Pregnancy induced TMA in severe preeclampsia results from complement-mediated thromboinflammation.

Preeclampsia is a multifactorial vascular disease unique to human pregnancy. While genetic and antiangiogenic factors are important contributors to preeclampsia susceptibility, recent studies have shown that dysregulation and/or over-activation of the complement system has an integral role in disease etiology. Furthermore, the role of the coagulation cascade may be underappreciated in the development of the disease. Traditionally, for research purposes, the pool of preeclampsia cases has been divided into non-severe and severe disease depending on the onset and severity of the symptoms. However, of particular interest are a small but important minority of cases that present with symptoms likening to those of hemolysis, elevated liver enzymes and low platelets syndrome, atypical hemolytic uremic syndrome, or thrombotic thrombocytopenic purpura, all thrombotic microangiopathy (TMA) diseases, with the hallmark mechanisms of endothelial dysfunction and aberrant activation of complement and coagulation cascades. We therefore propose a third class, severe TMA-like preeclampsia to be included in the categorization of preeclampsia patients. Identifying these patients would target research, diagnostic differentiation, and novel treatment options to the subclass of patients with life-threatening disease that are most likely to benefit from next-generation drug development.

Eculizumab Treatment for Postpartum HELLP Syndrome and aHUS-Case Report.

Preeclampsia is a pregnancy-specific disorder affecting ca 3% of all pregnant women. Preeclampsia is the source of severe pregnancy complications. Later life consequences for mother and infant include increased risk of cardiovascular disease. Preeclampsia is caused by the dysfunction of the endothelium with subsequent activation of complement and coagulation systems. HELLP syndrome is considered to be an extreme complication of preeclampsia but it can also present independently. Diagnostic symptoms in HELLP syndrome are Hemolysis, Elevated Liver enzymes, and Low Platelets. Similar phenotype is present in thrombotic microangiopathies (TMAs) and HELLP syndrome is considered part of the TMA spectrum. Here, we present a case of severe preeclampsia and HELLP syndrome, which exacerbated rapidly and eventually led to need of intensive care, plasma exchange, and hemodialysis. The patient showed signs of hemolysis, disturbance in the coagulation, and organ damage in liver and kidneys. After comprehensive laboratory testing and supportive care, the symptoms did not subside and treatment with complement C5 inhibitor eculizumab was started. Thereafter, the patient started to recover. The patient had pregnancy-induced aHUS. Earlier initiation of eculizumab treatment may potentially shorten and mitigate the disease and hypothetically decrease future health risks of preeclamptic women.

Activation of the Complement System in the Lower Genital Tract During Pregnancy and Delivery.

Background: Human pregnancy alters profoundly the immune system. The local involvement and mechanisms of activation of the complement system in the cervicovaginal milieu during pregnancy and delivery remain unexplored. Objectives: To determine whether normal pregnancy and delivery are associated with local activation of complement or changes in the immunoglobulin profile in the cervix. Study Design: This study was designed to assess IgA, IgG, and complement activation in the cervicovaginal area in three groups of patients: i) 49 pregnant women (week 41+3-42+0) not in active labor, ii) 24 women in active labor (38+4-42+2), and iii) a control group of nonpregnant women (n=23) at child-bearing age. We collected mucosal samples from the lateral fornix of the vagina and external cervix during routine visits and delivery. The Western blot technique was used to detect complement C3 and its activation products. For semiquantitative analysis, the bands of the electrophoresed proteins in gels were digitized on a flatbed photo scanner and analyzed. IgA and IgG were analyzed by Western blotting and quantified by ELISA. One-way ANOVA and Tukey's Multiple Comparison tests were used for statistical comparisons. Results: A higher abundance but lower activation level of C3 in both the external cervix (P<0.001) and lateral fornix of the vagina (P<0.001) was observed during delivery (58 ± 22, n= 24) in comparison to the groups of nonpregnant (72 ± 13%; mean ± SD, n=23) and pregnant women (78 ± 22%, n=49). Complement activating IgG was detected in higher abundance than IgA in the cervicovaginal secretions of pregnant women. In a small proportion samples also C3-IgG complexes were detected. Conclusions: Our results reveal an unexpectedly strong activation of the complement system and the presence IgG immunoglobulins in the cervicovaginal area during pregnancy, active labor, and among nonpregnant women. In contrast to the higher amounts of C3 in the cervicovaginal secretions during labor, its activation level was lower. Complement activating IgG was detected in higher concentrations than IgA in the mucosal secretions during pregnancy and labor. Taken together our results imply the presence a locally operating humoral immune system in the cervicovaginal mucosa.

Smoking during pregnancy reduces vitamin D levels in a Finnish birth register cohort.

