bims-reprim Biomed News
on Reproductive immunology
Issue of 2020‒11‒08
six papers selected by
Iva Filipovic
Karolinska Institutet


  1. Am J Reprod Immunol. 2020 Nov 06. e13373
    Brady CA, Williams C, Sharps MC, Shelleh A, Batra G, Heazell AEP, Crocker IP.
      Chronic Histiocytic Intervillositis (CHI) is a pregnancy disorder characterised by infiltration of maternal macrophages into the intervillous space of the human placenta, often with accompanying perivillous fibrin deposition. CHI is associated strongly with fetal growth restriction and increased risk of miscarriage and stillbirth. Although rare, affecting 6 in every 10000 pregnancies beyond 12 weeks' gestation, the rate of recurrence is high at 25-100%. To date, diagnosis of CHI can only be made post-delivery upon examination of the placenta due to a lack of diagnostic biomarkers, and criteria varies across publications. No treatment options have shown proven efficacy, and CHI remains a serious obstetric conundrum. Although its underlying aetiology is unclear, due to the presence of maternal macrophages and the reported increased incidence in women with autoimmune disease, CHI is hypothesised to be an inappropriate immune response to the semi-allogeneic fetus. Given this lack of understanding, treatment approaches remain experimental with limited rationale. However, there is recent evidence that immunosuppression and antithrombotic therapies may be effective in preventing recurrence of associated adverse pregnancy outcomes. With similarities noted between the pathological features of CHI and acute rejection of solid organ transplants, further investigation of this hypothesis may provide a basis for tackling CHI and other immune-related placental conditions. This review will explore parallels between CHI and allograft rejection and identify areas requiring further confirmation and exploitation of this comparison.
    Keywords:  HLA; Pregnancy; graft rejection; macrophages; miscarriage; placenta; stillbirth
    DOI:  https://doi.org/10.1111/aji.13373
  2. J Reprod Immunol. 2020 Oct 03. pii: S0165-0378(20)30135-2. [Epub ahead of print]142 103214
    Abrahams VM, Tang Z, Mor G, Guller S.
      Alterations in the number and protein/gene expression of Hofbauer cells (HBCs) may play a role in microbial-driven/cytokine-mediated placental inflammation, and in subsequent pregnancy complications such as villitis, histologic chorioamnionitis, and the fetal inflammatory response syndrome. Pyroptosis is an inflammatory form of cell death mediated by the inflammasome, a multi-protein complex which drives the processing and secretion of interleukin 1 beta (IL-1β). Pyroptosis can be triggered by bacterial lipopolysaccharide (LPS) and adenosine triphosphate (ATP) in non-placental macrophages through activation of the NLRP3 inflammasome. However, the role of inflammasome activation and pyroptosis in HBC pathophysiology remains unclear. HBCs isolated from human term placentas were treated with or without LPS or ATP, alone or in combination. Treatment of HBCs with both LPS and ATP induced the rapid secretion of high levels of IL-1β and at the same time, cell death associated with nuclear condensation and cellular swelling. HBC treatment with both LPS and ATP induced caspase-1 activation, gasdermin D (GSDMD) cleavage, which mediates pyroptosis, and IL-1β processing. Caspase-1 activation, GSDMD cleavage, IL-1β processing, and IL-1β secretion were all significantly reduced following NLRP3 knockdown; inhibition of caspase-1; and inhibition of P2X7, the receptor that mediates K+ efflux. Together, our data indicate that LPS and ATP treatment stimulated NLRP3 inflammasome activation and pyroptosis in HBCs leading to the rapid release of IL-1β. Since the localization of HBCs confers a unique ability to influence microbial-associated placental and fetal inflammation, these studies suggest a key role for the inflammasome and pyroptosis in mediating HBC driven inflammation.
    Keywords:  Infection; Inflammasome; Macrophage; Placenta; Pyroptosis
    DOI:  https://doi.org/10.1016/j.jri.2020.103214
  3. J Immunol. 2020 Nov 02. pii: ji2000713. [Epub ahead of print]
    Guzeloglu-Kayisli O, Guo X, Tang Z, Semerci N, Ozmen A, Larsen K, Mutluay D, Guller S, Schatz F, Kayisli UA, Lockwood CJ.
