Interleukin-10 (IL-10), first recognized for its ability to inhibit activation and effector function of T cells, monocytes, and macrophages, is a multifunctional cytokine with diverse effects on most hemopoietic cell types. The principal routine function of IL-10 appears to be to limit and ultimately terminate inflammatory responses. In addition to these activities, IL-10 regulates growth and/or differentiation of B cells, NK cells, cytotoxic and helper T cells, mast cells, granulocytes, dendritic cells, keratinocytes, and endothelial cells. IL-10 plays a key role in differentiation and function of a newly appreciated type of T cell, the T regulatory cell, which may figure prominently in control of immune responses and tolerance in vivo. Uniquely among hemopoietic cytokines, IL-10 has closely related homologs in several virus genomes, which testify to its crucial role in regulating immune and inflammatory responses. This review highlights findings that have advanced our understanding of IL-10 and its receptor, as well as its in vivo function in health and disease.

Interleukin-10 and the interleukin-10 receptor.

Regulatory T Cells and Immune Tolerance

Class Switch Recombination and Hypermutation Require Activation-Induced Cytidine Deaminase (AID), a Potential RNA Editing Enzyme

CD4 T cells play critical roles in mediating adaptive immunity to a variety of pathogens. They are also involved in autoimmunity, asthma, and allergic responses as well as in tumor immunity. During TCR activation in a particular cytokine milieu, naive CD4 T cells may differentiate into one of several lineages of T helper (Th) cells, including Th1, Th2, Th17, and iTreg, as defined by their pattern of cytokine production and function. In this review, we summarize the discovery, functions, and relationships among Th cells; the cytokine and signaling requirements for their development; the networks of transcription factors involved in their differentiation; the epigenetic regulation of their key cytokines and transcription factors; and human diseases involving defective CD4 T cell differentiation.

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Differentiation of Effector CD4 T Cell Populations

The immune system has evolved to mount an effective defense against pathogens and to minimize deleterious immune-mediated inflammation caused by commensal microorganisms, immune responses against self and environmental antigens, and metabolic inflammatory disorders. Regulatory T (Treg) cell–mediated suppression serves as a vital mechanism of negative regulation of immune-mediated inflammation and features prominently in autoimmune and autoinflammatory disorders, allergy, acute and chronic infections, cancer, and metabolic inflammation. The discovery that Foxp3 is the transcription factor that specifies the Treg cell lineage facilitated recent progress in understanding the biology of regulatory T cells. In this review, we discuss cellular and molecular mechanisms in the differentiation and function of these cells.

Regulatory T Cells: Mechanisms of Differentiation and Function

Nasal cavity structural anomalies in children and adolescents at high risk of sleep-disordered breathing: An exploratory cone-beam computed tomography study.

The nasal septum cartilage is a specialized hyaline cartilage important for normal midfacial growth. Abnormal midfacial growth is associated with midfacial hypoplasia and nasal septum deviation (NSD). However, the underlying genetics and associated functional consequences of these two anomalies are poorly understood. We have previously shown that loss of Bone Morphogenetic Protein 7 (BMP7) from neural crest (BMP7 ncko ) leads to midfacial hypoplasia and subsequent septum deviation. In this study we elucidate the cellular and molecular abnormalities underlying NSD using comparative gene expression, quantitative proteomics, and immunofluorescence analysis. We show that reduced cartilage growth and septum deviation are associated with acquisition of elastic cartilage markers and share similarities with osteoarthritis (OA) of the knee. The genetic reduction of BMP2 in BMP7 ncko mice was sufficient to rescue NSD and suppress elastic cartilage markers. To our knowledge this investigation provides the first genetic example of an in vivo cartilage fate switch showing that this is controlled by the relative balance of BMP2 and BMP7. Cellular and molecular changes similar between NSD and knee OA suggest a related etiology underlying these cartilage abnormalities.

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Nasal Septum Deviation as the Consequence of BMP-Controlled Changes to Cartilage Properties.

