Biomedical subjects

Ulrike Gimsa

Publications and source records attributed to Ulrike Gimsa.

11 recordsLinked to original sources

PubMed2006

Tolerogenic effect of fiber tract injury: reduced EAE severity following entorhinal cortex lesion.

Despite transient, myelin-directed adaptive immune responses in regions of fiber tract degeneration, none of the current models of fiber tract injuries evokes disseminated demyelination, implying effective mechanisms maintaining or re-establishing immune tolerance. In fact, we have recently detected CD95L upregulation accompanied by apoptosis of leukocytes in zones of axonal degeneration induced by entorhinal cortex lesion (ECL), a model of layer-specific axonal degeneration. Moreover, infiltrating monocytes readily transformed into ramified microglia exhibiting a phenotype of immature (CD86+/CD80-) antigen-presenting cells. We now report the appearance of the axonal antigen neurofilament-light along with increased T cell apoptosis and enhanced expression of the pro-apoptotic gene Bad in cervical lymph nodes after ECL. In order to test the functional significance of such local and systemic depletory/regulatory mechanisms on subsequent immunity to central nervous system antigens, experimental autoimmune encephalomyelitis was induced by proteolipid protein immunization 30 days after ECL. In three independent experiments, we found significantly diminished disease scores and infiltrates in lesioned compared to sham-operated SJL mice. This is consistent with a previous meta-statistical analysis (Goodin et al. in Neurology 52:1737-1745, 1999) rejecting the O-hypothesis that brain trauma causes or exacerbates multiple sclerosis. Conversely, brain injuries may involve long-term tolerogenic effects towards brain antigens.

Animals↗

PubMed2006

3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitor Atorvastatin mediated effects depend on the activation status of target cells in PLP-EAE.

The effect of Atorvastatin on transcriptional activity in murine experimental autoimmune encephalomyelitis (EAE) induced by PLP peptide 139-151 was analyzed by DNA microarray technique in lymph nodes and spinal cord at onset (10 days), height (20 days) and first remission (30 days) of disease. Fourteen genes were selectively influenced by Atorvastatin in EAE mice. They are mainly related to immune cell functions and regulation of cell-to-cell interaction. Interestingly, seven genes were also differentially regulated in CFA-injected control mice. But qualitative and quantitative differences to EAE mice argue for a dependency of statin effects on the activation status of target cells. Differential regulation of the newly detected candidate genes of statin effects COX-1 and HSP-105 and the previously known statin-responsive genes ICAM-1 and CD86 was confirmed by Western blot and immunohistochemistry. Flow cytometric analysis of lymph node cells revealed that the effect of Atorvastatin treatment in non-immunized healthy animals resembled the effect of immunization with PLP peptide regarding changes of T helper cells, activated B cells and macrophages. In EAE mice, these effects were partially reversed by Atorvastatin treatment. Monitoring of expression of the newly identified candidate genes and patterns of lymphocyte subpopulations might predict the responsiveness of multiple sclerosis patients to statin treatment.

Animals↗

PubMed2006

Reproductive protein protects functionally sterile honey bee workers from oxidative stress.

Research on aging shows that regulatory pathways of fertility and senescence are closely interlinked. However, evolutionary theories on social species propose that lifelong care for offspring can shape the course of senescence beyond the restricted context of reproductive capability. These observations suggest that control circuits of aging are remodeled in social organisms with continuing care for offspring. Here, we studied a circuit of aging in the honey bee (Apis mellifera). The bee is characterized by the presence of a long-lived reproductive queen caste and a shorter-lived caste of female workers that are life-long alloparental care givers. We focus on the role of the conserved yolk precursor gene vitellogenin that, in Caenorhabditis elegans, shortens lifespan as a downstream element of the insulin/insulin-like growth factor signaling cascade. Vitellogenin protein is synthesized at high levels in honey bee queens and is abundant in long-lived workers. We establish that vitellogenin gene activity protects worker bees from oxidative stress. Our finding suggests that one mechanistic explanation for patterns of longevity in bees is that a reproductive regulatory pathway has been remodeled to extend life. This perspective is of considerable relevance to research on longevity regulation that builds largely on inference from solitary model species.

Age Factors↗

PubMed2005

CD25 regulatory T cells determine secondary but not primary remission in EAE: impact on long-term disease progression.

