The Role of Kisspeptin in Immune Tolerance Formation During Pregnancy

by Katleho Matlatse

Have you ever wondered why pregnancy loss is an experience many women are and have been facing for centuries? But the more persistent question is why women experience recurrent pregnancy loss? and why, after the development of new technologies and novel knowledge, the incidence of it occurring is not reducing?

1-2% of women will experience recurrent pregnancy loss (Ford & Schust, 2009). Pregnancy loss, also known as loss of clinical pregnancy or miscarriage, is defined as the loss of fetus before the 20 completed weeks of gestational age. Recurrent pregnancy loss (RPL) occurs when women experience three or more consecutive miscarriages. When the etiology is often unknown or spontaneous, this is classified as idiopathic recurrent miscarriage (IRM). An imbalance in placental hormones and or immune dysregulation may give rise to implantation failure and eventually lead to pregnancy loss. The tumour metastasis suppressor decapeptide, kisspeptin, and its receptor, GPR54, are expressed in the placenta and are thought to play an important role in
embryo implantation, early placentation, and trophoblast invasion. Furthermore, kisspeptin regulates the behavior of regulatory lymphocytes thereby altering concentrations of IL-10 and IL-17A, events key for maternal immune tolerance.

If Kisspeptin increases the formation of aTreg (adaptive T regulatory) cells, would an increase occur in pro-inflammatory ( IL-17A) and anti-inflammatory (IL-10)? What would the mode of mechanism look like?

The study hypothesizes that in pregnancy, the expression of kisspeptin influences that of anti-inflammatory and pro-inflammatory cytokines which are key in setting maternal immune tolerance. To achieve this, the authors collected blood samples from nonpregnant women of reproductive age (from 23-37 years of age) but compared that data with peripheral blood samples of women in trimester I, II and II. The authors performed extraction of peripheral blood mononuclear cells (PBMCs) from blood samples, followed by immunomagnetic separation methods to extract CD4+ T cells. The cells
were induced with different concentrations of Kisspeptin, IDO and Lipopolysaccharide and incubated. To induce aTreg cells, the authors introduced cytokine specific monoclonal antibodies along with kisspeptin, IDO and liposaccharide (LPS) stimulation followed by ELISA tests (which detect protein expression) and Flow cytometry to evaluate lymphocyte phenotype.

Research done before this study suggested that increasing the production of aTreg cells, by increasing the production of anti-inflammatory cytokine IL-10 and reducing the production of IL-17A, a pro-inflammatory cytokine enhances immune tolerance. This ultimately reduces the immune response. Inducing aTreg cells with Kisspeptin, significantly increases the formation of increased CD4+ T cells at different concentrations during trimester I, II and III. This study discovered that aTreg cells, when induced with the hormone kisspeptin, enhanced the production of IL-10, and significantly reduces the production of IL-17A (prevents differentiation of Th17 lymphocytes) by CD4+ T lymphocytes of peripheral blood of women. An increase in anti-inflammatory cytokines, reduces immune response. Therefore, kisspeptin has shown to increase immune tolerance between the maternal-fetal interface (from the maternal body to the fetus) antigens, which ultimately determines the outcome of
pregnancy. What is interesting in this paper is that it stimulates the idea that pregnancy loss is not just a result of environmental factors, genetics, but rather hormone dysregulation can play a part. I believe more studies need to be done on hormone regulation between the maternal-fetal interface and how we can significantly reduce pregnancy loss.

References
Ford, H. B. & Schust, D. J., 2009. Recurrent Pregnancy Loss: Etiology, Diagnosis, and Therapy. Obstetrics and Gynecology, 2(2), pp. 76-83.
Gorbunova, O. L. & Shirshev, S. V., 2014. The role of Kisspeptin in Immune Tolerane Formation during Pregnancy. Volume 457.

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