Frank Reister

Interleukin 21-induced granzyme B-expressing B cells infiltrate tumors and regulate T cells

The pathogenic impact of tumor-infiltrating B cells is unresolved at present, however, some studies suggest that they may have immune regulatory potential. Here, we report that the microenvironment of various solid tumors includes B cells that express granzyme B (GrB, GZMB), where these B cells can be found adjacent to interleukin (IL)-21-secreting regulatory T cells (Treg) that contribute to immune tolerance of tumor antigens. Because Tregs and plasmacytoid dendritic cells are known to modulate T-effector cells by a GrB-dependent mechanism, we hypothesized that a similar process may operate to modulate regulatory B cells (Breg). IL-21 induced outgrowth of B cells expressing high levels of GrB, which thereby limited T-cell proliferation by a GrB-dependent degradation of the T-cell receptor ζ-chain. Mechanistic investigations into how IL-21 induced GrB expression in B cells to confer Breg function revealed a CD19(+)CD38(+)CD1d(+)IgM(+)CD147(+) expression signature, along with expression of additional key regulatory molecules including IL-10, CD25, and indoleamine-2,3-dioxygenase. Notably, induction of GrB by IL-21 integrated signals mediated by surface immunoglobulin M (B-cell receptor) and Toll-like receptors, each of which were enhanced with expression of the B-cell marker CD5. Our findings show for the first time that IL-21 induces GrB(+) human Bregs. They also establish the existence of human B cells with a regulatory phenotype in solid tumor infiltrates, where they may contribute to the suppression of antitumor immune responses. Together, these findings may stimulate novel diagnostic and cell therapeutic approaches to better manage human cancer as well as autoimmune and graft-versus-host pathologies.

Determinants of maternal hair cortisol concentrations at delivery reflecting the last trimester of pregnancy

Hair cortisol concentrations (HCC) are emerging as a promising marker of chronic psychosocial stress. However, limited information on relevant correlates of this biomarker in late pregnancy is available. In the Ulm SPATZ Health Study mothers were recruited between 04/2012 and 05/2013 shortly after delivery in the University Medical Center Ulm, Germany. Cortisol concentrations of N=768 participants were determined by HPLC-MS/MS in the scalp-near 3cm of maternal hair reflecting stress exposure over the preceding three months. Sociodemographic characteristics, pregnancy-related variables and comorbidities were assessed. We conducted bivariate and multiple linear regression analyses using log transformed HCC. In bivariate analyses, significantly higher cortisol concentrations were found in obese compared to normal weight (b=0.32, p<0.001) and smoking as opposed to non-smoking mothers (b=0.34, p=0.002). Conversely, primary C-section was associated with lower HCC compared to spontaneous delivery. Besides, a strong impact of season of delivery with significantly higher HCC in summer and autumn as opposed to winter (both bs=0.58, p<0.001) was found. Further determinants of HCC were maternal education, number of persons in the household, premature delivery and hair characteristics. In a mutually adjusted model, all but education, multiple jobholding, hair characteristics and premature delivery remained statistically significant. Maternal hair cortisol in the last trimester of pregnancy is determined by many factors. Delivery mode, body mass index and season of delivery should be considered when investigating the association between HCC and further outcomes in mothers shortly after delivery.

Changing Societal and Lifestyle Factors and Breastfeeding Patterns Over Time

BACKGROUND: Breastfeeding is an important determinant of early infant immune function and potentially future health. Although numerous studies have reported rising breastfeeding initiation rates and duration, few longitudinally investigated the impact of shifting societal and lifestyle factors on breastfeeding patterns in developed nations. METHODS: The Ulm Birth Cohort Study (UBCS) and Ulm SPATZ Health Study (SPATZ) cohorts consist of newborns and their mothers recruited, respectively, from 2000 to 2001 and 2012 to 2013 at the University Medical Center Ulm, Germany. Cox proportional hazards models were used to estimate crude and mutually adjusted hazard ratios for study effect (time trend) and individual risk factors on noninitiation and duration of predominant and total breastfeeding. RESULTS: Compared with UBCS mothers, SPATZ mothers had lower cessation rates of both predominant breastfeeding by 4 months and total breastfeeding by 6 months: hazard ratio (95% confidence interval) 0.79 (0.67–0.93) and 0.71 (0.60–0.82), respectively. However, this crude time trend was limited to mothers with higher educational achievement. Similar time trend effects were observed among less educated mothers only after adjustment for early cessation risk factors. Mutually adjusted hazard ratios for individual risk factors were similar in both studies: low education, high BMI, smoking within 6 weeks of delivery, and cesarean delivery were associated with early breastfeeding cessation beginning at 6 weeks. In addition, actively abstaining from drinking alcohol was associated with lower rates of early cessation. CONCLUSIONS: Our results suggest widening socioeconomic disparity in breastfeeding and potentially subsequent child health, which may require new targeted interventions.

