Ruben-J. Kuon

The “killer cell story” in recurrent miscarriage: Association between activated peripheral lymphocytes and uterine natural killer cells

Peripheral and uterine NK cells (pNK, uNK) can be distinguished according to their receptor expression. Recent studies indicate an association of elevated pNK and uNK with recurrent miscarriage (RM). This study aimed to analyze pNK and uNK in patients with RM and healthy controls. Out of n=590 RM patients screened according to a standard diagnostic protocol, n=268 couples with ≥3 consecutive RM were identified. Subgroups consisted of n=151 primary RM (pRM), n=85 secondary RM (sRM), n=32 tertiary RM (tRM) and n=42 healthy controls. Finally, n=147 idiopathic RM (iRM) and n=121 non-iRM patients were identified. Peripheral blood levels of CD45+CD3-CD56+CD16+ NK cells were determined in non-pregnant patients and controls in the mid-luteal phase by FACS. In n=129 RM patients a uterine biopsy was taken to evaluate CD56+ NK cells by immunohistochemistry. PRM showed higher absolute pNK than sRM (median/μl (Q1;Q3): 234 (147;306) vs 176 (128;245), p=0.02). Further a trend towards higher pNK percentages in pRM was detected. UNK numbers did not differ between RM subgroups and did not correlate with pNK. However, the rate of highly elevated uNK was increased in iRM compared to non-iRM patients (p=0.04). Further, higher numbers of CD45+CD3-DR+ (p<0.01) and CD45+CD3+CD8+DR+ (p=0.04) peripheral lymphocytes were associated with higher uNK numbers. In conclusion, elevated pNK were present in pRM patients. Although pNK and uNK numbers did not correlate, the association between high CD45+CD3-DR+ and CD45+CD3+CD8+DR+ peripheral lymphocytes and uNK might indicate that activated NK, B and T cells provide cytokines for the differentiation of uNK.

Uterine natural killer cells in patients with idiopathic recurrent miscarriage

Uterine natural killer (uNK) cells are major players during implantation and early pregnancy. The aim of our study was to analyze uNK cell concentration in the endometrium of idiopathic recurrent miscarriage (iRM) patients and fertile controls.

Higher prevalence of colonization with Gardnerella vaginalis and gram-negative anaerobes in patients with recurrent miscarriage and elevated peripheral natural killer cells

The role of vaginal infections in recurrent miscarriage (RM) is discussed controversially and screening is not recommended in international guidelines. Peripheral and uterine NK cells (pNK, uNK) play an important role in the establishment of a healthy pregnancy and are targets of immune diagnostics in RM patients. The aim of this study was to analyze the composition of the vaginal microbiota in RM patients and to correlate the findings to clinical characteristics as well as NK cell parameters. In total, n=243 RM patients with ≥3 consecutive miscarriages were recruited between 11/2011 and 03/2016. Vaginal swabs were analyzed by microbiological culture. Further, a cervical swab was taken in n=187 patients and the presence of Chlamydia trachomatis was evaluated by a molecular assay. Peripheral blood levels of CD45+CD3-CD56+CD16+ pNK (determined by four-color fluorescence flow cytometry) and CD56+ uNK (uterine biopsy, determined by immunohistochemistry) were analyzed. The prevalence of Gardnerella vaginalis colonization in RM patients was 19.0%, gram-negative anaerobes 20.5%, Candida species 7.9%, group B Streptococcus 11.0% and Enterobacteriaceae 14.8%. Commensal lactobacilli were absent in 14.5% of the women. Chlamydia trachomatis was detected in n=1 case (0.53%). The prevalence of Gardnerella vaginalis and gram-negative anaerobes in RM patients with elevated pNK (>280/μl, n=69) was significantly higher (p=0.012, p=0.04) compared to patients with normal pNK (n=174). In conclusion, RM patients with elevated pNK suffer more often from colonization by Gardnerella vaginalis and gram-negative anaerobes. This might indicate an association between the vaginal microbiota, local inflammation, changes in immune parameters and miscarriage.

Impaired Neonatal Outcome after Emergency Cerclage Adds Controversy to Prolongation of Pregnancy.

