The conundrum of pre-eclampsia : from candidate genes to complement system

The human pregnancy is a unique immunological process. The foetus is tolerated and nourished through the complex yet transient organ, placenta, which bears the genetic fingerprint of the developing baby. Human placentation involves several waves of invasion, whereby the placenta is deeply attached to layers of the uterine wall, through the mucosal lining of the uterus, the decidua and into the underlying muscle, the myometrium. In order for adequate but not inappropriate depth of placentation to occur, the maternal immune system must be fine-tuned to tolerate yet control the invasive trophoblast cells, which originate in the placenta. Pre-eclampsia is a common vascular disease of the human pregnancy. Pre-eclampsia, particularly in its severe form, is intrinsically linked to failure of deep-placentation. While pre-eclampsia has long been known to have a familial, i.e. genetic component, the genes contributing to the disease have not been well characterised thus far. This thesis addresses the question of role of the complement system in pre-eclampsia by comparing pre-eclamptic women to non-pre-eclamptic controls using several methods. Using immunofluorescence and immunohistochemistry, placental tissues were stained for one angiogenic receptor and nine components of the complement system to determine the localisation and extent of complement activation, and on the other hand, complement regulation in placentae from pre-eclamptic and healthy pregnancies. In two candidate gene studies, the variants within coding regions and flanking sequences surrounding exons of a key complement regulator, membrane cofactor-protein (CD46) gene (MCP/CD46) and activator, complement component 3 gene (C3) were explored in women with a history of severe pre-eclampsia and non-pre-eclamptic controls. Finally, using a targeted exomic sequencing approach we studied known candidate genes in pre-eclampsia to identify low-frequency variants in the Finnish population that may predispose to or protect from pre-eclampsia. We combined pre-eclamptic patients from the FINNPEC (Finnish genetics of pre-eclampsia consortium) and the national FINRISK studies to characterise health consequences of the most important variants that associate to pre-eclampsia. While we did not find a genetic association to pre-eclampsia in the membrane bound complement regulator, MCP, we found three out of forty-three observed single nucleotide polymorphisms to be associated with pre-eclampsia in the C3. Furthermore, a section of tight linkage disequilibrium was identified within the C3 that depending on the sequence context, may predispose to, or protect from pre-eclampsia. Most recently, the first maternal genetic association of the fms related tyrosine kinase 1 gene (FLT1) coding for an anti-angiogenetic marker soluble fms-like tyrosine kinase 1 elevated in pre-eclampsia was discovered. Two SNPs within the FLT1 protect women from not only pre-eclampsia, but also from heart failure in later life. The work presented in this thesis sheds light to some of the many inherited traits that contribute to the aetiology of pre-eclampsia. The results present a first genetic association to pre-eclampsia in C3 and they may provide a maternal genetic link between angiogenesis process during pregnancy and heart failure in later life. The crucial effect of the complement system for the successful pregnancy is demonstrated by genetic association as well as comparative localisation of complement components on the pre-eclamptic and healthy placenta tissue.Raskausaika on ainutlaatuinen immunologinen tapahtuma ihmisen elinkierrossa. Sikiötä ravitsee monimutkainen mutta väliaikainen elin, istukka, joka edustaa perimältään sikiön geneettistä sormenjälkeä. Istukan tehtävä on myös ylläpitää toleranssia äidin immuunipuolustuksessa lapsen kudosten suojelemiseksi. Ihmisen plasentaatiossa toistuvat istukkasolujen invaasioprosessit varmistavat, että elin kiinnittyy äidin kohdunseinämään limakalvokerrosten alle aina kohdunalaiseen lihaskudokseen asti. Jotta istukan kiinnittyminen ulottuu oikealle tasolle, äidin immuunipuolustuksen pitää olla virittynyt siten, että istukan invasoivia trofoblastisoluja siedetään ja kontrolloidaan samanaikaisesti. Pre-eklampsia on yleinen monitekijäinen raskaudenaikainen verisuonisairaus. Etenkin vaikea pre-eklampsia liittyy keskeisesti syväplasentaation ilmiöön. Pre-eklampsian tiedetään esiintyvän suvuittain, joten perintötekijöillä on tärkeä osa taudin puhkeamisessa, mutta suurinta osaa pre-eklampsialle altistavista geeneistä ei vielä tunneta. Väitöskirjassani käsittelen useaa menetelmää hyödyntäen luontaisen immunipuolustuksen komplementtijärjestelmän merkitystä pre-eklampsiataudissa vertailemalla pre-eklamptikkoäitejä ja äitejä, joilla ei ole ollut pre-eklampsiadiagnosia. Istukkakudosleikkeitä värjättiin immunofluoresenssi ja immunohistokemiallisin menetelmin yhtä angiogeneettistä reseptoria ja yhdeksää komplementtitekijää tunnistavilla vasta-aineilla komplementtiaktivaation ja -regulaation sijainnin ja laajuuden tutkimiseksi istukkakudoksessa. Kahdessa kandidaattigeenitutkimuksessa kuvattiin koodaavien alueiden ja niitä ympäröivien geenialueiden perimänvaihtelua keskeisessä komplementin säätelijässä MCP/CD46 ja toisaalta aktivaattorissa C3. Hyödyntämällä kohdennettua eksomisekvensointimenetelmää tutkimme myös muita tunnettuja kandidaattigeenejä pre-eklampsiataudissa tunnistaaksemme harvinaisia perimänvaihtelun muotoja suomalaisessa väestössä, jotka liittyvät pre-eklampsiatautiin. Yhdistimme FINNPEC (Finnish genetics of pre-eclampsia consortium) aineistoon ja FINRISKI-tutkimukseen kirjattujen potilaiden tietoja kuvataksemme pre-eklampsiaan liittyvien perimänvaihteluiden yhteyttä sairastavuuteen taudin jälkeen. MCP-geenistä ei löydetty pre-eklampsiaan liittyviä perimänvaihtelun muotoja, mutta C3-geenissä kuvatuista pistemutaatiosta kolmen todettiin liittyvän pre-eklampsiaan. Lisäksi C3-geenin keskivaiheilla kuvattiin sekvenssialue, jossa on vahva kytkentäepätasapaino. Riippuen alueen emäsjärjestyksestä, sen todettiin jokoaltistavan tai suojaavan pre-eklampsiataudilta. Viimeisimpänä kuvattiin ensimmäistä kertaa äidin perinnöllinen suojaava tekijä FLT1-geenistä, joka koodaa verisuonien muodostukseen liittyvää tekijää sFlt-1, jonka lisääntyneen määrän verenkierrossa tiedetään liittyvän pre-eklampsiariskiin. Kahden pistemutaation FLT1-geenissä todettiin suojaavan paitsi pre-eklampsialta, myös sydämen vajaatoiminnalta. Väitöskirjassani esittelemä tutkimus lisää ymmärrystä monista perintötekijöistä, jotka liittyvät pre-eklampsiataudin kehittymiseen. Tuloksissa kuvataan ensimmäistä kertaa perinnöllinen yhteys pre-eklampsiataudin ja C3 geenin välillä. Toisaalta äidin verisuontenmuodostusta säätelevän tekijän osalta osoitetaan perinnöllinen yhteys raskaudenaikaisenterveyden ja vähentyneen sydämen vajaatoimintaan sairastuvuuden välillä. Komplementtijärjestelmän keskeinen merkitys terveessä raskaudessa käy ilmi sekä perintötekijöiden kautta että kudosvärjäystutkimuksen keinoin pre-eklampsiaraskauksien ja terveiden raskauksien istukoita vertailemalla