Delivery Mode, Duration of Labor, and Cord Blood Adiponectin, Leptin, and C-Reactive Protein: Results of the Population-Based Ulm Birth Cohort Studies

Background Numerous studies have reported associations between delivery mode and health outcomes in infancy and later life. Previous smaller studies indicated a relationship between delivery mode and newborn inflammation potentially constituting a mediating factor. We aimed to determine the influence of delivery mode and duration of labor on cord blood concentrations of adiponectin, leptin, and high-sensitivity C-reactive protein (hs-CRP). Methods In the Ulm SPATZ Health Study, 934 singleton newborns and their mothers were recruited during their hospital stay in the University Medical Center Ulm, Southern Germany, from 04/2012-05/2013. Inflammatory biomarkers were measured by ELISAs (n = 836). Delivery mode was analyzed categorically (elective cesarean (reference), active labor delivery: emergency cesarean, assisted vaginal, and spontaneous vaginal); duration of labor continuously. Following log-transformation, linear regression was used to estimate geometric means ratios (GMR) adjusted for potential confounders for the effects of delivery mode and duration of labor on each biomarker separately. Independent replication was sought in the similarly conducted Ulm Birth Cohort Study recruited from 11/2000-11/2001. Results Individually, active labor delivery modes as well as increasing duration of labor were associated with higher leptin and hs-CRP concentrations. After mutual adjustment, the associations with delivery modes were attenuated but those for duration of labor remained statistically significant (GMR (95%CI) 1.10 (1.00; 1.21) and 1.15 (1.04; 1.27) for leptin and hs-CRP per hour of labor, respectively). No significant adjusted associations were observed between delivery modes and adiponectin concentrations. These findings were replicated in an independent birth cohort study. Conclusions Cord blood leptin and hs-CRP concentrations were associated with duration of labor rather than delivery mode. Further research is warranted to investigate these associations with additional cytokines involved in inflammatory response to delineate the inflammatory profile. Subsequently, research on determinants of these associations and their role in development of chronic disease is needed.

The Association of Hair Cortisol with Self-Reported Chronic Psychosocial Stress and Symptoms of Anxiety and Depression in Women Shortly after Delivery.

BACKGROUND Psychosocial stress during pregnancy including anxiety and depression is known to have adverse health effects on newborns. However, measuring these psychological constructs is complex with psychological, endocrinological, and physiological systems being affected. Hair cortisol concentrations (HCC), assumed to reflect long-term endocrine consequences of stress exposure, represent a promising instrument for epidemiological research. However, the association between HCC and questionnaire-based instruments is unclear. METHODS In the Ulm SPATZ Health Study, mothers were recruited shortly after delivery in the University Medical Centre Ulm, Germany between April 2012 and May 2013. HCC of 768 participants were determined in scalp-near 3 cm maternal hair segments, assumed to reflect cortisol exposure over the last trimester of pregnancy. Chronic stress, anxiety, and depressive symptomatology were self-reported in questionnaire-based instruments. Spearman correlation coefficients between HCC and these instruments as well as means of HCC in highly and low stressed subgroups were calculated. RESULTS HCC were not correlated with self-reported chronic stress, anxiety, or depressive symptomatology. Furthermore, the investigation of sub-populations did not reveal substantial differences of HCC across highly and low stressed women. CONCLUSIONS HCC were not found to correlate with self-reports of chronic stress, anxiety, or depressive symptomatology. Among other things, these findings could reflect problems with questionnaire-based assessments obtained shortly after delivery such as recall bias and/or suggest that associations between cortisol secretion and psychosocial stress are difficult to detect due to, e.g. a strong physiological increase of cortisol in the last trimester.

