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.
Highlights
Progesterone is critical for pregnancy in most mammalian species
In 1989, together with Gerard Chaouat we demonstrated progesterone receptors (PRs) in peripheral pregnancy, but not, in non-pregnancy lymphocytes, and showed that the percentage of PR+ peripheral lymphocytes increase throughout normal gestation [9, 10]
progesterone induced blocking factor (PIBF) is present in the cytoplasmic granules of mouse decidual natural killer (NK) cells [59] and by inhibiting perforin release [60, 61] contributes to the low cytotoxic activity of these lymphocytes (Figure 1)
Summary
Progesterone production gradually rises during gestation to reach a level of 100-500 nm in the sera of pregnant women and 1-10 μm in placental tissue. Decades ago, it became evident, that in addition to its endocrine effects, progesterone mediates interactions between the endocrine and immune systems. The lowest effective concentration was 10 μg/mL, which is approximately 100-fold higher than the concentrations found in maternal blood in the 3rd trimester of pregnancy, but relevant to those, found at the foeto-maternal interface [7] They assumed that the immune-modulating effects of progesterone might account for the acceptance of the semi-allogeneic foetus by the maternal immune system, and they called progesterone “nature’s immunosuppressant”. The remarkable difference in progesterone sensitivity suggested the presence of specific binding sites in lymphocytes of pregnant, but not in those of non-pregnant women
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