bims-reprim 2021-06-20 papers

Issue of 2021‒06‒20
five papers selected by
Iva Filipovic
Karolinska Institutet

Front Immunol. 2021 ;12 657552

Systemic Characterization of Novel Immune Cell Phenotypes in Recurrent Pregnancy Loss.

Hong Liu, Xin-Xiu Lin, Xiao-Bo Huang, Dong-Hui Huang, Su Song, Yang-Jiao Chen, Jing Tang, Ding Tao, Zhi-Nan Yin, Gil Mor, Ai-Hua Liao.

Recurrent pregnancy loss (RPL) is a disturbing disease in women, and 50% of RPL is reported to be associated with immune dysfunction. Most previous studies of RPL focused mainly on the relationship between RPL and either T cells or natural killer (NK) cells in peripheral blood and the decidua; few studies presented the systemic profiles of the peripheral immune cell subsets in RPL women. Herein, we simultaneously detected 63 immune cell phenotypes in the peripheral blood from nonpregnant women (NPW), women with a history of normal pregnancy (NP) and women with a history of RPL (RPL) by multi-parameter flow cytometry. The results demonstrated that the percentages of naïve CD4+ T cells, central memory CD4+ T cells, naïve CD8+ T cells, mature NK cells, Vδ1+ T cells and the ratio of Vδ1+ T cells/Vδ2+ T cells were significantly higher in the RPL group than those in the NPW and NP groups, whereas the percentages of terminal differentiated CD4+ T cells, effective memory CD4+ T cells, immature NK cells and Vδ2+ T cells were significantly lower in the RPL group than those in the NPW and NP groups. Interestingly, we found that peripheral T helper (TPH) cells were more abundant in the NPW group than in the NP and RPL groups. Moreover, the percentage of Vδ2+PD-1+ gamma-delta (γδ) T cells was extremely high, above the 95th percentile limit, in the NP group compared with the NPW and RPL groups, which has never been reported before. In addition, we also determined the 5th percentile lower limit and 95th percentile upper limit of the significantly changed immunological parameters based on the files of the NPW group. Taken together, this is the first study to simultaneously characterize the multiple immune cell subsets in the peripheral blood at a relatively large scale in RPL, which might provide a global readout of the immune status for clinicians to identify clinically-relevant immune disorders and guide them to make clear and individualized advice and treatment plans.

Keywords: NK cell; flow cytometry; immune cell; peripheral T helper cell; recurrent pregnancy loss; γδT cell

DOI: https://doi.org/10.3389/fimmu.2021.657552

Clin Transl Immunology. 2021 ;10(6): e1294

Extreme prematurity and sepsis strongly influence frequencies and functional characteristics of circulating γδ T and natural killer cells.

Khaleda Rahman Qazi, Georg B Jensen, Marieke van der Heiden, Sophia Björkander, Giovanna Marchini, Maria C Jenmalm, Thomas Abrahamsson, Eva Sverremark-Ekström.

Objectives: Extremely low gestational age neonates with extremely low birthweight (ELGAN/ELBW) are highly susceptible to infection. This is linked to their relatively immature immune system which is not yet fully compatible with an extra-uterine environment. Here, we performed a longitudinal characterisation of unconventional T and natural killer (NK) cells in ELGAN/ELBW during their first months of life.Methods: Peripheral blood mononuclear cells were collected from 97 ELGAN/ELBW at 14 and 28 days of life and at a time point corresponding to postmenstrual week 36 + 0. γδ T-cell, NKT-cell, mucosa-associated invariant T-cell and NK cell frequencies and characteristics were analysed by flow cytometry. As control, cells from 14-day-old full-term (FT) infants were included.
Results: Extreme prematurity had significant bearing on γδ T-cell and NK cell frequencies and characteristics. ELGAN/ELBW had significantly higher proportions of γδ T cells that were skewed towards effector and effector memory phenotypes, characteristics that were maintained throughout the study period. Expression of the gut homing receptor CCR9 was also more common in γδ T cells from ELGAN/ELBW. Conversely, NK cell frequencies were markedly lower and skewed towards a cytotoxic phenotype in the ELGAN/ELBW group at 14 days of age. Culture-proven sepsis with an onset during the first 14 days after birth further manifested these differences in the γδ T- and NK cell populations at 14 days of age.
Conclusion: Prematurity strongly influences the levels of γδ T and NK cells, in particular in cases where sepsis debuts during the first 2 weeks of life.

Keywords: extreme preterm; gestational age; natural killer cells; neonatal immunity; sepsis; unconventional T cells

DOI: https://doi.org/10.1002/cti2.1294

Commun Biol. 2021 Jun 17. 4(1): 651

Menstrual flow as a non-invasive source of endometrial organoids.

Tereza Cindrova-Davies, Xiaohui Zhao, Kay Elder, Carolyn J P Jones, Ashley Moffett, Graham J Burton, Margherita Y Turco.