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 dis-ease etiology. Furthermore, the role of the coagulation cascade may be underappreciated in the develop-ment 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 syn-drome, or thrombotic thrombocytopenic purpura, all thrombotic microangiopathy (TMA) diseases, with the hallmark mechanisms of endothelial dysfunction and aberrant activation of complement and coagu-lation 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 dif-ferentiation, and novel treatment options to the subclass of patients with life-threatening disease that are most likely to benefit from next-generation drug development. (c) 2021 The Authors. Published by Elsevier Inc. on behalf of American Society for Histocompatibility and Immunogenetics. This is an open access article under the CC BY-NC-ND license (http://creativecommons. org/licenses/by-nc-nd/4.0/).Peer reviewe

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.Peer reviewe

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.Peer reviewe

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

Editorial : Innate Immunity in Normal and Adverse Pregnancy

Non peer reviewe

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.Peer reviewe

High relative amount of nodular calcification in femoral plaques is associated with milder lower extremity arterial disease.

Peer reviewe

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 (PPeer reviewe

ECCO - A new initiative to support early-career researchers in the complement field

Research on the complement system, like most areas of immunology, has seen tremendous progress over the last decades. Further advances in the complement field will rely on the next generation of scientific leaders, which are today's early-career researchers (ECRs). ECRs are emerging scientists who obtained their PhD degree within the past five years. They represent a distinct population within the scientific community, and accordingly have unique needs. Unfortunately, ECRs are faced with significant challenges that require customized solutions. The current paper provides a snapshot of the major obstacles ECRs face, such as an unhealthy work-life balance, lack of mentor and peer support, and uncertain career prospects. Efforts must consequently be taken to ensure stability and success of ECRs, not only to benefit these researchers in the early stages of their career, but the entire field of complement research. The Early-Career Complementologists (ECCO) was, therefore, launched as a new Task Force to support ECRs in the complement field. This new initiative aims to support and connect ECRs in the complement field worldwide. Furthermore, ECCO is supported by both the International Complement Society (ICS) and the European Complement Network (ECN); two professional societies led by scientists investigating the complement system