Title CD56-pozitivne NK stanice i CD138-pozitivne plazma stanice u bazalnoj decidui i histopatološka obilježja posteljica nakon liječenja neplodnosti uzrokovane endometriozom Title (english) CD56-positive NK cells and CD138-positive plasma cells in the basal decidua and histopathological characteristics of placentas after treatment of the endometriosis-related infertility Author Stipe Dumančić Mentor Jelena Marušić (mentor)Committee member Damir Roje (predsjednik povjerenstva)Committee member Zoran Meštrović (član povjerenstva)Committee member Merica Glavina Durdov (član povjerenstva)Granter University of Split Defense date and country 2025-04-15, Croatia Scientific / art field, BIOMEDICINE AND HEALTHCARE Universal decimal classificationUDC ) 618 - Gynaecology. Obstetrics Abstract Uvod: Endometrioza je kroničan, estrogen-ovisan poremećaj povezan s neplodnošću, ponajprije zbog štetnog učinka na ovarijsku rezervu i receptivnost endometrija. Slično ektopičnim endometriotičnim lezijama, eutopični endometrij kod endometrioze pokazuje izmijenjene imunološke odgovore, uključujući poremećen broj prirodnoubilačkih stanica (NK) i plazma stanica. Postupci medicinski potpomognute oplodnje (MPO) predstavljaju mogućnost liječenja neplodnosti kod zahvaćenih žena, no dostupna literatura ukazuje na višu učestalost nepovoljnih perinatalnih ishoda u trudnoćama s endometriozom. Ipak, histopatološke značajke posteljice i imunološki odgovori u trudnoćama kod pacijentica s neplodnošću uzrokovanom endometriozom, a koji mogu pridonijeti tim ishodima, nisu dovoljno istraženi. Cilj: Cilj ove disertacije bio je istražiti histopatološke promjene posteljica, uz analizu ukupnog broja CD56-pozitivnih NK stanica i CD138-pozitivnih plazma stanica u uzorcima bazalne decidue (BD) jednoplodovih trudnoća nakon liječenja neplodnosti uzrokovane endometriozom. Sekundarni ishodi uključivali su učestalost perinatalnih komplikacija te povezanost faktora endometrioze s brojem imunoloških stanica decidue i histopatološkim karakteristikama posteljice. Materijali i metode: Ova disertacija objedinjuje rezultate dviju monocentričnih istraživanja slučaja i kontrola, koje su obuhvatile histopatološku analizu posteljica te imunohistokemijsku (IHC) analizu CD56 i CD138 biljega u BD uzorcima trudnoća nakon liječenja neplodnosti uzrokovane endometriozom, muškog faktora neplodnosti te fizioloških trudnoća. Minimalna potrebna izračunata veličina uzorka iznosila je 91 posteljicu. Lezije posteljice kategorizirane su prema Amsterdamskom konsenzusu o patologiji posteljica te su podijeljene u anatomske, upalne, lezije vilozne zrelosti i poremećaje vaskularne perfuzije. IHC analiza provedena je primjenom primarnih monoklonskih mišjih protutijela za CD56 i CD138, uz sekundarna protutijela prema standardiziranom protokolu. CD56 i CD138 pozitivne stanice prijavljene su kao ukupan broj stanica po 1 mm² BD uz pomoć mikroskopa Olympus BX46 i Olympus Image Analyzer sustava. Rezultati: U istraživanja je bilo uključeno 107 sudionica s terminskim posteljicama, raspoređenih u tri skupine: MPO Endometrioza (n=36), MPO muški čimbenik (n=31) i fiziološke trudnoće (n=40). Posteljice iz trudnoća s endometriozom pokazale su veću učestalost posteljičnih lezija u odnosu na kontrolne skupine, uključujući pojačano stvaranje sincicijalnih čvorova, skraćene pupkovine i višu učestalost poremećaja vaskularne malperfuzije (subkorijalno i perivilozno taloženje fibrina, interviloznu trombozu te fetalnu vaskularnu malperfuziju visokog stupnja). U prilagođenom regresijskom modelu čimbenik endometrioze bio je povezan s pojačanim stvaranjem sincicijalnih čvorova i hipertorzijom pupkovine. Trudnoće povezane s endometriozom imale su veću učestalost krvarenja u ranoj trudnoći i prijetećeg prijevremenog porođaja, kao i veću stopu carskih rezova te češću pojavu novorođenčadi s najnižom porođajnom masom. Uzorci BD posteljica iz trudnoća s endometriozom pokazali su najnižu medijalnu vrijednost CD56-pozitivnih NK stanica u usporedbi s kontrolnim skupinama, pri čemu je njihova smanjena prisutnost bila povezana s određenim posteljičnim lezijama (nezrelost resica, vilitis nepoznate etiologije niskog stupnja, intervilozna tromboza i pojačano perivilozno taloženje fibrina). S druge strane, nisu uočene značajne razlike u broju CD138-pozitivnih plazma stanica između ispitivanih skupina. Zaključak: Dobiveni rezultati upućuju na moguću izmijenjenu imunološku reakciju majke, temeljenu na sniženoj infiltraciji NK stanica, što može otežati pravilnu invaziju trofoblasta, remodeliranje spiralnih žila miometrija i razvoj posteljice, a čime je kompromitirana posteljična perfuzija koja pridonosi nepovoljnim perinatalnim ishodima u trudnoćama nakon liječenja neplodnosti uzrokovane endometriozom. S druge strane, adaptivna imunost, predstavljena infiltracijom plazma stanica, nije prikazana značajnom u patogenezi endometrioze. Uočeni poremećaji posteljične perfuzije naglašavaju potrebu za povećanim nadzorom funkcije posteljice u trudnoćama nakon MPO liječenja neplodnosti uzrokovane endometriozom. Buduća istraživanja trebala bi biti usmjerena na otkrivanje molekularnih mehanizama endometrioze na disfunkciju posteljice i razvoja perinatalnih komplikacija. Identifikacija potencijalnih biomarkera ili terapijskih intervencija usmjerenih na poremećaj imunološkog odgovora i vaskularno remodeliranje mogla bi poboljšati ishode trudnoća s endometriozom.
