Biomedical subjects

Christoph D Schmid

Publications and source records attributed to Christoph D Schmid.

6 recordsLinked to original sources

PubMed2006

EPD in its twentieth year: towards complete promoter coverage of selected model organisms.

The Eukaryotic Promoter Database (EPD) is an annotated non-redundant collection of eukaryotic POL II promoters, experimentally defined by a transcription start site (TSS). Access to promoter sequences is provided by pointers to positions in the corresponding genomes. Promoter evidence comes from conventional TSS mapping experiments for individual genes, or, starting from release 73, from mass genome annotation projects. Subsets of promoter sequences with customized 5' and 3' extensions can be downloaded from the EPD website. The focus of current development efforts is to reach complete promoter coverage for important model organisms as soon as possible. To speed up this process, a new class of preliminary promoter entries has been introduced as of release 83, which requires less stringent admission criteria. As part of a continuous integration process, new web-based interfaces have been developed, which allow joint analysis of promoter sequences with other bioinformatics resources developed by our group, in particular programs offered by the Signal Search Analysis Server, and gene expression data stored in the CleanEx database. EPD can be accessed at http://www.epd.isb-sib.ch.

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PubMed2006

CNS immune privilege: hiding in plain sight.

Central nervous system (CNS) immune privilege is an experimentally defined phenomenon. Tissues that are rapidly rejected by the immune system when grafted in sites, such as the skin, show prolonged survival when grafted into the CNS. Initially, CNS immune privilege was construed as CNS isolation from the immune system by the blood-brain barrier (BBB), the lack of draining lymphatics, and the apparent immunoincompetence of microglia, the resident CNS macrophage. CNS autoimmunity and neurodegeneration were presumed automatic consequences of immune cell encounter with CNS antigens. Recent data have dramatically altered this viewpoint by revealing that the CNS is neither isolated nor passive in its interactions with the immune system. Peripheral immune cells can cross the intact BBB, CNS neurons and glia actively regulate macrophage and lymphocyte responses, and microglia are immunocompetent but differ from other macrophage/dendritic cells in their ability to direct neuroprotective lymphocyte responses. This newer view of CNS immune privilege is opening the door for therapies designed to harness autoreactive lymphocyte responses and also implies (i) that CNS autoimmune diseases (i.e. multiple sclerosis) may result as much from neuronal and/or glial dysfunction as from immune system dysfunctions and (ii) that the severe neuronal and glial dysfunction associated with neurodegenerative disorders (i.e. Alzheimer's disease) likely alters CNS-specific regulation of lymphocyte responses affecting the utility of immune-based therapies (i.e. vaccines).

Animals↗

PubMed2005

Stealth proteins: in silico identification of a novel protein family rendering bacterial pathogens invisible to host immune defense.

There are a variety of bacterial defense strategies to survive in a hostile environment. Generation of extracellular polysaccharides has proved to be a simple but effective strategy against the host's innate immune system. A comparative genomics approach led us to identify a new protein family termed Stealth, most likely involved in the synthesis of extracellular polysaccharides. This protein family is characterized by a series of domains conserved across phylogeny from bacteria to eukaryotes. In bacteria, Stealth (previously characterized as SacB, XcbA, or WefC) is encoded by subsets of strains mainly colonizing multicellular organisms, with evidence for a protective effect against the host innate immune defense. More specifically, integrating all the available information about Stealth proteins in bacteria, we propose that Stealth is a D-hexose-1-phosphoryl transferase involved in the synthesis of polysaccharides. In the animal kingdom, Stealth is strongly conserved across evolution from social amoebas to simple and complex multicellular organisms, such as Dictyostelium discoideum, hydra, and human. Based on the occurrence of Stealth in most Eukaryotes and a subset of Prokaryotes together with its potential role in extracellular polysaccharide synthesis, we propose that metazoan Stealth functions to regulate the innate immune system. Moreover, there is good reason to speculate that the acquisition and spread of Stealth could be responsible for future epidemic outbreaks of infectious diseases caused by a large variety of eubacterial pathogens. Our in silico identification of a homologous protein in the human host will help to elucidate the causes of Stealth-dependent virulence. At a more basic level, the characterization of the molecular and cellular function of Stealth proteins may shed light on fundamental mechanisms of innate immune defense against microbial invasion.

