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L Stitz

Publications and source records attributed to L Stitz.

At least 37 records · Page 2Linked to original sources
PubMed1996

[Immunopathology of Borna disease in the horse: clinical, virological and neuropathologic findings].

Tissues from nine horses and one donkey suffering from natural Borna disease were investigated. Clinically, all animals demonstrated progressive reduced mentation and aggravating gait disturbances. During the clinical course anorexia and progressive loss of proprioception were observed. Cranial nerve failure was accompanied by signs of pharyngeal paralysis, sialorrhea, bruxism, and by blindness. Virologically, infectious virus was detected in the brain of all animals investigated but was not found regularly in all areas of the brain. However, in all cases, infectivity was found in the thalamus and the hippocampal area. In contrast, in other compartments of the central nervous system virus was not detected regularly. These findings correlate well to the results obtained from assaying Borna virus-specific RNA by Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR) and virus specific antigen by immunohistochemistry. No evidence of infection was found in the autonomic nervous system and peripheral organs. Immunomorphologically, lymphocytic inflammatory reactions and increased expressions of MHC class I and class II antigen were found in the brain as well as in the trigeminal and olfactory system. No evidence of inflammation was found in the retina. From the finding that BDV-proteins and nucleic acids were even more abundant in the trigeminal system as compared to the olfactory system, we conclude that infection may have occurred via the trigeminal nerve.

Animals↗
PubMed1995

European swine virus as a possible source for the next influenza pandemic?

According to phylogenetic data, about 100 years ago an avian influenza virus passed the species barrier (possibly first) to pigs and (possibly from there) to humans. In 1979 an avian influenza A virus (as a whole, without reassortment) again entered the pig population in northern Europe, forming a stable lineage. Here it is shown that the early North European swine viruses exhibit higher than normal evolutionary rates and are highly variable with respect to plaque morphology and neutralizability by monoclonal antibodies. Our results are consistent with the idea that, in order to pass the species barrier, an influenza A virus needs a mutator mutation to provide an additional number of variants, from which the new host might select the best fitting ones. A mutator mutation could be of advantage under such stress conditions and might enable a virus to pass the species barrier as a whole even twice, as it seems to have happened about 100 years ago. This stressful situation should be over for the recent swine lineage, since the viruses seem to be adapted already to the new host in that the most recent isolates--at least in northern Germany--are genetically stable and seem to have lost the putative mutator mutation again.

Animals↗
PubMed1995

Presence of CD4+ and CD8+ T cells and expression of MHC class I and MHC class II antigen in horses with Borna disease virus-induced encephalitis.

Tissues from 9 horses and 1 donkey suffering from natural Borna disease were investigated immunomorphologically. Lymphocytic inflammatory reactions and increased expressions of MHC class I and class II antigen were found in the brain as well as in the trigeminal and olfactory system. Perivascular inflammatory infiltrates were dominated by CD4+ T cells, whereas the majority of CD8+ T cells were disseminated intraparenchymally. No evidence of inflammation was found in the retina. Borna disease virus proteins and nucleic acids were present in the hippocampus, thalamus and medulla oblongata in all 10 animals, in the cerebral cortex, retina, trigeminal ganglion and nerve in 9, in the olfactory epithelium in 6 and in roots and proximal parts of large peripheral nerves in 3. No evidence of infection was found in the autonomic nervous system, lung, heart, liver, kidney or gut. BDV- proteins and nucleic acids were even more abundant in the trigeminal system than in the olfactory system, suggesting that infection may have occurred via the trigeminal nerve.

Animals↗
PubMed1995

Neutralizing antibodies in Borna disease virus-infected rats.

Borna disease is a neurologic syndrome caused by infection with a nonsegmented, negative-strand RNA virus, Borna disease virus. Infected animals have antibodies to two soluble viral proteins, p40 and p23, and a membrane-associated viral glycoprotein, gp18. We examined the time course for the development of neutralization activity and the expression of antibodies to individual viral proteins in sera of infected rats. The appearance of neutralizing activity correlated with the development of immunoreactivity to gp18, but not p40 or p23. Monospecific and monoclonal antibodies to native gp18 and recombinant nonglycosylated gp18 were also found to have neutralizing activity and to immunoprecipitate viral particles or subparticles. These findings suggest that gp18 is likely to be present on the surface of the viral particles and is likely to contain epitopes important for virus neutralization.

Animals↗
PubMed1995

Immunopathogenic role of T-cell subsets in Borna disease virus-induced progressive encephalitis.