Coloboma, a congenital disorder characterized by gaps in ocular tissues, is caused when the choroid fissure fails to close during embryonic development. Several loci have been associated with coloboma, but these represent less than 40% of those that are involved with this disease. Here, we describe a novel coloboma-causing locus, BMP3. Whole exome sequencing and Sanger sequencing of patients with coloboma identified three variants in BMP3, two of which are predicted to be disease causing. Consistent with this, bmp3 mutant zebrafish have aberrant fissure closure. bmp3 is expressed in the ventral head mesenchyme and regulates phosphorylated Smad3 in a population of cells adjacent to the choroid fissure. Furthermore, mutations in bmp3 sensitize embryos to Smad3 inhibitor treatment resulting in open choroid fissures. Micro CT scans and Alcian blue staining of zebrafish demonstrate that mutations in bmp3 cause midface hypoplasia, suggesting that bmp3 regulates cranial neural crest cells. Consistent with this, we see active Smad3 in a population of periocular neural crest cells, and bmp3 mutant zebrafish have reduced neural crest cells in the choroid fissure. Taken together, this data suggests that Bmp3 controls Smad3 phosphorylation in neural crest cells to regulate early craniofacial and ocular development.

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Analysis of BMP3 variants in the causality of ocular coloboma

Selection-induced gene expression in thymocytes

Printed electronics offer new possibilities in the design of footprints and integrated mechatronic systems. Fast and uncomplicated customization and cost-efficient fabrication are further benefits of this technology. In combination with other production processes like pick-and-place systems or fused filament fabrication (FFF), functional applications like communication or sensing devices can be produced in a very flexible way. The authors demonstrate how to produce a capacitive sensor system on three millimeter window glass by combining the piezo-jet technology and a pick-and-place system within a single five-axis CNC machine. The piezo-jet system is used to produce the circuitry by printing silver micro paste onto the glass plate. The process is maskless, works with a standoff-distance between one and ten millimeters and can process inks and pastes with a viscosity from 50 mPas to 200,000 mPas. The pick-and-place system puts all necessary surface mounted devices (SMD) directly onto the liquid paste which contains adhesives. The only process that takes place outside the machine is the sintering. However, by integrating an ultra violet (UV) or near infrared (NIR) curing system this process step could also be carried out within the machine. After the sintering the system is fully functional and does not require any further post-processing. The system consists of a micro-controller, two capacitive proximity detection ICs, resistors and capacitors. The digital outputs of the sensors could be used to control any given application, for reasons of illustration the functionality of the system is shown by an additionally mounted LED-strip. The system is easy to design and quick to adapt since the electronic layout is based on the standard layout of the IC-provider and the used software uncomplicated and open-source. Due to the placement at the back of the glass the system is perfectly protected against mechanical and chemical influences. It detects all kind of materials so the sensors can be triggered while wearing gloves or by people with a hand prosthesis. Moreover, the sensitivity can be easily adjusted over the software of the microcontroller which makes the application easy adaptable to several conditions. By recognizing different touch patterns, different operating modes can be performed. Currently the sensor system works as a touch switch, but it could also be adapted to realize a low-cost distance sensor. The flexibility of the used five axis system in combination with the high standoff-distance of the piezo-jet print head offers the possibility to print such systems on a wide spectrum of three-dimensional bodies. Even printing around or into corners is possible. With this method existing components can be functionalized electronically without having to redesign them. The produced demonstrator shows the possibility to extend a component by operating elements, but the capabilities go much further. Existing components can not only be extended by numerous sensor functions, communication elements such as Bluetooth or W-Lan antennas can also be realized in this way.

Daniel Graf

Papers

Nasal cavity structural anomalies in children and adolescents at high risk of sleep-disordered breathing: An exploratory cone-beam computed tomography study.

Nasal Septum Deviation as the Consequence of BMP-Controlled Changes to Cartilage Properties.

Analysis of BMP3 variants in the causality of ocular coloboma

Selection-induced gene expression in thymocytes

Customizable Capacitive Sensor System Using Printed Electronics on Window Glass