ×400: a, subgroup Ia (with repeated implantation failure) in the early stage of the secretion phase; b, control group III in the middle stage of the secretion phase; c, subgroups Ia and Ib (with repeated implantation failure), comparison group II and control group III; d, subgroups Ia and Ib (with repeated implantation failure), comparison group II and control group III in the early and middle stage of the secretion phase; * p < 0.05, ** p < 0.01

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4. Fig. 3. Correlations between CD56+ expression and CD107a or NKG2D expressions in the endometrial stroma: a, main group I (with repeated implantation failure); b, comparison group II; correlations between CD16+ expression and CD107a or NKG2D expressions in the endometrial stroma; c, main group I (with repeated implantation failure); d, comparison group II

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