Pregnancy Close to the Edge: An Immunosuppressive Infiltrate in the Chorionic Plate of Placentas from Uncomplicated Egg Cell Donation

In pregnancies achieved after egg donation (ED) tolerance towards a completely allogeneic fetus is mediated by several complex immunoregulatory mechanisms, of which numerous aspects are still unknown. A distinct lesion not described previously in the literature, was repeatedly found in the chorionic plate in a substantial portion of placentas from ED pregnancies, but never in placentas from normal term pregnancies. The aim of this study was to assess its origin and its cellular composition. The relation between the lesion, the clinical and histological parameters were assessed. In addition we investigated the relation with the number of HLA-mismatches and KIR genotype of mother and child

Increased complement C4d deposition at the maternal-fetal interface in unexplained recurrent miscarriage

C4d is a footprint of antibody-mediated classical complement activation, and has evolved as a useful diagnostic marker of antibody-mediated rejection. It is unknown if complement activation, as reflected by C4d deposition plays a role in unexplained recurrent miscarriage. In a case-control study products of conception of 35 women with three or more unexplained consecutive miscarriages within 20 weeks of gestation with the same partner (case group), 22 women with one spontaneous sporadic miscarriage and no history of complicated pregnancy(ies) (control group 1), and 40 women who underwent an elective abortion for psychosocial reasons (control group 2) were included. Immunohistochemical staining for C4d was performed on products of conception. Positivity for C4d was scored semi-quantitatively. C4d deposition was present in products of conception of 14 out of 35 women with unexplained recurrent miscarriage (40.0%), compared to 6 out of 22 women with a sporadic miscarriage (27.3%), and 4 out of 40 women with an elective abortion (10.0%) (p=0.020). C4d is increased at the maternal-fetal interface in women with unexplained recurrent miscarriage, which may reflect an aberrant anti-fetal immunity in these women. Further knowledge of the specific pathogenic mechanism may lead to the development of new treatment strategies for this group of women

Patient characteristics of the two ED groups of pregnancies, those with and without the lesion in the chorionic plate.

<p>Average (range).</p>*<p> <b>p<0.05.</b></p

Antibodies.

†<p>Tris/EDTA: 0.1 mol/L (pH 9.0).</p>*<p>Envision: Dako, North America Inc, USA (anti-mouse and anti-rabbit Envision HRP).</p

Higher expression of the macrophage marker CD14+, the M2 marker CD163+ and DC-Sign in the lesion.

<p>Immunohistochemical stainings of egg donation placentas. In the left panel serial slides with no lesion present and in the right panel serial slides with the lesion present in the chorionic plate. From top to bottom are depicted the stainings H&E, Cytokeratin-7, CD56+, CD8+, CD14+ and CD163+. We observed a higher expression of the macrophage marker CD14+ and the M2 marker CD163+.</p

Significant relationship between the presence of the lesion in the chorionic plate and histological parameters.

<p>A. Bar graph of placental histological scores in percentage. B. Incidence of histological parameters in placentas with and without the lesion in the chorionic plate. A significant relationship was found between the presence of the lesion in the chorionic plate and intervillositis and histological parameters in the decidua; including chronic deciduitis, presence of plasma cells in the decidua and fibrin deposition in the decidua. Number (percentage) Fisher's exact test. * p<0.05 ** p<0.01.</p

Combination of fetal HLA-C2 and maternal KIR B, in comparison with the presence of the lesion in the chorionic plate.

<p>Number (percentage).</p><p>Fisher exact (2-sided) p = 0.087.</p

Combination of fetal HLA-C and maternal KIR haplotypes, in comparison with the presence of the lesion in the chorionic plate.

<p>Number.</p><p>Fisher exact (2-sided).</p

Human decidual tissue contains differentiated CD8+ effector-memory T cells with unique properties

During pregnancy, maternal lymphocytes at the fetal-maternal interface play a key role in the immune acceptance of the allogeneic fetus. Recently, CD4(+)CD25(bright) regulatory T cells have been shown to be concentrated in decidual tissue, where they are able to suppress fetus-specific and nonspecific immune responses. Decidual CD8(+) T cells are the main candidates to recognize and respond to fetal HLA-C at the fetal-maternal interface, but data on the characteristics of these cells are limited. In this study we examined the decidual and peripheral CD8(+) T cell pool for CD45RA, CCR7, CD28, and CD27 expression, using nine-color flow cytometry. Our data demonstrate that decidual CD8(+) T cells mainly consist of differentiated CD45RA(-)CCR7(-) effector-memory (EM) cells, whereas unprimed CD45RA(+)CCR7(+) naive cells are almost absent. Compared with peripheral blood EM CD8(+) T cells, the decidual EM CD8(+) T cells display a significantly reduced expression of perforin and granzyme B, which was confirmed by immunohistochemistry of decidual tissue sections. Interestingly, quantitative PCR analysis demonstrates an increased perforin and granzyme B mRNA content in decidual EM CD8(+) T cells in comparison with peripheral blood EM CD8(+) T cells. The presence of high levels of perforin and granzyme B mRNA in decidual EM T cells suggests that decidual CD8(+) T cells pursue alternative means of EM cell differentiation that may include a blockade of perforin and granzyme B mRNA translation into functional perforin and granzyme B proteins. Regulation of decidual CD8(+) T cell differentiation may play a crucial role in maternal immune tolerance to the allogeneic fetu