OBJECTIVE: Maternal vitamin D level in pregnancy may have implications for both the mother and fetus. Deficiency of vitamin D has been linked to several pregnancy complications and fetal skeletal health. Smoking has been associated with reduced serum level of the vitamin D metabolite, 25-hydroxyvitamin D (25(OH)D). DESIGN: A nested case-control study within the Finnish Maternity Cohort, a population-based cohort which includes first-trimester sera from 98 % of pregnancies in Finland since 1987. The selection consisted of women with uncomplicated pregnancies. We studied serum concentration of 25(OH)D in 313 non-smoking and forty-six self-reported smoking pregnant women. SETTING: We hypothesize that pregnant smokers may have an increased risk of low 25(OH)D levels especially during winter months. PARTICIPANTS: A control group from an unpublished pregnancy complication study consisting of 359 uncomplicated pregnancies. Individuals who reported that they do not smoke were considered 'non-smokers' (n 313) and those who reported continued smoking after the first trimester of pregnancy were considered 'smokers' (n 46). RESULTS: Smokers had significantly lower levels of 25(OH)D irrespective of sampling time (P<0·0001). Furthermore, during the low sun-exposure season, only 14 % of smokers met the guideline level of 40 nmol/l for serum 25(OH)D in comparison with 31 % of non-smokers. CONCLUSIONS: Expectant mothers who smoke have an increased risk of vitamin D deficiency during low sun-exposure months in northern regions. Further studies are needed to assess the associated risks for maternal and fetal health as well as possible long-term implications for the infant.

Regulation of the complement system and immunological tolerance in pregnancy.

Preeclampsia is a serious vascular complication of the human pregnancy, whose etiology is still poorly understood. In preeclampsia, exacerbated apoptosis and fragmentation of the placental tissue occurs due to developmental qualities of the placental trophoblast cells and/or mechanical and oxidative distress to the syncytiotrophoblast, which lines the placental villi. Dysregulation of the complement system is recognized as one of the mechanisms of the disease pathology. Complement has the ability to promote inflammation and facilitate phagocytosis of placenta-derived particles and apoptotic cells by macrophages. In preeclampsia, an overload of placental cell damage or dysregulated complement system may lead to insufficient clearance of apoptotic particles and placenta-derived debris. Excess placental damage may lead to sequestration of microparticles, such as placental vesicles, to capillaries in the glomeruli of the kidney and other vulnerable tissues. This phenomenon could contribute to the manifestations of typical diagnostic symptoms of preeclampsia: proteinuria and new-onset hypertension. In this review we propose that the complement system may serve as a regulator of the complex tolerance and clearance processes that are fundamental in healthy pregnancy. It is therefore recommended that further research be conducted to elucidate the interactions between components of the complement system and immune responses in the context of complicated and healthy pregnancy.

The Immunogenetic Conundrum of Preeclampsia.

Pregnancy is an immunological challenge to the mother. The fetal tissues including the placenta must be protected from activation of the maternal immune system. On the other hand, the placental tissue sheds into the maternal circulation and must be adequately identified and phagocytized by the maternal immune system. During a healthy pregnancy, numerous immunosuppressive processes take place that allow the allograft fetus to thrive under exposure to humoral and cellular components of the maternal immune system. Breakdown of immune tolerance may result in sterile inflammation and cause adverse pregnancy outcomes such as preeclampsia, a vascular disease of the pregnancy with unpredictable course and symptoms from several organs. Immunological incompatibility between mother and fetus is strongly indicated in preeclampsia. Recently, genetic factors linking immunological pathways to predisposition to preeclampsia have been identified. In this mini-review genetic variation in immunological factors are discussed in the context of preeclampsia. Specifically, we explore immunogenetic and immunomodulary mechanisms contributing to loss of tolerance, inflammation, and autoimmunity in preeclampsia.

Complement activation and regulation in preeclamptic placenta.

Preeclampsia (PE) is a common disorder of pregnancy originating in the placenta. We examined whether excessive activation or poor regulation of the complement system at the maternal-fetal interface could contribute to the development of PE. Location and occurrence of complement components and regulators in placentae were analyzed. Cryostat sections of placentae were processed from 7 early-onset PE (diagnosis <34 weeks of gestation), 5 late-onset PE, 10 control pregnancies, and immunostained for 6 complement activators and 6 inhibitors. Fluorescence was quantified and compared between PE and control placentae. Gene copy numbers of complement components C4A and C4B were assessed by a quantitative PCR method. Maternal C4 deficiencies (≥1 missing or non-functional C4) were most common in the early-onset PE group (71%), and more frequent in late-onset PE compared to healthy controls (60 vs. 38%). Complement C1q deposition differed significantly between control and patient groups: controls and early-onset PE patients had more C1q than late-onset PE patients (mean p = 0.01 and p = 0.005, respectively). C3 activation was analyzed by staining for C3b/iC3b and C3d. C3d was mostly specific to the basal syncytium and C3b/iC3b diffuse in other structures, but there were no clear differences between the study groups. Activated C4 and membrane-bound regulators CD55, CD46, and CD59 were observed abundantly in the syncytiotrophoblast. Syncytial knots, structures enriched in PE, stained specifically for the classical pathway inhibitor C4bp, whereas the key regulator alternative pathway, factor H (FH) showed a wider distribution in the placenta. Differences in C1q deposition between late- and early-onset PE groups may be indicative of the different etiology of PE symptoms in these patients. Irregular distribution of the complement regulators C4bp and FH in the PE placenta and a higher frequency of C4A deficiencies suggest a disturbed balance between complement activation and regulation in PE.