Ovarian insufficiency and early pregnancy loss induced by activation of the innate immune system
Adrian Erlebacher, … , Albert F. Parlow, Laurie H. Glimcher
Adrian Erlebacher, … , Albert F. Parlow, Laurie H. Glimcher
Published July 1, 2004
Citation Information: J Clin Invest. 2004;114(1):39-48. https://doi.org/10.1172/JCI20645.
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Article Immunology

Ovarian insufficiency and early pregnancy loss induced by activation of the innate immune system

Abstract

We describe a murine model of early pregnancy failure induced by systemic activation of the CD40 immune costimulatory pathway. Although fetal loss involved an NK cell intermediate, it was not due to lymphocyte-mediated destruction of the fetus and placenta. Rather, pregnancy failure resulted from impaired progesterone synthesis by the corpus luteum of the ovary, an endocrine defect in turn associated with ovarian resistance to the gonadotropic effects of prolactin. Pregnancy failure also required the proinflammatory cytokine TNF-α and correlated with the luteal induction of the prolactin receptor signaling inhibitors suppressor of cytokine signaling 1 (Socs1) and Socs3. Such links between immune activation and reproductive endocrine dysfunction may be relevant to pregnancy loss and other clinical disorders of reproduction.

Authors

Adrian Erlebacher, Dorothy Zhang, Albert F. Parlow, Laurie H. Glimcher

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Figure 1

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Decreased serum progesterone concentrations following systemic CD40 liga...
Decreased serum progesterone concentrations following systemic CD40 ligation precedes overt embryo resorption. Mice either were treated with control rat IgG or agonistic anti-CD40 antibodies (FGK45) once on E4 and sacrificed 24 hours later on E5, or were treated daily on E4–7 and sacrificed on E8. (A) Serum progesterone concentrations. Data represent mean ± SEM of six mice per group. Progesterone concentrations in FGK45-treated mice were significantly reduced compared with those in control mice. *P < 0.001. (B–E) Implantation sites on E5 from mice treated with rat IgG (B and D) or FGK45 (C and E). (B and C) Whole-mount preparations of uteri, with arrowheads indicating two implantation sites. (D and E) Paraffin sections of implantation sites stained with anti-CD45 antibodies to visualize all leukocytes (red), and counterstained with DAPI to visualize all cell nuclei (blue). The mesometrial pole of each implantation site is oriented toward the top of the panel. A recently implanted embryo can be seen in the center of each section (arrowhead). Immunostaining is representative of two to three mice per group, encompassing a total of 15–20 implantation sites in each group. Scale bar: 0.5 mm.