Borna disease is an immunopathological virus-induced encephalopathy comprising severe inflammation and degenerative brain cell lesions which results in organ atrophy and chronic debility in rats. CD4+ and CD8+ T cells have been reported to be involved in the development of this disease of the central nervous system. A virus-specific homogeneous T-cell line, established in vitro after immunization of rats with the recombinant 24-kDa virus-specific protein, showed antigen-specific proliferation in the presence of the 24-kDa but not the 38-kDa Borna disease virus-specific protein, another major virus-specific antigen. This T-cell line, P205, was found to exhibit characteristics of a T-helper cell: CD4+ CD8- IL-2- IL-4- IFN-gamma+ IL-6+ IL-10+. Furthermore, this T-cell line expressed the alpha/beta T-cell receptor and the alpha 4 integrin (VLA-4). Adoptive transfer of this helper cell resulted in an increase of antibody titers and two different types of disease in virus-infected rats after cyclophosphamide-induced immunosuppression. (i) Rats receiving T cells between 10 and 18 days after treatment with cyclophosphamide showed an acute lymphoproliferative disease in the gut and lungs within 9 days after adoptive transfer and died. (ii) Passive transfer within the first 5 days after immunosuppressive treatment resulted in typical Borna disease associated with neurological symptoms such as ataxia and paresis starting 14 to 16 days after transfer. Immunohistological analysis of the brains of rats with Borna disease uniformly revealed the presence of CD8+ T cells in encephalitic lesions in addition to CD4+ cells that were found in the brains of recipients of the virus-specific CD4+ T-cell line, irrespective of whether neurological symptoms developed or not. However, recipient rats treated with antibodies against CD8+ T cells developed neither encephalitis nor disease. Therefore, CD4+ T cells appear to accumulate in the brain and cause perivascular inflammatory lesions which alone obviously do not cause disease. In contrast, the presence of CD8+ cells apparently directly correlates with the development of neurological symptoms.

Animals↗
PubMed1994

Immune-mediated brain atrophy. CD8+ T cells contribute to tissue destruction during borna disease.

Borna disease (BD) is a virus-induced immunopathologic disease of the central nervous system in a variety of species from birds to primates and probably in humans. Severe inflammatory reactions lead to tissue destruction and finally to cortical brain atrophy. After experimental infection of the rat, intraparenchymal CD8+ T cells, MHC class I Ags on Borna disease virus (BDV)-infected neurons, and numerous nerve cell lesions were present. Treatment of BDV-infected rats with the mAb OX-8 directed against CD8+ cells inhibited the immunopathologic reactions and reduced MHC class I Ag expression. Neuronal lesions were minimal and no loss of brain substance could be observed. Because BDV has no acute cytopathic effects, we provide evidence that the presence of CD8+ T cells within the brain parenchyma and the expression of MHC class I Ags on neurons play a major role for immunopathologic brain tissue destruction and virus-infected neurons in vivo can be destroyed by T cell-mediated cytotoxicity.

Animals↗
PubMed1994

Borna disease in naturally infected cattle.

Based on the immunohistochemical demonstration of viral antigen and on the histological brain lesions, Borna disease was diagnosed in a cow and a bull which had suffered from a severe, subacute progressive disorder of the central nervous system. Virus-specific antigen was characteristically localized in neurons, predominantly in the perikaryon and dendrites. In a serum sample available from one of the animals a Borna disease virus antibody titre of 1 in 80 was demonstrated. This is the first report of the natural disease in cattle.

Animals↗
PubMed1994

Characterization of a Borna disease virus glycoprotein, gp18.

Borna disease virus is a nonsegmented negative-strand RNA virus that causes neurologic disease in a wide variety of animal hosts. Here we describe identification and characterization of the first glycoprotein in this viral system. The 18-kDa glycoprotein, gp18, has been purified from infected rat brain. Isolation and microsequencing of this protein allowed identification of a 16.2-kDa open reading frame in the viral antigenome. Lectin binding and endoglycosidase sensitivity assays indicate that gp18 is an unusual N-linked glycoprotein.

Amino Acid Sequence↗
PubMed1993

Lysis of major histocompatibility complex class I-bearing cells in Borna disease virus-induced degenerative encephalopathy.

CD8+ as well as CD4+ T cells and macrophages are of crucial importance for the pathogenesis of Borna disease in rats. This virus-induced immunopathological disease of the brain is characterized by neurological symptoms in the acute phase and chronic debility associated with severe loss of brain tissue in the late stage. We demonstrate here the cytotoxic activity of T lymphocytes in the brain of intracerebrally infected rats. T cells isolated from the brain of infected rats lyse major histocompatibility complex (MHC) class I-bearing target cells in the absence of MHC class II. Borna disease virus (BDV)-infected syngeneic skin cells and astrocytes, the latter one of the relevant target cells in vivo, were significantly lysed whereas infected allogeneic target cells were not. Most relevant to the in vivo situation, primary brain cell cultures propagated from the hippocampus of BDV-infected rats containing considerable numbers of neurons were lysed in vitro. Blocking experiments using antibodies directed against MHC class I antigen provided further evidence for the presence and activity of classical cytotoxic T lymphocytes. Antibodies against MHC class II antigen did not influence lysis of skin target cells but had an effect on lysis of astrocytes at late time points. Lymphocytes isolated from spleen, peripheral blood, or lymph nodes did not show cytotoxic activity. These results verify, on the cellular level, earlier findings that strongly suggest the involvement of CD8+ T cells in brain cell lesions, resulting in brain atrophy long after infection of rats with BDV. This is further evidenced by the presence of CD8+ T cells in direct proximity to neuronal cell lesions. Interestingly, the cytolytic capacity, demonstrated in vitro and strongly correlated to organ destruction, does not result in elimination of the virus but the virus persists in the central nervous system.

