Progesterone induced blocking factor in health and disease

Abstract

The foetus expressing paternal antigens ought to be “rejected” by the maternal immune system. However, the immunological relationship of the mother and the foetus does not follow the rules of transplantation immunology. Maternal immune functions are re-adjusted during pregnancy, to create a tolerant environment for the developing foetus. Progesterone and its downstream mediator; the progesterone induced blocking factor (PIBF) are important in this process. The mRNA transcribed from the PIBF1 gene contains 18 exons, and codes for a 90 kDa protein. The 90 kDa form is associated with the centrosome and plays a role in cell cycle regulation, while smaller isoforms produced by alternative spicing are secreted, and bind to the glycosylphosphatidylinositol (GPI) anchored PIBF receptor. Upon ligation, the former forms a heterodimer with the alpha chain of the interleukin-4 (IL-4) receptor and activates the Janus kinase/signal transducers and activators of transcription (Jak/STAT) pathway, via which, PIBF induces increased production of T helper2 (Th2) cytokines. PIBF regulates natural killer (NK) cytotoxicity, by inhibiting perforin release from the cytoplasmic granules of NK cells. During normal human pregnancy, the serum concentrations of PIBF increase with gestational age, and lower than normal serum levels predict spontaneous pregnancy termination. Depletion of PIBF during the peri-implantation period in mice, results in lower implantation and increased resorption rates, together with increased decidual and peripheral NK activity, downregulation of the genes implicated in T cell activation in CD4+ cells, and Th1 differentiation of the T cells. PIBF is expressed in rapidly proliferating immature cells as well as several tumours, and regulates invasion. The PIBF gene has been identified in the chromosomal region 13q21-q22—which is a common site for somatic deletions in a variety of malignant tumours. These data suggest that PIBF might be involved in tumorigenesis.

Gamma delta (γδ) T cells in the female reproductive tract: active participants or indifferent bystanders in reproductive success?

“…Progesterone can also enhance γδ T-cell immune-regulatory function by increasing their secretion of progesterone-induced blocking factor (PIBF), which has immunomodulatory functions in pregnancy including reducing NK cell cytotoxicity and increasing Th2-related and immunosuppressive cytokines IL-4 and IL-10 [ 52 , 54 ]. PIBF also promotes decidualization and may also play a role in embryo implantation [ 55 ].…”

“…Evidence points to the possibility that Vδ2 + cells are functionally unchecked or increased in several pregnancy disorders. Pregnant women with a history of recurrent miscarriage as well as second- or third-trimester women at risk of preterm birth have decreased circulating Vδ1 + cells and increased Vδ2 + cells compared with healthy pregnant women [ 55 , 92 ]. In the first trimester decidua, Vδ1 + cells outnumber Vδ2 + cells in healthy pregnancies while Vδ2 + cells predominate in recurrent miscarriage patients [ 46 ].…”

Progesterone as an Anti-Inflammatory Drug and Immunomodulator: New Aspects in Hormonal Regulation of the Inflammation

“…Progestins bind to PRs located in immune cells, including NK, macrophages, dendritic cells, and T cells, as well as in non-immune cells, such as epithelial and endothelial cells. Then, PIBF is secreted, binds to the PIBF receptor, and activates signaling pathways that lead to the appropriate cytokine production [ 51 ]. P 4 induces PIBF in leukemia cell lines, and progesterone receptor antagonist mifepristone decrease PIBF mRNA and protein synthesis [ 48 ].…”

Exploring Progesterone Deficiency in First-Trimester Miscarriage and the Impact of Hormone Therapy on Foetal Development: A Scoping Review

“…Additionally, progesterone plays an important role during implantation as it supports decidualisation, controls uterine contraction, and regulates maternal immune tolerance to the foetal semi-allograft [16]. Moreover, it stimulates lymphocytes to release progesteroneinduced blocking factor (PIBF), which is an essential mediator that plays an important role in the control of anti-foetal immune responses throughout pregnancy [17,18]. Hence, progesterone deficiency is associated with TM [8].…”