      Vertical transmission of the Zika virus (ZIKV) causes severe fetal defects, but the exact pathogenic mechanism is unclear. We identified up to a 10,480-fold higher expression of viral attachment factors AXL, GAS6, and PROS1 and a 3880-fold increase in ZIKV infectiousness/propagation in human term decidual stromal cells versus trophoblasts. Moreover, levels of viral attachment factors and ZIKV are significantly increased, whereas expression of innate immune response genes are significantly decreased, in human first trimester versus term decidual cells. ZIKV-infected decidual cell supernatants increased cytotrophoblasts infection up to 252-fold compared with directly infected cytotrophoblasts. Tizoxanide treatment efficiently inhibited Zika infection in both maternal and fetal cells. We conclude that ZIKV permissiveness, as well as innate immune responsiveness of human decidual cells, are gestational age dependent, and decidual cells augment ZIKV infection of primary human cytotrophoblast cultures, which are otherwise ZIKV resistant. Human decidual cells may act as reservoirs for trimester-dependent placental transmission of ZIKV, accounting for the higher Zika infection susceptibility and more severe fetal sequelae observed in early versus late pregnancy. Moreover, tizoxanide is a promising agent in preventing perinatal Zika transmission as well as other RNA viruses such as coronavirus.
    DOI:  https://doi.org/10.4049/jimmunol.2000713
  4. Am J Reprod Immunol. 2020 Nov 03. e13368
    Jacobs SO, Sheller-Miller S, Richardson LS, Urrabaz-Garza R, Radnaa E, Menon R.
      PROBLEM: This study localized CD45+ immune cells and compared changes in their numbers between term, not in labor (TNIL) and term, labor (TL) human fetal membranes.METHOD OF STUDY: Fetal membranes (amniochorion) from normal TNIL and TL subjects were analyzed by immunohistochemistry (IHC), immunofluorescence (IF), and flow cytometry for evidence of total (CD45+ ) immune cells as well as innate immune cells (neutrophils, macrophages and NK cells) using specific markers. Fetal origin of immune cells was determined using polymerase chain reaction (PCR) for SRY gene in Y chromosome.
    RESULTS: CD45+ cells were localized in human fetal membranes for both TNIL and TL. A 3-fold increase in CD45+ cells was seen in TL fetal membranes of (7.73% ± 2.35) compared to TNIL (2.36% ± 0.78). This increase is primarily contributed by neutrophils. Macrophages and NK cells did not change in the membranes between TNIL and TL. Leukocytes of fetal origin are present in the fetal membranes.
    CONCLUSIONS: The fetal membranes without decidua contain a small proportion of immune cells. Some of these immune cells in the fetal membrane are fetal in origin. There is a moderate increase of immune cells in the fetal membranes at term labor; however, it is unclear whether this is a cause or consequence of labor. Further functional studies are needed to determine their contribution to membrane inflammation associated with parturition.
    Keywords:  Innate immune cells; fetal membrane; term labor
    DOI:  https://doi.org/10.1111/aji.13368
  5. Front Immunol. 2020 ;11 575197
    Abu-Raya B, Michalski C, Sadarangani M, Lavoie PM.
      The risk and severity of specific infections are increased during pregnancy due to a combination of physiological and immunological changes. Characterizing the maternal immune system during pregnancy is important to understand how the maternal immune system maintains tolerance towards the allogeneic fetus. This may also inform strategies to prevent maternal fatalities due to infections and optimize maternal vaccination to best protect the mother-fetus dyad and the infant after birth. In this review, we describe what is known about the immunological changes that occur during a normal pregnancy.
    Keywords:  cellular immune response; fetal; gestation; humoral immune response; immune system; immunity
    DOI:  https://doi.org/10.3389/fimmu.2020.575197
  6. Cell Rep. 2020 Nov 03. pii: S2211-1247(20)31314-0. [Epub ahead of print]33(5): 108325
    Jeljeli M, Riccio LGC, Chouzenoux S, Moresi F, Toullec L, Doridot L, Nicco C, Bourdon M, Marcellin L, Santulli P, Abrão MS, Chapron C, Batteux F.
      Endometriosis is a frequent, chronic, inflammatory gynecological disease characterized by the presence of ectopic endometrial tissue causing pain and infertility. Macrophages have a central role in lesion establishment and maintenance by driving chronic inflammation and tissue remodeling. Macrophages can be reprogrammed to acquire memory-like characteristics after antigenic challenge to reinforce or inhibit a subsequent immune response, a phenomenon termed "trained immunity." Here, whereas bacille Calmette-Guérin (BCG) training enhances the lesion growth in a mice model of endometriosis, tolerization with repeated low doses of lipopolysaccharide (LPSlow) or adoptive transfer of LPSlow-tolerized macrophages elicits a suppressor effect. LPSlow-tolerized human macrophages mitigate the fibro-inflammatory phenotype of endometriotic cells in an interleukin-10 (IL-10)-dependent manner. A history of severe Gram-negative infection is associated with reduced infertility duration and alleviated symptoms, in contrast to patients with Gram-positive infection history. Thus, the manipulation of innate immune memory may be effective in dampening hyper-inflammatory conditions, opening the way to promising therapeutic approaches.
    Keywords:  IL-10; LPS; bacterial infections; endometriosis; fibrosis; immunology; inflammation; macrophages; mice; trained immunity
    DOI:  https://doi.org/10.1016/j.celrep.2020.108325