Amino Acid Sequence↗

PubMed2004

The Eukaryotic Promoter Database EPD: the impact of in silico primer extension.

The Eukaryotic Promoter Database (EPD) is an annotated non-redundant collection of eukaryotic POL II promoters, experimentally defined by a transcription start site (TSS). There may be multiple promoter entries for a single gene. The underlying experimental evidence comes from journal articles and, starting from release 73, from 5' ESTs of full-length cDNA clones used for so-called in silico primer extension. Access to promoter sequences is provided by pointers to TSS positions in nucleotide sequence entries. The annotation part of an EPD entry includes a description of the type and source of the initiation site mapping data, links to other biological databases and bibliographic references. EPD is structured in a way that facilitates dynamic extraction of biologically meaningful promoter subsets for comparative sequence analysis. Web-based interfaces have been developed that enable the user to view EPD entries in different formats, to select and extract promoter sequences according to a variety of criteria and to navigate to related databases exploiting different cross-references. Tools for analysing sequence motifs around TSSs defined in EPD are provided by the signal search analysis server. EPD can be accessed at http://www.epd. isb-sib.ch.

Animals↗

PubMed2002

Role of immune cells in animal models for inherited neuropathies: facts and visions.

Mice heterozygously deficient in the peripheral myelin adhesion molecule P0 (P0+/- mice) are models for some forms of Charcot-Marie-Tooth (CMT) neuropathies. In addition to the characteristic hallmarks of demyelination, elevated numbers of CD8-positive T-lymphocytes and F4/80-positive macrophages are striking features in the nerves of these mice. These immune cells increase in number with age and progress of demyelination, suggesting that they might be functionally related to myelin damage. In order to investigate the pathogenetic role of lymphocytes, the myelin mutants were cross-bred with recombination activating gene 1 (RAG-1)-deficient mice, which lack mature T- and B-lymphocytes. The immunodeficient myelin mutants showed a less severe myelin degeneration. The beneficial effect of lymphocyte-deficiency was reversible, since demyelination worsened in immunodeficient myelin-mutants when reconstituted with bone marrow from wild-type mice. Ultrastructural analysis revealed macrophages in close apposition to myelin and demyelinated axons. We therefore cross-bred the P0+/- mice with spontaneous osteopetrotic (op) mutants deficient in the macrophage colony-stimulating factor (M-CSF), hence displaying impaired macrophage activation. In the corresponding double mutants the numbers of macrophages were not elevated in the peripheral nerves, and the demyelinating phenotype was less severe than in the genuine P0+/- mice, demonstrating that macrophages are also functionally involved in the pathogenesis of genetically mediated demyelination. We also examined other models for inherited neuropathies for a possible involvement of immune cells. We chose mice deficient in the gap junction component connexin 32, a model for the X-linked form of CMT. Similar to P0-deficient mice, T-lymphocytes and macrophages were elevated and macrophages showed a close apposition to degenerating myelin. We conclude that the involvement of T-lymphocytes and macrophages is a common pathogenetic feature in various forms of slowly progressive inherited neuropathies.

Animals↗

PubMed2002

Heterogeneous expression of the triggering receptor expressed on myeloid cells-2 on adult murine microglia.

Microglial activation is an early and common feature of almost all neuropathologies, including multiple sclerosis, Alzheimer's disease and mechanical injury. To better understand the relative contributions microglia make toward neurodegeneration and neuroprotection, we used TOGA(R) to identify molecules expressed by microglia and regulated by inflammatory signals. Triggering receptor expressed on myeloid cells-2 (TREM-2) was among the mRNAs identified as being expressed by unactivated microglia, but down-regulated by lipopolysaccharide/interferon gamma. In the healthy CNS, not all microglia expressed TREM-2. Microglial expression of TREM-2 varied not only between brain regions but also within each brain region. Brain regions with an incomplete blood-brain barrier had the lowest percentages of TREM-2- expressing microglia, whereas the lateral entorhinal and cingulate cortex had the highest percentages. A novel form of TREM-2b that lacked a transmembrane domain was detected, perhaps indicating a soluble form of the protein. Taken together, these data suggest that (1) subsets of microglia are specialized to respond to defined extracellular signals; and (2) regional variations in TREM-2 expression may contribute to the varying sensitivities of different brain regions to similar pathological signals.

Amino Acid Sequence↗