B Cell Activation and Escape of Tolerance Checkpoints:Recent Insights from Studying Autoreactive B Cells

Autoreactive B cells are key drivers of pathogenic processes in autoimmune diseases by the production of autoantibodies, secretion of cytokines, and presentation of autoantigens to T cells. However, the mechanisms that underlie the development of autoreactive B cells are not well understood. Here, we review recent studies leveraging novel techniques to identify and characterize (auto)antigen-specific B cells. The insights gained from such studies pertaining to the mechanisms involved in the escape of tolerance checkpoints and the activation of autoreactive B cells are discussed. In addition, we briefly highlight potential therapeutic strategies to target and eliminate autoreactive B cells in autoimmune diseases

Pictures of preterm infants elicit increased affective responses and reduced reward-motivation or perspective taking in the maternal brain

Preterm-birth increases the risk of several physical, cognitive, neuromotor, and psychosocial problems in children, and is also related to difficulties in the parent-child relationship. Research suggests that the development of early parent-child interactions in general is affected by deviations from typical infant facial characteristics, which may also be important in the case of small, preterm born infants. Therefore, we examined mothers' (N = 22, of whom 17 had no direct experience with preterm birth) neural responses to pictures of preterm and fullterm infants using functional magnetic resonance imaging (fMRI). We also explored whether neural responses to preterm and full-term infants correlated with mothers' self-reported tendencies to be nurturing and protective with children, and with mothers' ratings of affection or aversion toward pictures of preterm infants. Results revealed that, compared to pictures of full-term infants, those of preterm infants elicited more activity in specific areas of the brain (dmPFC, right insula, left caudate, hippocampi, parahippocampi, and PAG), that have previously been associated with processing of negative emotions and with empathy. In addition, less activity was seen in one area of the brain (vmPFC) known to be associated with reward-motivation or mental state understanding and perspective-taking. Higher self-reported maternal nurturance was associated with increased activity to pictures of preterm infants vs full-term infants in the caudate, which might reflect approach- or reward-related processing. To conclude, neural responses to preterm infants are related to reward-motivation, mentalizing, negative emotions, and empathy. Future studies should examine whether such neural processing of preterm infant stimuli might underlie difficulties in the parent-child relationship of parents with a preterm child

What a cute baby! Preliminary evidence from a fMRI study for the association between mothers ? neural responses to infant faces and activation of the parental care system

Infant facial characteristics, i.e., baby schema, are thought to automatically elicit parenting behavior and affective orientation toward infants. Only a few studies, conducted in non-parents, have directly examined the neural underpinnings of this baby schema effect by manipulating distinctiveness of baby schema in infant faces. This study aims to further our understanding of the intuitive nature of parenting, by studying the baby schema effect in mothers of young children (at least one child aged between 2 and 6 years old). Functional magnetic resonance imaging (fMRI) was used to examine mothers’ (N = 23) neural responses to unfamiliar infant faces varying in distinctiveness of baby schema. Also, it was studied how this neural activation to infant faces was associated with maternal nurturance. Results revealed that infant faces elicited widespread activation in bilateral visual cortices, the hippocampus, sensory-motor areas, parietal and frontal cortices, and the insula, which was not modulated by the distinctiveness of baby schema in the infant faces. Furthermore, higher self-reported maternal nurturance was related to increased neural responses to infant faces in the putamen and amygdala, brain regions known to be associated with reward and salience processing. These findings could suggest that in our small sample of mothers some of the core networks involved in reward and salience processing might be less sensitive to variation in distinctiveness of baby schema. Also, unfamiliar infant faces seem to be rewarding only for mothers who report high nurturance. These findings should be considered preliminary, because they need to be replicated in studies with larger samples

The formation of mutated IgM memory B cells in rat splenic marginal zones is an antigen dependent process

Previous studies in rodents have indicated that only a minor fraction of the immunoglobulin heavy chain variable region (IGHV-Cμ) transcripts carry somatic mutations and are considered memory B cells. This is in marked contrast to humans where nearly all marginal zone B (MZ-B) cells are mutated. Here we show in rats that the proportion of mutated IgM+ MZ-B cells varies significantly between the various IGHV genes analyzed, ranging from 27% mutated IGHV5 transcripts to 65% mutated IGHV4 transcripts. The observed data on mutated sequences in clonally-related B cells with a MZ-B cell or follicular B (FO-B) cell phenotype indicates that mutated IgM+ MZ-B and FO-B cells have a common origin. To further investigate the origin of mutated IgM+ MZ-B cells we determined whether mutations occurred in rearranged IGHV-Cμ transcripts using IGHV4 and IGHV5 genes from neonatal rat MZ-B cells and FO-B cells. We were not able to detect mutations in any of the IGHV4 and IGHV5 genes expressed by MZ-B cells or FO-B cells obtained from neonatal rat spleens. Germinal centres (GCs) are absent from neonatal rat spleen in the first few weeks of their life, and no mutations were found in any of the neonatal sequences, not even in the IGHV4 gene family which accumulates the highest number of mutated sequences (66%) in the adult rat. Therefore, these data do not support the notion that MZ-B cells in rats mutate their IGHV genes as part of their developmental program, but are consistent with the notion that mutated rat MZ-B cells require GCs for their generation. Our findings support that the splenic MZ of rats harbors a significant number of memory type IgM+ MZ-B cells with mutated IGHV genes and propose that these memory MZ-B cells are probably generated as a result of an antigen driven immune response in GCs, which still remains to be proven