Gestational Weight Gain and Fetal-Maternal Adiponectin, Leptin, and CRP: results of two birth cohorts studies

Gestational weight gain (GWG) is an important modifiable factor known to influence fetal outcomes including birth weight and adiposity. Unlike behaviors such as smoking and alcohol consumption, the effect of GWG throughout pregnancy on fetal development and other outcomes has not been extensively studied. The aim of this study was to investigate the relationship of GWG with endocrine factors such as adiponectin, leptin, and C-reactive protein which may be associated with inflammatory response, fetal growth, and adiposity later in life. Data were obtained from the Ulm Birth Cohort Study (UBCS) and the Ulm SPATZ Health Study, two methodologically similar birth cohort studies including newborns and their mothers recruited from 11/2000–11/2001 and 04/2012–05/2013. In the two included birth cohorts we consistently observed statistically significant positive associations between GWG beginning as early as the second trimester with fetal cord blood leptin and stronger association beginning as early as the first trimester with post-delivery maternal serum leptin. Total weight gain exceeding commonly accepted recommended guidelines was consistently associated with higher leptin levels in both cord blood and post-delivery maternal serum. These results suggest a potential pathomechanistic link between fetal environment and surrogate markers of long-term health.

Alterations of hair cortisol and dehydroepiandrosterone in mother-infant-dyads with maternal childhood maltreatment

BackgroundChild maltreatment (CM) has severe effects on psychological and physical health. The hypothalamic-pituitary-adrenal (HPA) axis, the major stress system of the body, is dysregulated after CM. The analysis of cortisol and dehydroepiandrosterone (DHEA) in scalp hair presents a new and promising methodological approach to assess chronic HPA axis activity. This study investigated the effects of CM on HPA axis activity in the last trimester of pregnancy by measuring the two important signaling molecules, cortisol and DHEA in hair, shortly after parturition. In addition, we explored potential effects of maternal CM on her offspring’s endocrine milieu during pregnancy by measuring cortisol and DHEA in newborns’ hair.MethodsCM was assessed with the Childhood Trauma Questionnaire (CTQ). Cortisol and DHEA were measured in hair samples of 94 mothers and 30 newborns, collected within six days after delivery. Associations of maternal CM on her own and her newborn’s cortisol as well as DHEA concentrations in hair were analyzed with heteroscedastic regression models.ResultsHigher CM was associated with significantly higher DHEA levels, but not cortisol concentrations in maternal hair. Moreover, maternal CM was positively, but only as a non-significant trend, associated with higher DHEA levels in the newborns’ hair.ConclusionsResults suggest that the steroid milieu of the mother, at least on the level of DHEA, is altered after CM, possibly leading to non-genomic transgenerational effects on the developing fetus in utero. Indeed, we observed on an explorative level first hints that the endocrine milieu for the developing child might be altered in CM mothers. These results need extension and replication in future studies. The measurement of hair steroids in mothers and their newborns is promising, but more research is needed to better understand the effects of a maternal history of CM on the developing fetus.

Altered hair endocannabinoid levels in mothers with childhood maltreatment and their newborns

The endocannabinoid (EC) system possesses anti-inflammatory properties and seems to be altered in trauma-exposed individuals. In an intergenerational approach, this study investigated the link between childhood maltreatment (CM) experiences and alterations in the EC system. Hair samples of N = 142 mothers and N = 91 newborns were analyzed, retrospectively assessing EC regulation during the last trimester of pregnancy with four ECs: 1-arachidonoylglycerol (1-AG), N-oleoylethanolamide (OEA), N-stearoylethanolamide (SEA), and N-palmitoylethanolamide (PEA). Compared to mothers without CM, hair of mothers with CM showed significantly higher levels of 1-AG and lower levels of SEA. Newborns of mothers with CM exhibited higher levels of 1-AG and OEA. Furthermore, the higher the severity of maternal CM, the lower were maternal SEA levels and the higher neonatal OEA levels. Findings indicate altered EC levels during the last trimester of pregnancy in mothers with CM and their developing fetus, highlighting potential intergenerational effects from one generation to the other.