Abstract (english) Introduction: Endometriosis is a chronic, estrogen-dependent condition linked to infertility, primarily due to its detrimental effects on ovarian reserve and endometrial receptivity. Comparable to ectopic endometriotic lesions, the eutopic endometrium in endometriosis patients shows exhibits immune response irregularities, including alterations in natural killer (NK) and plasma cell activity. Assisted reproductive technology (ART) offers a viable fertility treatment for these patients, yet literature show endometriosis pregnancies are associated with a heightened risk of adverse perinatal outcomes. Despite this, here remains a data scarcity on the histopathologic characteristics of placenta and immunological responses in term pregnancies of patients with endometriosis-related infertility, which could contribute to these adverse outcomes. Aim: This dissertation aimed to explore histopathologic alterations of term placentas, and to investigate total counts of CD56-positive NK cells and CD138-positive plasma cells in the basal decidua (BD) samples in singleton pregnancies after ART treatment of endometriosisrelated infertility. Secondary outcomes encompassed the incidence of perinatal complications and examining the potential relationship of endometriosis factor on the decidual immune cell counts and placental pathology. Materials and methods: This dissertation integrates data from two case-control studies which provided placental histopathologic examination alongside immunohistochemical (IHC) analysis of CD56 and CD138 immune cell markers in term BD samples from pregnancies after ART treatment of endometriosis-related infertility, male factor infertility and physiological pregnancies. The minimum required samples size was calculated to be 91 placentas. Placental lesions were reported according to the Amsterdam Placental Workshop Group Consensus as anatomic, inflammatory, villous maturation and vascular malperfusion disorders. IHC study was conducted using primary monoclonal mouse antibodies for CD56 and CD138, followed by secondary antibody application under a standardized protocol, while CD56 and CD138 positive cells were quantified as the total cell count for each studied antibody per 1 mm² of BD (Olympus BX46 and Olympus Image Analyzer). Results: Studies examined term placentas with BD of 107 participants, according to ART Endometriosis (n=36), ART Male factor (n=31) and Physiological (n=40) pregnancies’ group. Endometriosis placentas yielded higher incidence of placental lesions compared to control groups including increased syncytial knot formation, shortened placental cords, and a higher frequency of vascular malperfusion disorders (subchorionic and perivillous fibrin deposition, intervillous thrombosis, and high-grade fetal vascular malperfusion). Endometriosis factor was associated with increased syncytial knots’ formation and placental cord hypercoiling in adjusted regression model. Endometriosis pregnancies experienced higher number of early pregnancy bleeding and imminent preterm labor events, as well as higher cesarean delivery with newborns frequently presenting with lowest birthweight. The BD from endometriosis placentas exhibited the lowest median CD56-positive NK cells’ count compared to control groups, associated with odds for several placental lesions (immature villous ramification, low grade villitis of unknown etiology, intervillous thrombosis and increased perivillous fibrin). Conversely, no significant differences were observed in CD138-positive plasma cell counts across the study groups. Conclusions: These findings could suggest potential impaired maternal immune response based on altered NK cell infiltration, which may hinder proper trophoblast invasion, vascular remodeling and placental development, with compromised placental perfusion contributing to adverse perinatal outcomes in pregnancies after ART treatment of endometriosis-related infertility. However, adaptive immunity with plasma cell infiltration did not show potential influence associated with endometriosis pathogenesis. The observed placental malperfusion lesions highlight the need for increased surveillance of placental function in pregnancies complicated by endometriosis, even in cases conceived through ART. Future research should aim to elucidate the molecular pathways linking endometriosis to placental dysfunction and perinatal complications. Identifying potential biomarkers or therapeutic interventions targeting immune dysregulation and vascular remodeling in endometriosis-related pregnancies may improve maternal and fetal outcomes.
Keywords
neplodnost povezana s endometriozom
potpomognuta oplodnja
prirodne stanice ubojice
plazma stanice
posteljica
Keywords (english)
endometriosis-related infertility
assisted reproductive technology
natural killer cells
plasma cells
placenta
Language croatian URN:NBN urn:nbn:hr:171:413145 Study programme Title: Translational Research in Biomedicine - TRIBE Type of resource Text File origin Born digital Access conditions Open access Terms of use Created on 2025-04-25 13:10:40
