*2.4. Monocytes in Preeclampsia*

In considering the pathogenesis of PE, grea<sup>t</sup> emphasis is being made on oxidative stress and endothelial dysfunction occurring in the maternal body. Insu fficient placentation causes abnormally regulated blood pressure in the maternal cardiovascular system, followed by blood supply shortages and, as a consequence, ischemia/reperfusion of the placenta. It is believed that under these conditions the hypoxic placenta synthesizes and secretes increased quantities of vasoactive substances promoting the release of a the number of signal factors such as placental debris, exosomes, microvesicles, cell-free nucleic acids, and pro-inflammatory cytokines into maternal blood flow. The presence of these markers is well described and highly symptomatic [80–82]. The situation eventually leads to a pronounced inflammatory response, oxidative stress and enhances apoptosis of placental cells [83]. Elevated levels of pro-inflammatory cytokines produced by various cell types lead to dramatic changes in the patterns of surface molecules of the endothelium and result in systemic endothelial dysfunction and subsequent hypertension [84–86]. Detailed reviews concerning the delicate immune balance in normal pregnancy and in PE are available from scientific databases [3,87].

Inflammation is a pronounced feature of PE; it involves cells of both adaptive and innate immunity. Due to the fact that monocytes circulate in the blood only for a few days, their quantity and composition reflect the severity of the patient's clinical condition. Since generalized inflammation is a well-known feature of PE, changes in monocyte quantity and subset profile should be expected. Indeed, Wang and colleagues analyzed clinical records of more than three hundred patients with PE and found that in PE group the absolute monocyte count and the monocyte-lymphocyte ratio were significantly higher as compared with the control group (Table 1) [88]. As revealed by ROC-analysis, the monocyte-lymphocyte ratio has good diagnostic accuracy to distinguish between the normal condition and PE. In the work of Brien and colleagues, an increase in monocyte counts was also found typical for PE; the authors used CD14 marker to identify monocytes [89].


**Table 1.** Summary observations concerning monocyte–macrophage system in preeclampsia (PE).


**Table 1.** *Cont.*

Characterization of monocyte subpopulations in PE became a subject of interest after 2010 [22,23]. Recent investigations confirm the previous findings on its relevance. In recent work of Alahakoon and colleagues, the authors estimated quantities of classical, intermediate and non-classical monocytes in blood samples from preeclamptic patients (with or without intrauterine growth restriction, IUGR) and uncomplicated pregnancies [92]. The authors observed a significantly lower content of classical monocytes for both PE groups (with or without IUGR), while the number of inflammatory monocytes which combined intermediate and non-classical subsets for these groups was significantly increased as compared with the control. Similar results were obtained by Jabalie et al. who observed a decline in the percentage of classical monocytes paralleled by an increase in the percentage of intermediate and non-classical monocytes in blood samples from preeclamptic women with or without metabolic syndrome [90].

Ma and colleagues analyzed cytokine profiles of serum from women with PE and also estimated the percentage of blood monocytes positive for M1 and M2 macrophage markers [93]. The counts of CD14+CD11c+CD163-(M1) monocytes in PE group were significantly increased, which correlated with the increased level of pro-inflammatory factors (IL-1, IL-6, and MCP-1). However, the works concerning M1 and M2 macrophage markers in the blood of women with PE are few, which indicates the necessity of further studies in this field.

Several studies focused on the composition of umbilical cord blood in PE have obvious scientific novelty since fetal participation is rarely considered in the context of PE. Interestingly, the authors come to the same observation: a significant reduction in the classical monocyte subset and a significant increase in non-classical monocyte subset were observed for the cord blood in PE group [91].

Summarizing these data leads to a general conclusion that the observed PE-associated changes in counts and composition of blood monocytes towards the prevalence of non-classical subset indicate progression of the inflammation symptoms in the maternal organism. The upheaval of inflammatory reaction during PE is possibly caused by extracellular agents, which appear in blood, and cytokines, which activate monocytes [103]. Since monocyte counts are included in routine clinical blood tests, and given that phenotyping of monocytes by flow cytometry is a straightforward procedure, appearance of monocyte-based tests for PE prediction as a routine practice may be expected. Surely it would require a prospective study to assess the prognostic value of monocyte profile indicators in the blood of a pregnan<sup>t</sup> woman who would have PE and absolute standardization of all manipulations. To date, none of the existing tests reliably evaluates the risks of PE. At present, only a few markers associated with PE, such as endoglin, placental growth factor (PlGF) and sFlt-1 (soluble fms-like tyrosine kinase 1), have been sufficiently studied.
