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Adaptation mechanisms within the B cell composition for successful human and murine pregnancies.

  • Introduction A well-balanced immune maternal status is essential for favourable outcome of pregnancy. Due to their complexities, not all immune adaptations that promote tolerance during pregnancy are known. To understand the adaptation of the B cell compartment, we analysed and compared B cell lymphopoiesis in different lymphoid tissues in a number of murine models. Furthermore, we focused on the humoral immune response during pregnancy. We analysed immunoglobulin profiles in human subjects and mice during pregnancy. These cellular alterations are subject to the influence of chemokines, among others. Therefore, we assessed serum levels of B cell activation factor to clarify its effects during pregnancy. Methods For analysis of the human peripheral B cell compartment, peripheral blood samples from age-matched non-pregnant and pregnant women without pregnancy complications, immunological disease or acute/chronic inflammation were collected and sub-classified into four different groups: non-pregnant, and first, second, or third trimester of pregnancy. The experiments, based on a mouse model, were performed with 8-week-old female mice: clinically healthy non-pregnant (CBA/J (H2k)), pregnant mice with normal gestation (BALB/c (H2d) x CBA/J (H2k)), and mice with pregnancy loss (DBA/2J (H2d) x CBA/J (H2k)). Subsequently, peripheral blood mononuclear cells from blood and lymphatic organs were isolated following standard protocols. The B cell analysis was performed by flow cytometry. The immunoglobulin serum levels of the human and murine subgroups were quantitated using Bio-Plex isotyping assay and analysed by a Bio-Plex reader. To quantify B cell activating factor (BAFF) in serum of pregnant and non-pregnant mice a BAFF enzyme-linked immunosorbent assay was used. The concentrations were determined by using a FLUOstar OPTIMA microplate reader. All statistical analyses were performed using the Kruskal–Wallis test with Dunn’s post-test in GraphPad Prism software. P values of < 0.05 were considered statistically significant. Results We were able to demonstrate B cell lymphopenia in mice bone marrow downstream of pre-pro B cells, irrespective of pregnancy outcome. The mature bone marrow B cells did not show this adjustment mechanism during normal gestation. Closer inspection of the splenic tissue revealed expansion and activation of marginal zone B cells in mice with a normal pregnancy. However, this was not observed in mice suffering from pregnancy disturbances. Natural antibodies secreted from marginal zone B cells were also present at higher concentrations in serum of pregnant mice, compared to non-pregnant animals. We also found significantly higher levels of natural antibodies in serum of pregnant women compared to non-pregnant age-matched controls. Analysis showed significantly lower levels of BAFF in mice with normal pregnancy as compared to non-pregnant mice. Conclusions We are able to show mechanisms within the B cell compartment as well as the change within the natural antibodies that might be crucial for successful pregnancy in both humans and mice. Furthermore, BAFF seems to play a central role as a mediator of peripheral B cell compartment and B cell lymphopoiesis in the bone marrow for successful pregnancy.

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Author: Katharina Beatrix Ziegler
Title Additional (German):Veränderungen des B Zell Kompartiments während einer Schwangerschaft bei Mensch und Maus
Referee:Prof. Marek Zygmunt, Prof. Petra Arck
Advisor:Prof. Marek Zygmunt, Prof. Federico Jensen, Dr.rer.nat. Damian Muzzio
Document Type:Doctoral Thesis
Year of Completion:2021
Date of first Publication:2021/11/30
Granting Institution:Universität Greifswald, Universitätsmedizin
Date of final exam:2021/11/17
Release Date:2021/11/30
GND Keyword:human pregnancy, B cell, mice pregnancy
Page Number:66
Faculties:Universitätsmedizin / Klinik und Poliklinik für Frauenheilkunde u. Geburtshilfe
DDC class:600 Technik, Medizin, angewandte Wissenschaften / 610 Medizin und Gesundheit