Animals↗
PubMed1993

Pathogenesis of Borna disease.

Borna disease represents a unique model of a virus-induced immunological disease of the brain. Naturally occurring in horses and sheep, the mechanisms of pathogenesis have been studied in experimental animals, namely in the rat. Many investigations have revealed that the infection of the natural hosts principally follows the same pathogenic pathways as observed in rats, leading to a severe encephalomyelitis. This affliction of the central nervous system results in severe neurological disorders that again, are fully comparable in laboratory animals to those in the natural and the different experimental hosts. In addition, alterations have been reported which are also based on the infection of the brain and do not result in the classical encephalitic clinical picture but rather in alterations of behavior. However, to all of our knowledge, the various clinical pictures of Borna disease are not caused by the infecting virus itself but rather by the hosts immune response towards it, i.e. by a virus-induced cell-mediated immunopathological reaction. The importance of virus-specific CD4+ T cells as exemplified by a cultured T cell line and of CD8+ T cells as shown by immunomodulatory substances and specific antibody treatment in vivo for the pathogenesis of acute Borna disease will be elucidated here. In addition, evidence will be provided that virus-specific CD8+ T cells are also responsible for the dramatic brain atrophy in the chronic phase of the disease in rats. Therefore, Borna disease not only lends itself exquisitely well to the study of the pathogenesis of an immunopathological disease of the brain but also represents one of the few models for immune-mediated tissue destruction that eventually leads to brain atrophy and clinically to dementia.

Animals↗
PubMed1993

Brain cell lesions in Borna disease are mediated by T cells.

Experimental Borna Disease (BD) in rats is characterized by severe lymphocytic encephalitis and by massive brain cell lesions finally leading to brain atrophy. Treatment of BDV-infected rats with monoclonal antibodies directed against CD4+ and CD8+ T cells could almost completely inhibit the immunopathological reactions and revealed less BDV-infected neurons and astrocytes that expressed MHC class I antigen. Brain cell lesions were minimal, and no obvious brain atrophy could be observed even late after infection. Since BDV itself is not known to exert cytopathic effects and since brain cell damage was independent of antibody titers, brain cell destruction correlates well with the intracerebral presence of CD8+ T cells and the expression of MHC class I antigens. Moreover, BDV-infected brain cells in vitro could be demonstrated to be lysed in a MHC class I-restricted manner. These findings provide evidence that virus-infected neurons can be destructed by T cell mediated cytotoxicity which results in organ atrophy and dementia.

Animals↗
PubMed1992

Induction of antigen-specific tolerance by cyclosporin A.

Recently, we reported preliminary evidence for the induction of tolerance in vivo by cyclosporin A (CSA) during a persistent virus infection in rats. In the present communication, those observations are verified and the findings extended to the functional level of cell-mediated immunity. Mice infected intracerebrally with lymphocytic choriomeningitis virus (LCMV) normally die from a fatal immune-mediated disease after 6-8 days but they do not succumb if treated intraperitoneally with 50 mg/kg/day of CSA. Immunosuppression initiated one day before infection and continued for at least two consecutive weeks resulted in the absence of immunopathologic disease of the brain and in the survival of mice, which were found to be persistently infected virus carriers. In these animals, no cytotoxic T cell activity could be detected. The effect of CSA was not due to a toxic effect on the immune response since immune reactivity was restored as early as 4 days after discontinuation of the drug in control animals. Neither secondary in vitro nor in vivo restimulation resulted in the generation of a cellular antiviral immune response. Cytotoxic T cell reactivity to third-party antigen, however, could be detected, although somewhat delayed. Additionally, spleen cells from CSA-treated mice did not clear the virus from LCMV-infected recipients upon adoptive transfer, whereas spleen cells from LCMV immune mice completely eliminated virus infection in carrier mice. However, mice immunosuppressed with CSA and infected with vesicular stomatitis virus (VSV) did not generate a primary immune response but were immunologically fully reactive to challenge infection, providing evidence for the absence of tolerance and the presence of antigen-specific temporal unresponsiveness. Thus, as exemplified by VSV infection in which the virus does not replicate to considerable titers in mice and viral antigens do not persist, the presence of the foreign antigen for prolonged periods of time could be shown to be a conditio sine qua non for CSA-induced tolerance.

