Biomedical subjects

T Derfuss

Publications and source records attributed to T Derfuss.

8 recordsLinked to original sources

PubMed2005

Immunoadsorption patients with multiple sclerosis: an open-label pilot study.

BACKGROUND: Immunoadsorption (IA) is occasionally applied in patients with acute relapses of multiple sclerosis (MS). This pilot study was undertaken to determine whether IA might help in secondary progressive and relapsing-remitting multiple sclerosis. DESIGN: IA was performed at 1-week intervals in 12 patients with secondary progressive or relapsing-remitting MS. These patients had an extended disability status scale (EDSS) score of 4.5-7 and an EDSS increase of 0.5 within 6 months before inclusion in the study despite conventional drug therapy. The change in the EDSS and that in the MS functional composite (MSFC) score, which consisted of quantitative tests of arm function, ambulation, visual acuity and cognition, served as the primary outcome variables, which were measured at baseline and at 3, 6 and 12 months. Changes in quality of life and cerebral lesions by magnetic resonance imaging (MRI) were also assessed at baseline and after the last immunoadsorption (month 3). RESULTS: A significant reduction of the median EDSS change was observed after the treatment period, which reversed 3 months after the immunoadsorptions had been stopped. Ten of 12 patients remained stable during the first year of follow-up with no significant changes of the MSFC scores. No significant changes in magnetic resonance imaging T2-hyperintense brain lesions or in the number of gadolinium-positive lesions and in the patients' quality of life were observed. Western blot analyses demonstrated a reduction of serum myelin-specific antibodies, which were collected in the adsorber eluates. CONCLUSIONS: Removal of immunoglobulins, including myelin-specific antibodies by immunoadsorption, seems to delay disease progression as defined by EDSS, MSFC and MRI, while the patients' quality of life did not deteriorate.

Adult↗

PubMed2002

Herpesviral proteins regulating apoptosis.

The induction of apoptosis of virus-infected cells is an important defense mechanism of the host. Apoptosis of an infected cell can be induced cell autonomously as a consequence of viral replication or can be mediated by CTLs attacking the infected cells. Herpesviruses have developed different strategies to interfere with cell-autonomous apoptosis and to block CTL-induced apoptosis mediated by death receptors such as Fas and TRAIL. Herpesviruses, which establish a lifelong persistence in the infected host, can be found principally in two different conditions, episomal persistence with a limited number of genes expressed and lytic replication with expression of almost all genes. To meet the need of the virus to enhance survival of the infected cell, herpesviruses have evolved different strategies that function during both episomal persistence and lytic replication. Herpesviruses, which encode 70 to more than 200 genes have incorporated cell homologous antiapoptotic genes, they code for multifunctional genes that can also regulate apoptosis, and, finally, they modulate the expression of cellular apoptosis-regulating genes to favor survival of the infected cells. Viral interference with host cell apoptosis enhances viral replication, facilitates virus spread and persistence, and may promote the development of virus-induced cancer.

Animals↗

PubMed2001

Herpesvirus saimiri replaces ZAP-70 for CD3- and CD2-mediated T cell activation.

The protein tyrosine kinase ZAP-70 plays a pivotal role involved in signal transduction through the T cell receptor and CD2. Defects in ZAP-70 result in severe combined immunodeficiency. We report that Herpesvirus saimiri, which does not code for a ZAP-70 homologue, can replace this tyrosine kinase. H. saimiri is an oncogenic virus that transforms human T cells to stable growth based on mutual CD2-mediated activation. Although CD2-mediated proliferation of ZAP-70-deficient uninfected T cells was absent, we could establish H. saimiri-transformed T cell lines from two unrelated patients presenting with ZAP-70 deficiencies. In these cell lines, CD2 and CD3 activation were restored in terms of [Ca(2+)](i), MAPK activation, cytokine production, and proliferation. Activation-induced tyrosine phosphorylation of zeta remained defective. The transformed cells expressed very high levels of the ZAP-70-related kinase Syk. This increased expression was not observed in the primary T cells from the patients and was not due to the transformation by the virus because transformed cell lines established from control T cells did not present this particularity. In conclusion, wild type H. saimiri can restore CD2- and CD3-mediated activation in signaling-deficient human T cells. It extends our understanding of interactions between the oncogenic H. saimiri and the infected host cells.

