Ovarian insufficiency and early pregnancy loss induced by activation of the innate immune system
Adrian Erlebacher, Dorothy Zhang, Albert F. Parlow, Laurie H. Glimcher
Adrian Erlebacher, Dorothy Zhang, Albert F. Parlow, Laurie H. Glimcher
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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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Systemic immune activation by CD40 ligation is unaffected by progesteron...
Systemic immune activation by CD40 ligation is unaffected by progesterone administration. Mice were sacrificed on E8 after daily treatment on E4–7 with rat IgG or FGK45 plus either concurrent progesterone injection (which produced no abortion with either rat IgG or FGK45) or concurrent sesame seed oil vehicle injection (which produced abortion with FGK45 only). (A) Elevated splenocyte numbers following FGK45 treatment in both groups. *P < 0.005. Data represent mean ± SD for three to four mice per group. (B–D) Three-color flow cytometric analysis of splenocytes to determine cell size and surface activation marker expression. In all panels, shaded histograms show data from rat IgG–treated mice, while open histograms show data from FGK45-treated mice. Data represent three mice per group. (B and C) Lymphocyte activation. Increased forward scatter (FSC), indicating increased cell size (B), and increased CD69 expression, indicating cell activation (C), were seen in B cells, NK cells, and a fraction of T cells following FGK45 treatment in both groups. (D) Dendritic cell activation. Increased CD80, CD86, and MHC class II expression, indicating cell activation, was seen on splenic CD11c+ cells following FGK45 treatment in both groups.