Introduction: Chronic histiocytic intervillositis (CHI) is a rare histopathological lesion in the placenta that is associated with poor reproductive outcomes. The intervillous infiltrate consists... Show moreIntroduction: Chronic histiocytic intervillositis (CHI) is a rare histopathological lesion in the placenta that is associated with poor reproductive outcomes. The intervillous infiltrate consists mostly of maternal mononuclear cells and fibrin depositions, which are both indicators for the severity of the intervillous infiltrate. The severity of the intervillous infiltrate as well as the clinical outcomes of pregnancy differ between cases. Our objective is to determine the relation between the severity of the intervillous infiltrate and the clinical outcomes of CHI. Methods: Cases of CHI were semi-quantitatively graded based on histopathological severity scores. Hereto, CD68 positive mononuclear cells were quantified, fibrin depositions visualized by both a PTAH stain and an immuo-histochemical staining, and placental dysfunction was assessed via thrombomodulin staining. Results: This study included 36 women with CHI. A higher CD68 score was significantly associated with a lower birthweight. Loss of placental thrombomodulin was associated with lower gestational age, lower birthweight, and a lower placenta weight. The combined severity score based on CD68 and PTAH was significantly associated with fetal growth restriction, and the joint score of CD68 and fibrin was associated with birthweight and placental weight. Discussion: More severe intervillous infiltrates in CHI placentas is associated with a lower birth weight and placental weight. Furthermore, this study proposes thrombomodulin as a possible new severity marker of placental damage. More research is needed to better understand the pathophysiology of CHI. Show less
Epidermal growth factor receptor (EGFR) signaling and components of the fibrinolytic system, including urokinase-type plasminogen activator (uPA) and thrombomodulin (TM), have been implicated in... Show moreEpidermal growth factor receptor (EGFR) signaling and components of the fibrinolytic system, including urokinase-type plasminogen activator (uPA) and thrombomodulin (TM), have been implicated in tumor progression. In the present study, we employed cBioPortal platform (http://www.cbioportal.org/), cancer cell lines, and an in vivo model of immunocompromised mice to evaluate a possible cooperation between EGFR signaling, uPA, and TM expression/function in the context of cervical cancer. cBioPortal analysis revealed that EGFR, uPA, and TM are positively correlated in tumor samples of cervical cancer patients, showing a negative prognostic impact. Aggressive human cervical cancer cells (CASKI) presented higher gene expression levels of EGFR, uPA, and TM compared to its less aggressive counterpart (C-33A cells). EGFR induces uPA expression in CASKI cells through both PI3K-Akt and MEK1/2-ERK1/2 downstream effectors, whereas TM expression induced by EGFR was dependent on PI3K/Akt signaling alone. uPA induced cell-morphology modifications and cell migration in an EGFR-dependent and -independent manner, respectively. Finally, treatment with cetuximab reduced in vivo CASKI xenografted-tumor growth in nude mice, and decreased intratumoral uPA expression, while TM expression was unaltered. In conclusion, we showed that EGFR signaling regulated expression of the fibrinolytic system component uPA in both in vitro and in vivo settings, while uPA also participated in cell-morphology modifications and migration in a human cervical cancer model. Show less
Every pregnancy is unique due to distinct maternal, paternal and fetal factors. Presumably, the immunological response differs between pregnancies, and certain pregnancies could be immunologically... Show moreEvery pregnancy is unique due to distinct maternal, paternal and fetal factors. Presumably, the immunological response differs between pregnancies, and certain pregnancies could be immunologically more challenging for the mother than others. In the present thesis, pregnancies presumed to be more immunologically challenging were studied. For example, in oocyte donation pregnancies, the fetus is completely allogeneic for the mother. Furthermore, based on findings in pregnancies complicated by pre-eclampsia and chronic intervillositis of unknown etiology (CIUE), it is postulated that the immune system plays a significant role in such pathophysiology. This thesis investigated oocyte donation pregnancies with and without pre-eclampsia and naturally conceived pregnancies complicated by pre-eclampsia or CIUE. Investigating immunologically challenging pregnancies improves our understanding of naturally conceived pregnancies and provides an interesting setting in which to test hypotheses relevant to transplantation immunology and tumour immunology. Henceforth, new discoveries in reproductive immunology could result in novel insights into the dynamics of the immune system. Future research should focus on more continuous study of the fetal-maternal interface during pregnancy and exploit the unique circumstances provided by some of the specific complications of pregnancy, such as FNAIT, ectopic pregnancies and placenta accreta. Show less
Preeclampsia is a syndrome of pregnancy characterised by hypertension and proteinuria and occurs in up to 5 percent of pregnant women. The pathophysiology of preeclampsia has not been fully... Show morePreeclampsia is a syndrome of pregnancy characterised by hypertension and proteinuria and occurs in up to 5 percent of pregnant women. The pathophysiology of preeclampsia has not been fully elucidated yet. The endothelium is known to play a key role in the pathogenesis and levels of vascular endothelial growth factor are decreased due to an angiogenic imbalance. In the first part of this thesis, genes associated with preeclampsia were investigated through meta-analysis; genes within the coagulation and immunology domains remained significantly associated with preeclampsia after meta-analysis. In the second and third part of this thesis, the possible role of a key regulator of coagulation and immunology on the endothelium, thrombomodulin, in preeclampsia was investigated in the placenta and the kidney. Diminished placental thrombomodulin expression was associated with the angiogenic imbalance of preeclampsia. Next, in the fourth part of this thesis the interplay between podocytes and endothelial cells in the glomerulus during the anti-angiogenic conditions in preeclampsia was reviewed. In the final part of this thesis the splicing pattern of vascular endothelial growth factor was investigated throughout different examples of glomerular disease. Show less
Boels, M.G.S.; Lee, D.H.; Berg, B.M. van den; Dane, M.J.C.; Vlag, J. van der; Rabelink, T.J. 2013