Autocrine Communication↗

PubMed2001

Signaling lymphocytic activation molecule (SLAM) regulates T cellular cytotoxicity.

Signaling lymphocytic activation molecule (SLAM) is a CD2-related surface receptor expressed by activated T cells and B cells. SLAM is a self ligand and enhances T cellular proliferation and IFN-gamma production. A defective SLAM associated protein (SAP) causes X-linked lymphoproliferative syndrome (XLP), a frequently lethal mononucleosis based on the inability to control EBV. We report that SLAM augments TCR-mediated cytotoxicity. In normal CD4(+) and CD8(+) T cells, SLAM enhanced TCR-mediated cytotoxicity. In CD4(+) and CD8(+) Herpesvirus saimiri (H.saimiri) infected T cells, SLAM engagement alone triggered cytotoxicity. Using H.saimiri-transformed T cells as a model system we found that SLAM-engagement promotes the release of lytic granules and a CD95-independent killing that requires extracellular Ca(2+), cytoskeletal rearrangements, and signaling mediated by mitogen-activated protein kinase kinases MEK1/2. SLAM-enhanced cytotoxicity implies an immunoregulatory function by facilitating the elimination of APC and a role in overcoming infections with pathogens requiring a cytotoxic immune response.

Antigens, CD↗

PubMed2001

[Multiple sclerosis. Chlamydia hypothesis in debate].

Recently, an association between multiple sclerosis and Chlamydia pneumoniae infection has been suggested. Because standardized PCR protocols are lacking, a series of studies could not clarify whether C. pneumoniae is present in brain tissue and CSF of MS patients. Therefore, other studies focused on the humoral immune response against C. pneumoniae: 24% of MS patients, but only 5% of the control patients showed intrathecally produced antibodies against C. pneumoniae. If an infection with C. pneumoniae was involved in the pathogenesis of MS, one would expect that, in analogy to other infections of the CNS, the oligoclonal bands in the CSF of MS patients would recognize the responsible agent. However, the results we obtained by affinity-mediated immunoblots showed that the oligoclonal bands in the CSF of MS patients are not directed against Chlamydia antigen. In contrast to this, we found that the immunoglobulins in the CSF of neuroborreliosis patients reacted strongly against Borrelia antigen in the affinity-mediated immunoblots. In light of these results we assume that the intrathecal immunoglobulin production against C. pneumoniae is part of a polyspecific immune response. Thus, it is not likely that C. pneumoniae is causally linked to the pathogenesis of multiple sclerosis.

Antigens, Bacterial↗

PubMed2001

Intrathecal antibody production against Chlamydia pneumoniae in multiple sclerosis is part of a polyspecific immune response.

