Immunological aspects of implantation disorders in uterine infertility
AbstractThe aim of the research was to study characteristics of endometrium of infertile women in the «implantation window» phase (morphological, immunohistochemical and types of microbiota).
Material and methods. 84 infertile women were examined, with the allocation of groups: the 1st – with tubal-peritoneal infertility (TPI) (n=44), the 2nd – with chronic endometritis (CE) (n=28), the 3rd – with external genital endometriosis (EGE) (n=12).
The comparison group included 10 healthy fertile women.
Hysteroscopy and pipelle biopsy of the endometrium in the «implantation window» phase were performed to assess microbiota by real-time polymerase chain reaction (Femoflor 16 tests). Pathomorphological and immunohistochemical studies of the expression of cytokines, chemokines, growth factors (TNFα, IL-10, NRF2, GM-CSF, CXCL16, ВСА1, TGF-β) were also performed. Chronic endometritis (CE) was confirmed when the CD138+ marker was detected, and the proliferative activity of the endometrium was confirmed when Ki-67 was overexpressed.
Results. According to the results of morphological examination of endometrial biopsies of all women (with CE, TPI, EGE), histotypes were identified – proliferative [endometrial polyp (EP) (35.0%), focal simple endometrial hyperplasia (EH) (27.5%) and micropolypes (32.5%)]; CE (16.7%, in combination with micropolypes – 50.0%, endometrial polyp (EP) – 13.3%, EH – 20.0%; «normal» (in the group with TPI, n=12).
The basis for determining endometrial phenotypes was the data of immunohistochemical studies of marker expression in the «implantation window» phase. In the group with CE, the following were distinguished: the picture of true inflammation (n=12), a proliferative type (n=8), a combination of inflammation with EP (n=8). The endometrium of women with EGE was represented by a proliferative phenotype (n=12), with TPI – proliferative (n=12), CE (n=20), a variant of «normal» phenotype (n=12). Women with «normal» endometrial phenotype were distinguished by the balanced secretion of cytokines with moderate dominance of inflammatory molecular network and lactobacillar type.
The inflammatory type of immunoregulation in CE was determined by synchronous trends in predominance of proinflammatory cytokines in the gland epithelium and stroma in comparison with anti-inflammatory ones (increased TNFα, GM-CSF, CXCL16, BCA1, decreased IL-10), with the lowest TGF-β index (1 point). The endometrial microbiota of women with CE was represented by non-lactobacillar type (63.3%) – twice as often as with the proliferative type (p=0.01, χ2=6.8) due to dysbiotic profile (47.6 vs 5.3%, p<0.001, χ2=15.9).
Risk of implantation disorders in case of proliferative phenotype is due to the immunomodulatory activity of GM-CSF (1.2 times higher in glandular cells than in the control, 1.2 times lower in stroma) on the background of moderate overexpression of TNFα, CXCL16 only in epithelial glands and a decrease in IL-10 – in stroma significantly more than in glands in comparison with control. Violations of uterine microbiome in the group were less common than in case of CE (non-lactobacillar profile – 31.6%, mixed – 26.3%).
The inflammatory basis of EP and focal endometrial hyperplasia in 28.6 and 28.6%, respectively, is proved by positive expression of CD138+ and excessive expression of Ki-67.
Conclusion. The introduction of the concept of a proper immune microenvironment of the endometrium into the phase of «implantation window» allows us to distinguish types of immune inflammation that differ from the «normal» phenotype: excessive (СE phenotype) and autoimmune inflammation (proliferative phenotype). The nature of molecular-adaptive interaction of microbiota and immunocompetent cells serves as a criterion for readiness of endometrium for blastocyst implantation.
Keywords:infertility; chronic endometritis; immunohisto-chemical study; molecular phenotypes; lactobacillary and dysbiotic types of microbiota
Funding. The study had no sponsor support.
Conflict of interest. The authors declare no conflict of interest.
Contribution. Сoncept and design of the study – Polina M.L., Radzinskiy V.E., Mikhaleva L.M.; data collection and processing, writing the text – Polina M.L., Vityazeva I.I., Shelenina L.A.
For citation: Polina M.L., Radzinskiy V.E., Mikhaleva L.M., Vitiazeva I.I., Shelenina L.A. Immunological aspects of implantation disorders in uterine infertility. Akusherstvo i ginekologiya: novosti, mneniya, obuchenie [Obstetrics and Gynecology: News, Opinions, Training]. 2023; 11. Supplement: 6–17. DOI: https://doi.org/10.33029/2303-9698-2023-11-suppl-6-17 (in Russian)
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