Assessment of the endometrium often necessitates a biopsy, which currently involves an invasive, transcervical procedure. Here, we present an alternative technique based on deriving organoids from menstrual flow. We demonstrate that organoids can be derived from gland fragments recovered from menstrual flow. To confirm they faithfully reflect the in vivo state we compared organoids derived from paired scratch biopsies and ensuing menstrual flow from patients undergoing in vitro fertilisation (IVF). We demonstrate that the two sets of organoids share the same transcriptome signature, derivation efficiency and proliferation rate. Furthermore, they respond similarly to sex steroids and early-pregnancy hormones, with changes in morphology, receptor expression, and production of 'uterine milk' proteins that mimic those during the late-secretory phase and early pregnancy. This technique has wide-ranging impact for non-invasive investigation and personalised approaches to treatment of common gynaecological conditions, such as endometriosis, and reproductive disorders, including failed implantation after IVF and recurrent miscarriage.

DOI: https://doi.org/10.1038/s42003-021-02194-y

Front Immunol. 2021 ;12 679424

Expression of the Carbohydrate Lewis Antigen, Sialyl Lewis A, Sialyl Lewis X, Lewis X, and Lewis Y in the Placental Villi of Patients With Unexplained Miscarriages.

Zhi Ma, Huixia Yang, Lin Peng, Christina Kuhn, Anca Chelariu-Raicu, Sven Mahner, Udo Jeschke, Viktoria von Schönfeldt.

Background: Lewis antigens such as Sialyl Lewis A (sLeA), Sialyl Lewis X (sLeX), Lewis X (LeX), and Lewis Y (LeY) are a class of carbohydrate molecules that are known to mediate adhesion between tumor cells and endothelium by interacting with its selectin ligands. However, their potential role in miscarriage remains enigmatic. This study aims to analyze the expression pattern of sLeA, sLeX, LeX, and LeY in the placental villi tissue of patients with a medical history of unexplained miscarriages.Methods: Paraffin-embedded slides originating from placental tissue were collected from patients experiencing a miscarriage early in their pregnancy (6-13 weeks). Tissues collected from spontaneous (n = 20) and recurrent (n = 15) miscarriages were analyzed using immunohistochemical and immunofluorescent staining. Specimens obtained from legally terminated normal pregnancies were considered as control group (n = 18). Assessment of villous vessel density was performed in another cohort (n = 10 each group) of gestation ages-paired placenta tissue. Protein expression was evaluated with Immunoreactive Score (IRS). Statistical analysis was performed by using Graphpad Prism 8.
Results: Expression of sLeA, sLeX, LeX, and LeY in the syncytiotrophoblast was significantly upregulated in the control group compared with spontaneous and recurrent miscarriage groups. However, no prominent differences between spontaneous and recurrent miscarriage groups were identified. Potential key modulators ST3GAL6 and NEU1 were found to be significantly downregulated in the recurrent miscarriage group and upregulated in the spontaneous group, respectively. Interestingly, LeX and LeY expression was also detected in the endothelial cells of villous vessels in the control group but no significant expression in miscarriage groups. Furthermore, assessment of villous vessel density using CD31 found significantly diminished vessels in all size groups of villi (small villi <200 µm, P = 0.0371; middle villi between 200 and 400 µm, P = 0.0010 and large villi >400 µm, P = 0.0003). Immunofluorescent double staining also indicated the co-localization of LeX/Y and CD31.
Conclusions: The expression of four mentioned carbohydrate Lewis antigens and their potential modulators, ST3GAL6 and NEU1, in the placenta of patients with miscarriages was significantly different from the normal pregnancy. For the first time, their expression pattern in the placenta was illustrated, which might shed light on a novel understanding of Lewis antigens' role in the pathogenesis of miscarriages.

Keywords: Lewis antigen; NEU1; ST3GAL6; unexplained miscarriage; villous vessel

DOI: https://doi.org/10.3389/fimmu.2021.679424

Genomics. 2021 Jun 09. pii: S0888-7543(21)00233-0. [Epub ahead of print]113(4): 2614-2622

B cells acquire a unique and differential transcriptomic profile during pregnancy.

Natalin Valeff, Damian O Muzzio, Franziska Matzner, Marcos Dibo, Janine Golchert, Georg Homuth, Martin C Abba, Marek Zygmunt, Federico Jensen.

Pregnancy alters B cell development and function. B cell activation is initiated by antigens binding to the BCR leading to B cell survival, proliferation, antigen presentation and antibody production. We performed a genome-wide transcriptome profiling of splenic B cells from pregnant (P) and non-pregnant (NP) mice and identified 1136 genes exhibiting differential expression in B cells from P mice (625 up- and 511 down-regulated) compared to NP animals. In silico analysis showed that B cell activation through BCR seems to be lowered during pregnancy. RT-qPCR analysis confirmed these data. Additionally, B cells from pregnant women stimulated in vitro through BCR produced lower levels of inflammatory cytokines compared to non-pregnant women. Our results suggest that B cells acquire a state of hypo-responsiveness during gestation, probably as part of the maternal immune strategy for fetal tolerance but also open new avenues to understand why pregnant women are at highest risk for infections.

Keywords: B cells; BCR; Cytokines; Pregnancy; Transcriptomic profile

DOI: https://doi.org/10.1016/j.ygeno.2021.06.016