Course of Stress during the Neonatal Intensive Care Unit Stay in Preterm Infants

Introduction: Understanding the course of stress during the neonatal intensive care unit stay may provide targets for interventions. Our aim was to describe the course of stress in preterm infants during the first 28 days of life, the influence of gestational age, and associations with clinical characteristics. Methods: In a single centre prospective cohort study, we included infants with a gestational age <30 weeks and/or birth weight <1,000 g. We measured stress over the first 28 days using the Neonatal Infant Stressor Scale (NISS). We plotted daily NISS total and subcategory scores by gestational age. The subcategories were (1) nursing, (2) skin-breaking, (3) monitoring and imaging, and (4) medical morbidity-related scores. We assessed associations of cumulative NISS scores over the first 7, 14, and 28 days with clinical characteristics using regression analyses. Results: We included 45 infants, with a median gestational age of 27 weeks. The mean daily NISS score was 66.5 (SD 8.7), with highest scores in the first 7 days of life. Scores decreased the slowest for the lowest gestational ages, in particular for nursing scores, rather than skin-breaking, monitoring and imaging, and medical morbidity-related scores. Adjusted for gestational age, infants with lower Apgar scores, sepsis, intraventricular haemorrhages, and on mechanical ventilation had significantly higher cumulative NISS scores at 7, 14, and 28 days. Conclusion: NISS scores varied greatly within infants and over time, with the highest mean scores in the first week after birth. The course of declining NISS scores in the first 28 days depended on gestational age at birth

Presence of Germline and Full-Length IgA RNA Transcripts Among Peritoneal B-1 Cells

Next to conventional B cells (or B-2 cells), peritoneal B-1 cells have been shown to contribute significantly to the production of IgA-secreting plasma cells in the gut. Evidence for this was mainly based on studies comprising manipulated animals, including lethally X-irradiated and transgenic mice. To examine the ability of peritoneal B-1 cells from untreated mice to switch actively to IgA in vivo, we performed RT-PCR analysis on FACS-sorted peritoneal B-cell subsets from untreated BALB/c mice in order to examine the presence of germline Cα mRNA and mature Cα mRNA transcripts. Germline Cα and mature Cα transcripts were readily detectable in peritoneal B-1 cells (defined as IgMbright/IgDdull), but not, or very little, in peritoneal B-2 cells (defined as IgMdull/IgDbright). Moreover, by subdividing the B-l-cell population in CD5+ B-1a cells and CD5- B-1b cells, it was shown that in vivo expression of germline Cα and mature Cα transcripts was largely restricted to the B-1b-cell lineage. These results indicate that peritoneal B-1 cells indeed are capable to switch to IgA under normal physiological conditions and hereby further support the view that B-1 cells contribute significantly to the mucosal IgA response, albeit this function appears to be restricted to the B-1b-cell subset

The Rotterdam Scan Study: design update 2016 and main findings

Imaging plays an essential role in research on neurological diseases in the elderly. The Rotterdam Scan Study was initiated as part of the ongoing Rotterdam Study with the aim to elucidate the causes of neurological disease by performing imaging of the brain in a prospective population-based setting. Initially, in 1995 and 1999, random subsamples of participants from the Rotterdam Study underwent neuroimaging, whereas from 2005 onwards MRI has been implemented into the core protocol of the Rotterdam Study. In this paper, we discuss the background and rationale of the Rotterdam Scan Study. Moreover, we describe the imaging protocol, image post-processing techniques, and the main findings to date. Finally, we provide recommendations for future research, which will also be topics of investigation in the Rotterdam Scan Study

The potential for prevention of dementia across two decades: The prospective, population-based Rotterdam Study

Background: Cardiovascular factors and low education are important risk factors of dementia. We provide contemporary estimates of the proportion of dementia cases that could be prevented if modifiable risk factors were eliminated, i.e., population attributable risk (PAR). Furthermore, we studied whether the PAR has changed across the last two decades. Methods: We included 7,003 participants of the original cohort (starting in 1990) and 2,953 participants of the extended cohort (starting in 2000) of the Rotterdam Study. Both cohorts were followed for dementia until ten years after baseline. We calculated the PAR of overweight, hypertension, diabetes mellitus, cholesterol, smoking, and education. Additionally, we assessed the PAR of stroke, coronary heart disease, heart failure, and atrial fibrillation. We calculated the PAR for each risk factor separately and the combined PAR taking into account the interaction of risk factors. Results: During 57,996 person-years, 624 participants of the original cohort developed dementia, and during 26,177 person-years, 145 participants of the extended cohort developed dementia. The combined PAR in the original cohort was 0.23 (95 % CI, 0.05-0.62). The PAR in the extended cohort was slightly higher at 0.30 (95 % CI, 0.06-0.76). The combined PAR including cardiovascular diseases was 0.25 (95 % CI, 0.07-0.62) in the original cohort and 0.33 (95 % CI, 0.07-0.77) in the extended cohort. Conclusions: A substantial part of dementia cases could be prevented if modifiable risk factors would be eliminated. Although prevention and treatment options of cardiovascular risk factors and diseases have improved, the preventive potential for dementia has not declined over the last two decades