Immune cell composition and cytokine expression in the pregnant and non-pregnant uterus

The success of implantation and further development of the embryo is heavily dependent on the endometrial immune cell composition and its ability to communicate with fetal semi-allogeneic trophoblast cells. Although our understanding of the immune cell population in the uterus has improved, its precise role in normal reproduction and reproductive disorders is still not fully resolved. Here, we examined immune cells and signal molecules derived from the endometrium around the time of implantation, in postmenopause, and in early pregnancy.

In study I, we analyzed cytokine and chemokine characteristics in menstrual blood from healthy nulliparous women with regular menstrual cycles, both before and after luteal phase endometrial scratching. The menstrual blood cytokine profile showed little interindividual variation and differed distinctly from peripheral blood. Endometrial scratching did not affect the cytokine profile in menstrual blood.

Study II examined the dynamics of endometrial MAIT cells in various reproductive states, including pre- and postmenopausal endometrium and in first trimester decidua. We also evaluated the impact of genetic and environmental factors on the endometrial MAIT cell population by comparing the size of the MAIT cell compartment in menstrual and peripheral blood from monozygotic twins. Additionally, we examined the tissue-residency of endometrial MAIT cells by using transplanted uteri as a model. Finally, we assessed the ability of MAIT cells to react against N. gonorrhoeae, a pathogen known to infect the female genital tract and pose a growing threat of antibiotic resistance. We found that the frequency of endometrial MAIT cells remained stable throughout the different reproductive stages of the endometrium, and that they exhibited both a more activated state and a tissue-resident phenotype compared to their peripheral counterparts. However, in the transplanted uteri, only MAIT cells positive for the recipients HLA were present within the uterus, suggesting that endometrial MAIT cells are transiently tissue-resident and replenished over time from the circulation. Last, we demonstrated that MAIT cells are functional and respond to N. gonorrhoeae.

In study III, we investigated the immune cell characteristics in vaginal blood from women with first trimester pregnancy bleeding and associated findings with pregnancy outcome (miscarriage/ not miscarriage). Saliva and serum proteome was analyzed and correlated to vaginal immune cell phenotype and outcome of pregnancy. We found that vaginal blood contained all main immune cell lineages, and that a higher frequency of tissue-resident CD49a+ NK cells in vaginal blood was associated with pregnancy loss. The frequency of vaginal blood tissue-resident NK cells correlated with levels of several maternal serum proteins.

In summary, this thesis provides valuable new insights into reproductive physiology and sheds light on various aspects of the uterine immune system. The findings from this research can be used for future comparisons with reproductive pathological states that may involve altered cytokine and immune cell composition.

List of scientific papers

I. THE CYTOKINE PROFILE OF MENSTRUAL BLOOD. Crona Guterstam Y, Strunz B, Ivarsson MA, Zimmer C, Melin AS, Jonasson AF, Björkström NK, Gidlöf SB. Acta Obstet Gynecol Scand. 2021 Feb;100(2):339-346.
https://doi.org/10.1111/aogs.13990

II. HUMAN ENDOMETRIAL MAIT CELLS ARE TRANSIENTLY TISSUE RESIDENT AND RESPOND TO NEISSERIA GONORRHOEAE. Bister J, Crona Guterstam Y, Strunz B, Dumitrescu B, Haij Bhattarai K, Özenci V, Brännström M, Ivarsson MA, Gidlöf SB, Björkström NK. Mucosal Immunol. 2021 Mar;14(2):357-365.
https://doi.org/10.1038/s41385-020-0331-5

III. IMMUNE CELL PROFILING OF VAGINAL BLOOD FROM PATIENTS WITH EARLY PREGNANCY BLEEDING. Crona Guterstam Y, Acharya G, Schott K, Björkström NK, , Gidlöf SB Ivarsson MA. [Submitted]