Sialic acid is a critical fetal defense against maternal complement attack
Markus Abeln, … , Anja Münster-Kühnel, Birgit Weinhold
Markus Abeln, … , Anja Münster-Kühnel, Birgit Weinhold
Published November 1, 2018
Citation Information: J Clin Invest. 2019;129(1):422-436. https://doi.org/10.1172/JCI99945.
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Research Article Immunology Reproductive biology

Sialic acid is a critical fetal defense against maternal complement attack

Abstract

The negatively charged sugar sialic acid (Sia) occupies the outermost position in the bulk of cell surface glycans. Lack of sialylated glycans due to genetic ablation of the Sia-activating enzyme CMP–sialic acid synthase (CMAS) resulted in embryonic lethality around day 9.5 post coitum (E9.5) in mice. Developmental failure was caused by complement activation on trophoblasts in Cmas–/– implants and was accompanied by infiltration of maternal neutrophils at the fetal-maternal interface, intrauterine growth restriction, impaired placental development, and a thickened Reichert’s membrane. This phenotype, which shared features with complement receptor 1-related protein Y (Crry) depletion, was rescued in E8.5 Cmas–/– mice upon injection of cobra venom factor, resulting in exhaustion of the maternal complement component C3. Here we show that Sia is dispensable for early development of the embryo proper but pivotal for fetal-maternal immune homeostasis during pregnancy, i.e., for protecting the allograft implant against attack by the maternal innate immune system. Finally, embryos devoid of cell surface sialylation suffered from malnutrition due to inadequate placentation as a secondary effect.

Authors

Markus Abeln, Iris Albers, Ulrike Peters-Bernard, Kerstin Flächsig-Schulz, Elina Kats, Andreas Kispert, Stephen Tomlinson, Rita Gerardy-Schahn, Anja Münster-Kühnel, Birgit Weinhold

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Figure 3

Infiltration of the fetal-maternal interface of Cmas–/– animals by maternal neutrophils.

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Infiltration of the fetal-maternal interface of Cmas–/– animals by mater...
(A) Gr-1 (neutrophils) immunohistochemical staining and quantification of Gr-1–positive cells surrounding fetal tissues of sagittal paraffin sections of uteri at E6.5 to E8.5. Insets show Gr-1–positive cells at the EPC and in the vicinity of fetal trophoblasts at the antimesometrial pole. E6.5 (control, n = 4; Cmas–/–, n = 5), E7.5 (control, n = 4; Cmas–/–, n = 4), and E8.5 (control, n = 5; Cmas–/–, n = 5). Error bars indicate SD. Scale bars: 12.5 μm (insets). (B) DBA lectin (dNK cells) immunohistochemical staining and quantification of sagittal paraffin sections of uteri at E6.5 to E8.5. Mean number of DBA lectin-positive cells in the decidua basalis. E6.5 (control, n = 4; Cmas–/–, n = 5), E7.5 (control, n = 8; Cmas–/–, n = 5), E8.5 (control, n = 5; Cmas–/–, n = 3). Error bars indicate SD. Staining of VE was only observed in control implants. (C) F4/80 (macrophages) immunohistochemical staining and quantification of sagittal paraffin sections of uteri from E6.5 to E8.5. Statistical analysis of the number of F4/80-positive cells surrounding fetal tissues. E6.5 (control n = 4; Cmas–/–, n = 4), E7.5 (control n = 6; Cmas–/–, n = 5), E8.5 (control n = 4; Cmas–/–, n = 5). Scale bars: 25 μm (insets). Error bars indicate SD. All statistical analyses were performed by Student’s t test (**P < 0.01; ***P < 0.001).