Objective Emergency cervical cerclage is one of the treatment options for the reduction of preterm birth. The aim of this study is to assess neonatal outcome after cerclage with special focus on adverse effects in very low birth weight infants. Study Design Retrospective cohort study. Classification of cerclages in history-indicated (HIC, n = 38), ultrasound-indicated (UIC, n = 29) and emergency/ physical examination-indicated (PEIC, n = 33) cerclage. Descriptive analysis of pregnancy and neonatal outcome (admission to NICU, duration of hospitalization, respiratory outcome (intubation, CPAP, FiO2max), neonatal complications (ROP, IVH)). Statistical comparison of perinatal parameters and outcome of neonates <1500 g after cerclage with a birth weight matched control group. Results Neonates <1500 g after PEIC show significantly impaired outcome, i.e. prolonged respiratory support (total ventilation in days, CPAP, FiO2max) and higher rates of neonatal complications (IVH ≥ II, ROP ≥ 2). Placental pathologic evaluation revealed a significantly higher rate of chorioamnionitis (CAM) after PEIC. Neonates <1500 g after UIC or HIC show no significant difference in neonatal complications or CAM. Conclusions In our study PEIC is associated with adverse neonatal outcome in infants <1500 g. The high incidence of CAM indicates a potential inflammatory factor in the pathogenesis. Large well-designed RCTs are required to give conclusive answers to the question whether to prolong or to deliver.

Kommentar zu: Immundiagnostik und -therapie des habituellen Aborts

Grosse-Wilde und Kuhn beschreiben in ihrem Übersichtsartikel Immundiagnostik und -therapie des habituellen Aborts den Wissensstand aus dem Jahr 1988 hinsichtlich der immunologischen Faktoren bei habituellem Abort, möglicher diagnostischer Verfahren und darauf basierender therapeutischer Optionen (. Abb. 1). Die Autoren beschreiben ein Versagen der fetomaternalen Immunregulation als eine bedeutende Ursache in der Pathogenese des habituellenAborts. Eine erhöhte immunologische Kompatibilität zwischen den Eltern sei demnach für das Fehlen einer adäquaten Induktion von schützenden Faktoren maßgeblich verantwortlich. Die Autoren führen eine Neubewertung der Thesen des immunologischen Paradoxons der Schwangerschaft von Sir PeterMedawar aus dem Jahr 1953 durch. 4 Es bestünde in der Schwangerschaft keine systemische, sondern vielmehr eine lokale Immunsuppression der Mutter. Immunsuppressiv wirkende Hormone und Proteine, welche fetalen, dezidualen oder trophoblastären Ursprungs sind, würden dies verursachen. 4 Die Plazenta übe keine uneingeschränkte, sondern eine selektive immunologische Barrierefunktion aus. Dies würde durch eine untypische Expression der „human leukocyte antigen“(HLA)-Antigene erreicht und durch eine Selektion der Stoffe, welche die Plazenta passieren. 4 Der Fet sei sehr wohl immunogen und aktiv daran beteiligt, seine Toleranz durch das maternale Immunsystem zu gewährleisten. 4 Der Uterus sei kein immunologisch privilegierter Ort, denn es werden auch Extrauteringraviditäten ausgetragen.

Immunologische Aspekte habitueller Aborte

ZusammenfassungHintergrundImmunologische Aspekte der Reproduktion gewinnen im Kontext der Diagnostik und Therapie habitueller Aborte zunehmend an Bedeutung.EinflussfaktorenEine Vielzahl an immunkompetenten Faktoren greift an der fetomaternalen Grenzzone in das Schicksal des heranwachsenden Embryos ein. Kommt es zur Abstoßung des Fetus, spielen auch immunologische Veränderungen eine wichtige Rolle. So wurde insbesondere in den letzten Jahren die zentrale Bedeutung der natürlichen Killerzellen in der Frühschwangerschaft erforscht.Diagnostik und TherapieBislang ist es jedoch nicht gelungen, eine spezifische immunologische Diagnostik einer gezielten Therapie zuzuordnen. Derzeit sind diverse immunmodulatorische Medikamente verfügbar, die teilweise einen Nutzen hinsichtlich der Lebendgeburtenrate zeigten. Noch sind die Fallzahlen aber zu klein, als dass immunologische Behandlungen außerhalb von klinischen Studien angewendet werden sollten.AbstractBackgroundImmunological aspects of reproduction are becoming increasingly important in the context of the diagnosis and treatment of recurrent miscarriage.Influencing factorsA number of immunological factors interact at the feto-maternal interphase and control the fate of the developing embryo. In case of miscarriage, immunological factors also play an important role. In recent years, research has focused mainly on the decisive role of natural killer cells during early gestation.Diagnostics and therapyHowever, so far no specific immunological diagnostic has been linked to a targeted therapy. Various immunomodulatory drugs, which have partially shown a benefit regarding the live birth rate, are available. However, the number of study populations is still too small to use immunological treatments outside clinical trials.