Multiple sclerosis (MS) is often characterized by several relapses and remissions during long-term disease, but neither the responsible cells nor the mechanisms are known to date. Using an animal model of multiple sclerosis, relapsing experimental autoimmune encephalomyelitis (R-EAE) CD4+CD25+ Treg cells expressing Foxp3 and CTLA-4 intracellularly and T lymphocytes expressing surface CTLA-4 were identified in the CNS. The first remission occurred even after depletion of Treg cells, but secondary remissions from EAE were ablated. Despite the unaltered first remission autoantigen rechallenge revealed already an amplified cytokine response during acute phase. These results indicate that the cellular composition during first attack of MS predicts long-term disease progression.

Animals↗

PubMed2005

Matching geometry and stimulation parameters of electrodes for deep brain stimulation experiments--numerical considerations.

Deep brain stimulation, the electric stimulation of basal ganglia nuclei, is a treatment for movement disorders such as Parkinson's disease. The underlying mechanisms are studied in animals, e.g. rodents. Designs and materials of commercially available microelectrodes, as well as experimentally applied driving signals vary tremendously. We used finite integration modeling to compare the electric field and current density distributions induced by various electrodes. Current density or field strength "hot spots", which are located particularly at sites of high curvature and material interfaces coincided with corrosion and erosion at poles and insulation, respectively, as shown by scanning electron microscopy of stainless steel electrodes. Cell constants, i.e. geometry factors relating the electrode impedance to the specific medium conductivity, were calculated to determine the electrode voltage for a given stimulation current. Nevertheless, for electrodes of the same cell constant but of different geometry, current and field distributions may be very dissimilar. We found geometry-dependent limiting values of the stimulation current, above which electric tissue damage may occur. These values limit the reach of the stimulation signal for a given electrode geometry. Also, electrode geometries determine the shape of the stimulated tissue volume. This study provides tools for choosing the most appropriate geometry for targeting different-sized brain areas.

Animals↗

PubMed2005

Choosing electrodes for deep brain stimulation experiments--electrochemical considerations.

Deep brain stimulation (DBS) is a therapy of movement disorders including Parkinson's disease (PD). Commercially available electrodes for animal models of Parkinson's disease vary in geometry and material. We characterized such electrodes and found a drift in their properties within minutes and up to about 60 h after immersion in cell culture medium, both with and without a stimulation signal. Electrode properties could largely be restored by proteolytic treatment for platinum/iridium electrodes but not for stainless steel ones. Short-term drift and irreversible aging could be followed by impedance measurements. Aging was accompanied by metal corrosion and erosion of the plastic insulation. For both materials, the degradation rates depended on the current density at the electrode surfaces. Fourier analysis of the DBS pulse (60 micros, repetition rate 130 Hz) revealed harmonic frequencies spanning a band of more than three decades, with significant harmonics up to the MHz range. The band is located in a window imposed by electrode processes and capacitive cell membrane bridging at the low and high frequency ends, respectively. Even though electrode processes are reduced at higher frequencies they only vanish above 1 MHz and cannot be avoided. Therefore, the use of inert electrode materials is of special importance. The neurotoxicity of iron makes avoiding stainless steel electrodes imperative. Future developments need to avoid the use of corrosive materials and current density hot spots at the electrode surface, and to reduce low frequency components in the DBS pulses in order to diminish electrode processes.

Brain↗

PubMed2005

Dopamine exerts no acute effects on Kv1.3 in activated encephalitogenic T cells.

Apart from a central function in the extrapyramidal motor system, dopamine has been suggested to play a role in neuroimmune interactions. Particularly in diseases of the central nervous system, such as multiple sclerosis, alterations in dopamine homeostasis might have immunological consequences. We investigated potential effects of dopamine stabilized by ascorbic acid on specifically activated encephalitogenic T cells at the peak of activation. Those cells exhibited an upregulation of voltage-sensitive K+ channels which play a role in many neurotransmitter responses of lymphocytes and fulfilled a prerequisite to respond to dopamine, i.e. stable expression of mRNA for dopamine receptors DRD1, DRD2 and DRD3. However, whole-cell and perforated whole-cell recordings revealed no change in voltage-sensitive K+ currents. Moreover, T cell proliferation was not changed in the presence of dopamine. Previously reported dopamine effects on T cells may be explained by a comparatively lower activation of the cells under investigation, suggesting an activation dependence of dopamine effects that may not be mediated by K+ channels. Alternatively, the occurrence of dopamine degradation products under unprotected conditions may account for the changes reported. Nevertheless, care should be taken when using the dopamine-protecting anti-oxidant ascorbic acid, since we found that it markedly inhibited both K+ currents and lymphocyte proliferation at higher concentrations.

