Inflammatory Characteristics of Monocytes from Pediatric Patients with Tuberous Sclerosis.

OBJECTIVE: Therapeutic options for the tuberous sclerosis complex (TSC) syndrome showed varying outcomes. Malfunctional tsc1/tsc2 genes leave mTOR uninhibited, a positive downstream modulator of the innate proinflammatory immune system, which has not yet been described in pediatric patients with TSC. METHODS: Using polymerase chain reaction (PCR) gene expression levels of monocytes after cultivation with lipopolysaccharide (LPS) or with LPS + mTOR inhibitor rapamycin, patients with TSC (n = 16) were compared with healthy subjects (n = 20). RESULTS: Compared with monocytes from healthy controls, LPS showed a more prominent gene expression pattern in patients with TSC (CCL24, CXCL10, IL-6, IL-10, and IL-1B). Proinflammatory reactions against LPS were modulated by rapamycin. With LPS + rapamycin monocytes from patients with TSC showed gene expression patterns different from healthy subjects. Furthermore, developmental differences were discernible in patients with TSC, compared with gene expression levels for patients 0 to 5 years to those 6 to 11 years of age, the latter with marked expression of IL-6 IL-1A, IL-1B, RIPK2, but also IL-10. CONCLUSION: The effects of LPS, even more of LPS with rapamycin on monocytes from patients with TSC suggested that inflammatory processes are distinct from those in healthy subjects. Furthermore, reaction to rapamycin indicates age-related gene expression levels. Our findings offer a model to decipher the unknown and varying gene expression pattern induced by rapamycin.

In the presence of IL-21 human cord blood T cells differentiate to IL-10-producing Th1 but not Th17 or Th2 cells.

IL-21, a member of the IL-2 cytokine family, is mainly produced by activated CD4(+) T cells and controls the activity of immune and also non-immune cells. As a pleiotropic cytokine, IL-21 acts on both innate and adaptive immune responses, suggesting that IL-21 may be a master regulator of the T-cell-dependent adaptive immune response. Although IL-21 is described as mostly promoting inflammation, evidence also suggests inhibitory effects of IL-21. However, its role, particularly in the human neonatal immune system, has not been detailed so far. Here, we assessed the effect of IL-21 in the specific context of the neonatal immune response and delineated differences between the human newborn and adult immune response. In umbilical cord blood, we demonstrated that IL-21 polarized naive CD4(+) T cells into T(h)1 cells, producing IL-10, a key negative regulator during certain infections and autoimmunity. Furthermore, IL-21 stimulation increased IFNγ secretion and inhibited the development of T(h)2 and T(h)17 cells and molecules associated with their function. Thus, in neonates, known to show limitations in establishing T(h)1 responses, IL-21 played a clear role in supporting T(h)1 responses in vitro, while appearing irrelevant for the adult immune response. Overall, we demonstrated the capability of IL-21 to induce the immunosuppressive cytokine IL-10 and outlined its potential to compensate the restricted T(h)1 response in human newborns and consequently to reduce the susceptibility for infectious diseases in the first period of life.

Structural Transformation to Attain Responsible BIOSciences (STARBIOS2): Protocol for a Horizon 2020 Funded European Multicenter Project to Promote Responsible Research and Innovation.

BACKGROUND: Promoting Responsible Research and Innovation (RRI) is a major strategy of the "Science with and for Society" work program of the European Union's Horizon 2020 Framework Programme for Research and Innovation. RRI aims to achieve a better alignment of research and innovation with the values, needs, and expectations of society. The RRI strategy includes the "keys" of public engagement, open access, gender, ethics, and science education. The Structural Transformation to Attain Responsible BIOSciences (STARBIOS2) project promotes RRI in 6 European research institutions and universities from Bulgaria, Germany, Italy, Slovenia, Poland, and the United Kingdom, in partnership with a further 6 institutions from Brazil, Denmark, Italy, South Africa, Sweden, and the United States. OBJECTIVE: The project aims to attain RRI structural change in 6 European institutions by implementing action plans (APs) and developing APs for 3 non-European institutions active in the field of biosciences; use the implementation of APs as a learning process with a view to developing a set of guidelines on the implementation of RRI; and develop a sustainable model for RRI in biosciences. METHODS: The project comprises interrelated research and implementation designed to achieve the aforementioned specific objectives. The project is organized into 6 core work packages and 5 supporting work packages. The core work packages deal with the implementation of institutional APs in 6 European institutions based on the structural change activation model. The supporting work packages include technical assistance, learning process on RRI-oriented structural change, monitoring and assessment, communication and dissemination, and project management. RESULTS: The project is funded by Horizon 2020 and will run for 4 years (May 2016-April 2020). As of June 2018, the initial phase has been completed. The participating institutions have developed and approved APs and commenced their implementation. An observation tool has been launched by the Technical Assistance Team to collect information from the implementation of APs; the Evaluation & Assessment team has started monitoring the advancement of the project. As part of the communication and dissemination strategy, a project website, a Facebook page, and a Twitter account have been launched and are updated periodically. The International Scientific Advisory Committee has been formed to advise on the reporting and dissemination of the project's results. CONCLUSIONS: In the short term, we anticipate that the project will have a considerable impact on the organizational processes and structures, improving the RRI uptake in the participating institutions. In the medium term, we expect to make RRI-oriented organizational change scalable across Europe by developing guidelines on RRI implementation and an RRI model in biosciences. In the long term, we expect that the project would help increase the ability of research institutions to make discoveries and innovations in better alignment with societal needs and values. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/11745.

Dendritic cells change IL-27 production pattern during childhood.

BACKGROUND: Interleukin-27 (IL-27) has been described to be highly expressed during the very first days after birth, but secretion of IL-27 by dendritic cells during the course of childhood has not been described. FINDINGS: In our present study we enrolled children (n = 55) in the range from 1 day of to 18 years of age and asked for a small whole blood sample. The capacity of dendritic cells to produce IL-27 during childhood was measured after whole blood culture with or without inflammatory stimuli. Results support recent findings of high IL-27 levels after birth and lowest levels in adults. Interestingly, we detected an interim peak production level at early adolescence. CONCLUSION: These data hint to prominent roles of IL-27 at the very start of post-natal life. Furthermore, a link has been given to so far not described immunological events during puberty.

IL-27 improves migrational and antiviral potential of CB dendritic cells.

Interleukin (IL)-27 is known to be increased considerably in cord blood (CB) dendritic cells (DCs) after TLR ligation. Previously, we demonstrated that also basal IL-27 levels are higher in CB DCs. Here, we examined effects of IL-27 on monocyte derived dendritic cells (moDCs) to approach its particular role in the specialized immune system of the human neonate. Exogenous IL-27 promotes IL-27 transcription in CB and adult blood (AB) moDCs. IL-27 acts on CB moDCs primarily by significantly augmenting IL-27 protein, secondarily by increasing transcription of CXCL10 among other chemokines, chemokine receptor CCR1, interferon stimulated genes, transcription factor IRF8 and genes involved in antigen presentation. Furthermore, CB moDCs respond to IL-27 with augmented IL-8 and Tumor necrosis factor (TNF)-α. The results suggest that IL-27 enhances migrational and antiviral properties of CB dendritic cells.