Präinvasive Läsionen und Zervixkarzinom in der Schwangerschaft

ZusammenfassungIm Rahmen der üblichen Schwangerschaftsvorsorge erfolgt meist im ersten Trimenon eine gynäkologische Untersuchung mit Inspektion der Zervix und Entnahme eines zytologischen Abstrichs. Hierbei zeigt sich bei bis zu 7 % der schwangeren Frauen ein auffälliger zytologischer Befund. Bei 0,05 % der Schwangeren wird zudem die Diagnose eines Zervixkarzinoms gestellt, das nach dem Mammakarzinom die häufigste Neoplasie in der Schwangerschaft ist. Die weitere Abklärung und Therapie präinvasiver und invasiver Läsionen der Zervix ist in der Schwangerschaft meist erschwert, sodass sich die betroffene Frau häufig in einem – oft als extrem belastend wahrgenommenen – Konflikt zwischen der eigenen Gesundheit und dem Wohlergehen des Kindes befindet. Aus Ermangelung prospektiver Studien beruhen viele Empfehlungen auf retrospektiven Daten. Aufgrund der besonderen Situation in graviditate muss die Therapie somit häufig individuell an die Patientin und ihre Bedürfnisse angepasst werden. Daher soll im Beitrag eine Übersicht gegeben werden über die aktuellen Empfehlungen zu Diagnostik und Therapie der dysplastischen Veränderungen und Neoplasien der Zervix während der Schwangerschaft.AbstractA gynecological examination with inspection and cytological assessment (via pap smear) of the cervix is part of routine prenatal care in Germany and mostly performed in the first trimester. In up to 7% of pregnant women abnormal cytological findings of the cervix are diagnosed. In 0.05% of pregnant women invasive cervical cancer is also diagnosed, which is the second most frequent neoplasm in pregnancy after breast cancer. Further clarification and treatment of preinvasive and invasive cervical lesions are mostly difficult during pregnancy, so that affected patients find themselves in an often extremely stressful conflict situation between the well-being of the unborn child and their own health; however, due to a lack of prospective studies many recommendations on diagnostics and treatment of cervical cancer during pregnancy are based on retrospective data. Due to the special circumstances in pregnancy, therapeutic and diagnostic interventions therefore have to be individually adapted to each patient and their needs. This review article gives a summary of the current recommendations on the treatment and diagnostics of dysplastic alterations and invasive lesions of the cervix during pregnancy.

Fetal growth and incidence of atopic dermatitis in early childhood: Results of the Ulm SPATZ Health Study

Fetal growth may be a precursory factor in observed association between birthweight and atopic dermatitis (AD), however, recent studies utilizing fetal ultrasound-based data have reported contradictory results. This study aims to clarify previous findings through comprehensive investigation of association between several trimester-specific ultrasound-based anthropometric measures with AD diagnosis by age 3 years. Measurements of 386 newborns in the Ulm SPATZ Health Study were converted into adjusted z-scores categorized as “low” (≤1 SD below mean), “normal,” or “high” (≥1 SD above mean). AD cases were defined using parent- or pediatrician-report of physician-diagnosis or clinical diagnosis. Adjusted risk ratios (RR) with 95% confidence intervals (95% CI) were calculated using modified Poisson regression. Compared to normal, both low and high 2nd trimester abdominal circumference [RR 1.51, (95% CI 1.01; 2.24) and 1.83 (1.21; 2.76)], high 2nd trimester head- abdominal circumference ratio [1.69 (1.16; 2.48)], and faltering 2nd to 3rd trimester [1.59 (1.04; 2.43)] head circumference were associated with greater AD risk. High 3rd trimester femur length [0.54 (0.31; 0.94)] was associated with lower risk. Using more inclusive exposure cut-points (0.8 SD), lower 1st trimester crown-rump length was also associated with greater AD risk. Our data suggest several different patterns of fetal growth may be differentially associated with AD.