Chronic intrathecal immunoglobulin (Ig) production is a hallmark of multiple sclerosis characterized by the presence of oligoclonal IgGs and, in addition, polyspecific recognition of different pathogens such as measles, rubella and herpes zoster virus. While the antigen specificity of the oligoclonal IgGs in multiple sclerosis is largely unknown, the oligoclonal IgGs arising during CNS infectious diseases are reactive against the specific pathogen. Recently, a link between Chlamydia pneumoniae and multiple sclerosis has been claimed. To test the possible role of C. pneumoniae in multiple sclerosis, we analysed (i) whether there is intrathecal IgG production against C. pneumoniae in multiple sclerosis and (ii) if the oligoclonal IgGs in the CSF of multiple sclerosis patients recognize C. pneumoniae. By studying paired serum-CSF samples from 120 subjects (definite multiple sclerosis, 46; probable multiple sclerosis, 12; other inflammatory neurological diseases, 35; other neurological diseases, 27) by enzyme-linked immunosorbent assay, we found that 24% of all patients with definite multiple sclerosis, but only 5% of patients with other inflammatory or non-inflammatory diseases, produced IgGs specific for C. pneumoniae intrathecally (definite multiple sclerosis versus other inflammatory neurological diseases: P = 0.027). The presence of intrathecal IgGs to C. pneumoniae was independent of the duration of disease and relatively stable over time. The major CSF oligoclonal IgG bands from multiple sclerosis patients with an intrathecal Ig production to C. pneumoniae did not react towards purified elementary bodies and reticulate bodies of C. pneumoniae on affinity-mediated immunoblot following isoelectric focusing (IEF-western blots). In contrast, the IgGs in the CSF of control patients with neuroborreliosis strongly reacted with their specific pathogen, Borrelia burgdorferi, by IEF-western blot analysis. Concomitant analysis of the CSF of 23 patients with a nested polymerase chain reaction for C. pneumoniae was negative in all cases. Together, our findings strongly suggest that the immune response to C. pneumoniae is part of a polyspecific intrathecal Ig production, as is commonly observed with other pathogens. This argues against a specific role for C. pneumoniae in multiple sclerosis.

Animals↗

PubMed2001

Prevalence of HSV-1 LAT in human trigeminal, geniculate, and vestibular ganglia and its implication for cranial nerve syndromes.

Herpes simplex virus type 1 (HSV-1) enters sensory neurons and can remain latent there until reactivation. During latency restricted HSV-1 gene expression takes place in the form of latency-associated transcripts (LAT). LAT has been demonstrated to be important not only for latency but also for reactivation, which may cause cranial nerve disorders. Tissue sections of the trigeminal ganglia (TG), geniculate ganglia (GG), and the vestibular ganglia (VG) from seven subjects were examined for the presence of LAT using the in situ hybridization technique. LAT was found on both sides in allTG (100%), on both sides of five subjects (70%) in the GG, and in none of the VG. Using a second more sensitive detection method (RT-PCR), we found LAT in the VG of seven of ten other persons (70%). This is the first study to demonstrate viral latency in the VG, a finding that supports the hypothesis that vestibular neuritis is caused by HSV-1 reactivation. The distribution of LAT in the cranial nerve ganglia indicates that primary infection occurs in the TG and GG and subsequently spreads along the faciovestibular anastomosis to the VG.

Adult↗

PubMed1998

Antiapoptotic activity of the herpesvirus saimiri-encoded Bcl-2 homolog: stabilization of mitochondria and inhibition of caspase-3-like activity.

Viruses have evolved different strategies to interfere with host cell apoptosis. Herpesvirus saimiri (HVS) and other lymphotropic herpesviruses code for proteins that are homologous to the cellular antiapoptotic Bcl-2. In this study HVS-Bcl-2 was stably expressed in the human leukemia cell line Jurkat and in the murine T-cell hybridoma DO to assess its antiapoptotic spectrum and to gain further insight into its mode of action. HVS- Bcl-2 prevented apoptosis that occurs as a result of a disturbance of intracellular homeostasis by, for example, DNA damage or menadione, which gives rise to oxygen radicals. In Jurkat cells, HVS-Bcl-2 also inhibited apoptosis mediated by the death receptor CD95. In DO cells, HVS-Bcl-2 did not interfere with CD95-mediated apoptosis but blocked dexamethasone-induced cell death. Mitochondrial damage is a central coordinating event in apoptosis induced by different stimuli. To assess the integrity of mitochondria, we used rhodamine 123, which is released upon disturbance of the mitochondrial membrane potential, and determined the release of cytochrome c into the cytosol. Both signs of mitochondrial damage were prevented by HVS-Bcl-2. This viral protein also inhibited the generation of caspase-3-like DEVDase activity and blocked the cleavage of poly(ADP-ribose) polymerase, a natural substrate of caspase-3-like proteases. In conclusion, HVS-Bcl-2 protects against a great variety of apoptotic stimuli, stabilizes mitochondria, and acts upstream of the generation of caspase-3-like activity.

Apoptosis↗