Adenosine Triphosphate↗

PubMed2005

Representation of individual gene expression in completely pooled mRNA samples.

Designing microarray experiments, scientists are often confronted with the question of pooling due to financial constraints, but discussion of the validity of pooling tends toward a sub-pooling recommendation. Since complete pooling protocols can be considered part of sub-pooling designs, gene expression data from three complete pooling experiments were analyzed. Data from complete pooled versus individual mRNA samples of rat brain tissue were compared to answer the question whether the pooled sample represents individual samples in small-sized experiments. Our analytic approach provided clear results concerning the Affymetrix MAS 5.0 signal and detection call parameters. Despite a strong similarity of arrays within experimental groups, the individual signals were evidently not appropriately represented in the pooled sample, with slightly more than half of all the genes considered. Our analysis reveals problems in cases of small complete pooling designs with less than six subjects pooled.

Animals↗

PubMed2004

Astrocytes protect the CNS: antigen-specific T helper cell responses are inhibited by astrocyte-induced upregulation of CTLA-4 (CD152).

Astrocytes are the first cells that are encountered by T cells invading the central nervous system (CNS) by crossing the blood-brain barrier. We show that primary astrocytes contribute to the immune privilege of the CNS by suppressing Th1 and Th2 cell activation, proliferation and effector function. Moreover, this astrocyte-mediated inhibition of Th effector cells was effective on already activated, proliferating cells. Transforming growth factor (TGF)-beta secreted by astrocytes or T cells was not the major factor in the inhibition. The inhibition of T-cell proliferation induced by astrocytes was mainly mediated by upregulation of CTLA-4 on already activated T cells, which occurred both with and without cell-cell contact. Upregulation of the inhibitory molecule CTLA-4 on autoreactive Th cells, as mediated by astrocytes, thus represents a novel mechanism for securing the immune privilege of the CNS.

Antigens, CD↗

PubMed2004

Production of neuroprotective NGF in astrocyte-T helper cell cocultures is upregulated following antigen recognition.

Astrocytic production of nerve growth factor (NGF) is increased during inflammation of the central nervous system (CNS). Here we show that cell-cell interaction between primary murine astrocytes and myelin basic protein (MBP)-specific T cell receptor (TCR) transgenic Th1 and Th2 cells significantly increased production of NGF. This upregulation was found to be dependent on antigen recognition. Neutralization of cytokines produced in cocultures did not affect NGF production. This novel finding suggests a neuroprotective role of astrocytes during T cell-mediated inflammation in the CNS.

Animals↗

PubMed2002

Astrocyte-induced T cell elimination is CD95 ligand dependent.

The brain has an intrinsic capacity to remove infiltrating T cells by inducing apoptosis. However, the pathways and cellular components driving this process are still under debate. Astrocytes seem to play an important role because they colocalize with apoptotic lymphocytes in vivo and induce apoptosis of transformed T cells in vitro. Since we previously demonstrated the expression of the death ligand CD95L (APO-1L/FasL) on astrocytes in the brain, we wanted to know whether nontransformed astrocytes induce cell death in nontransformed T cells, reflecting the in vivo situation and, if so, whether CD95/CD95 ligand interaction is important. T cell apoptosis measured by Annexin V binding and DNA fragmentation was significantly lower using CD95 ligand-deficient (gld) astrocytes compared to nondeficient controls. Moreover, neutralizing anti-CD95 ligand antibody reduced astrocyte-induced T cell apoptosis. Thus, adult astrocytes are capable of inducing the apoptotic death of T cells by involving the CD95/CD95 ligand pathway without undergoing cell death in vitro. Since astrocytic end-feet contribute to the formation of the blood-brain barrier, this depletion mechanism may play an important role as the first line of defense in the brain.

Animals↗