Animals↗
PubMed1992

Borna disease virus-infected astrocytes function in vitro as antigen-presenting and target cells for virus-specific CD4-bearing lymphocytes.

Astrocytes isolated from the brain of newborn Lewis rats and an astrocytic cell line were susceptible to infection with the neurotropic Borna disease virus in vitro. Since astrocytes also have been found to be infected in vivo it seemed appropriate to test this cell type for interaction with a Borna disease virus-specific CD4+ T cell line. Borna disease virus-infected astrocytes were found to be capable of presenting virus-specific antigen to virus-specific T cells in vitro. However, the response was significantly enhanced if the purified 38/39kDa Borna disease virus-specific protein was added exogenously to the cultures. Beside the function as antigen-presenting cells for various antigens including virus-specific protein and myelin basic protein, persistently infected astrocytes were also found to act as target cells for a CD4+ T cell line as shown in conventional 51Cr release assays after induction of MHC class II expression by gamma interferon. Infection of astrocytes alone did not cause expression of this self antigen. It could be shown that the ability of CD4+ BDV-specific T cells to mediate lysis was in part dependent on the stage of activation. Lymphocytes "activated" before testing exerted high lysis after only 4h of coincubation with target cells, whereas "resting" T cells did not cause significant lysis until 12h of coincubation. The dependence of the interaction between effector and target cells on MHC class II antigen was demonstrated by the finding that antibodies to Ia antigens reduced lysis of target cells.

Animals↗
PubMed1992

Influence of treatment with mouse immunoglobulin on the rate of viable neonates in the CBA/J x DBA/2 J model.

In the CBA/J (H-2k) x DBA/2J (H-2d) murine model, the protective value of pooled murine immunoglobulin i.p. was compared with that of serum taken 7 days after termination of CBA/J (H-2k) x BALB/c (H-2d) pregnancy. A control group of CBA/J females received treatment with autologous virgin serum. CBA/J females at 7 weeks of age were injected 3 days before mating with DBA/2J males and 3 days after sighting of the vaginal plug. An effect of treatment can be shown following IgG therapy (P less than 0.05). The highest rate of viable fetuses was documented in the immunoglobulin-treated females, while the rate of viable offspring did not differ in the two serum-treated animal groups.

Animals↗
PubMed1992

Infection with Borna disease virus: molecular and immunobiological characterization of the agent.

Borna disease virus (BDV), which seems to be distinct from all other known viruses, exhibits a unique mechanism of pathogenesis. This review highlights several aspects of the biology of infection with this virus and summarizes the preliminary characterization of the agent. Studies on BDV may help to illuminate several important areas of neurobiology, including the mechanisms regulating the replication of a new type of RNA virus in the nuclei of neural cells, the neuroinvasiveness and neurotropism of such viruses, their T cell-mediated immunopathology, tolerance in newborn animals to persistent viral infection of the central nervous system, and behavioral diseases and eating disorders induced by such agents.

Animals↗
PubMed1992

The 24K protein of Borna disease virus.

Based on partial amino acid sequences obtained from tryptic peptides of the purified 24K antigen of Borna disease virus (BDV), we identified and sequenced four independent cDNA clones established from BDV-infected MDCK cells. Each of the clones encodes a polypeptide of 201 residues (Mr 22461) that differs considerably from an amino acid sequence published recently. In vitro transcription/translation of both the wild-type and a 5' truncated clone lacking the first ATG codon yielded a peptide that comigrates on electrophoresis with a polypeptide immunoprecipitated from BDV-infected cells. The deduced amino acid sequence contains a putative signal for nuclear targeting.

Amino Acid Sequence↗
PubMed1992

Antigenic relationship and further characterization of two major Borna disease virus-specific proteins.

After immunization of mice with isolated Borna disease virus (BDV)-specific proteins having Mrs of 38/39K and 24K, monoclonal antibodies (MAbs) were obtained which were specific for one of the antigens in Western blot analysis. However, in immunoprecipitation assays it was found that some MAbs of each specificity reacted exclusively with their respective antigen from BDV-infected cells, whereas other MAbs coprecipitated the heterologous protein. The relationship between the 38/39K and 24K proteins was demonstrated by two-dimensional peptide mapping, which revealed four identical peptides. Additionally, it was found that neither the 38/39K nor the 24K protein is glycosylated, but that the 24K protein is phosphorylated at serine residues. Experiments employing various cell separation protocols revealed that the 38/39K and the 24K proteins are evenly distributed within infected cells; this was confirmed by immunofluorescence techniques using 38/39K- or 24K-specific MAbs. Iodination experiments clearly demonstrated that only the 38/39K protein is expressed on the surface of virus-infected cells.

Antibodies, Monoclonal↗