SummaryEpigenetic changes represent an attractive mechanism for understanding the phenotypic changes associated with human aging. Age‐related changes in DNA methylation at the genome scale have been termed ‘epigenetic drift’, but the defining features of this phenomenon remain to be established. Human epidermis represents an excellent model for understanding age‐related epigenetic changes because of its substantial cell‐type homogeneity and its well‐known age‐related phenotype. We have now generated and analyzed the currently largest set of human epidermis methylomes (N = 108) using array‐based profiling of 450 000 methylation marks in various age groups. Data analysis confirmed that age‐related methylation differences are locally restricted and characterized by relatively small effect sizes. Nevertheless, methylation data could be used to predict the chronological age of sample donors with high accuracy. We also identified discontinuous methylation changes as a novel feature of the aging methylome. Finally, our analysis uncovered an age‐related erosion of DNA methylation patterns that is characterized by a reduced dynamic range and increased heterogeneity of global methylation patterns. These changes in methylation variability were accompanied by a reduced connectivity of transcriptional networks. Our findings thus define the loss of epigenetic regulatory fidelity as a key feature of the aging epigenome.

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ObjectivesThe monoclonal anti-CD20 antibody rituximab is frequently applied in the treatment of lymphoma as well as autoimmune diseases and confers efficient depletion of recirculating B cells. Correspondingly, B cell-depleted patients barely mount de novo antibody responses during infections or vaccinations. Therefore, efficient immune responses of B cell-depleted patients largely depend on protective T cell responses.MethodsCD8+ T cell expansion was studied in rituximab-treated rheumatoid arthritis (RA) patients and B cell-deficient mice on vaccination/infection with different vaccines/pathogens.ResultsRituximab-treated RA patients vaccinated with Influvac showed reduced expansion of influenza-specific CD8+ T cells when compared with healthy controls. Moreover, B cell-deficient JHT mice infected with mouse-adapted Influenza or modified vaccinia virus Ankara showed less vigorous expansion of virus-specific CD8+ T cells than wild type mice. Of note, JHT mice do not have an intrinsic impairment of CD8+ T cell expansion, since infection with vaccinia virus induced similar T cell expansion in JHT and wild type mice. Direct type I interferon receptor signalling of B cells was necessary to induce several chemokines in B cells and to support T cell help by enhancing the expression of MHC-I.ConclusionsDepending on the stimulus, B cells can modulate CD8+ T cell responses. Thus, B cell depletion causes a deficiency of de novo antibody responses and affects the efficacy of cellular response including cytotoxic T cells. The choice of the appropriate vaccine to vaccinate B cell-depleted patients has to be re-evaluated in order to efficiently induce protective CD8+ T cell responses.

Background: Hyperoxia is a well-known cause of cerebral white matter injury in preterm infants with male sex being an independent and critical risk factor for poor neurodevelopmental outcome. Sex is therefore being widely considered as one of the major decisive factors for prognosis and treatment of these infants. But unfortunately, we still lack a clear view of the molecular mechanisms that lead to such a profound difference. Hence, using mousederived primary oligodendrocyte progenitor cells (OPCs), we investigated the molecular factors and underlying mechanisms behind the differential response of male and female cells towards oxidative stress. Results: We demonstrate that oxidative stress severely affects cellular functions related to energy metabolism, stress response, and maturation in the male-derived OPCs, whereas the female cells remain largely unaffected. CNPase protein level was found to decline following hyperoxia in male but not in female cells. This impairment of maturation was accompanied by the downregulation of nucleoporin and nuclear lamina proteins in the male cells. We identify Nup133 as a novel target protein affected by hyperoxia, whose inverse regulation may mediate this differential response in the male and female cells. Nup133 protein level declined following hyperoxia in male but not in female cells. We show that nuclear respiratory factor 1 (Nrf1) is a direct downstream target of Nup133 and that Nrf1 mRNA declines following hyperoxia in male but not in female cells. The female cells may be rendered resistant due to synergistic protection via the estrogen receptor alpha (ERα) which was upregulated following hyperoxia in female but not in male cells. Both Nup133 and ERα regulate mitochondrial function and oxidative stress response by transcriptional regulation of Nrf1. Conclusions: These findings from a basic cell culture model establish prominent sex-based differences and suggest a novel mechanism involved in the differential response of OPCs towards oxidative stress. It conveys a strong message supporting the need to study how complex cellular processes are regulated differently in male and female brains during development and for a better understanding of how the brain copes up with different forms of stress after preterm birth.