myelin-basic-protein and Necrosis

Understanding of the pathogenesis of neuromyelitis optica (NMO) is rapidly growing. In our immunohistochemical studies from 2006, the loss of AQP4 was evident in about 90% of NMO lesions, especially in perivascular areas of acute inflammatory lesions where immunoglobulins and complements were deposited. Glial fibrillary acidic protein (GFAP) was also weak or lost in those lesions. In contrast, myelin basic protein (MBP)-stained myelinated fibers were relatively preserved in those lesions where AQP4 was completely lost. In contrast to NMO lesions, AQP4 and GFAP were preserved or increased in demyelinating MS lesions. The loss of AQP4 in acute inflammatory lesions was evident in the largest areas compared with GFAP or MBP, which probably suggested the primary loss of AQP4 on astrocytes and the secondarily demyelination. In contrast, the immunostaining patterns in more chronic lesions of NMO mostly lacked AQP4 but were necrotic heterogeneously with demyelination and gliosis, or completely burn-out. Swelling and regressive changes of astrocytes were easily evident. In addition, the lesions lacking AQP4 was appeared by passive-transferred Lewis rats with human purified IgG from NMO patients. Accordingly, these evidences strongly suggest its humoral autoimmune astrocytopathy in the pathomechanism of NMO.

Topics: Animals; Aquaporin 4; Astrocytes; Autoantibodies; Glial Fibrillary Acidic Protein; Humans; Myelin Basic Protein; Necrosis; Neuromyelitis Optica; Rats; Spinal Cord

Japanese encephalitis (JE) virus is the most common cause of epidemic viral encephalitis in the world. The virus mainly infects neuronal cells and causes an inflammatory response after invasion of the parenchyma of the brain. The death of neurons is frequently observed, in which demyelinated axons are commonly seen. The mechanism that accounts for the occurrence of demyelination is ambiguous thus far. With a mouse model, the present study showed that myelin-specific antibodies appeared in sera, particularly in those mice with evident symptoms. Meanwhile, specific T cells proliferating in response to stimulation by myelin basic protein (MBP) was also shown in these mice. Taken together, our results suggest that autoimmunity may play an important role in the destruction of components, e.g., MBP, of axon-surrounding myelin, resulting in demyelination in the mouse brain after infection with the JE virus.

Topics: Animals; Antibodies, Viral; Apoptosis; Brain; Demyelinating Autoimmune Diseases, CNS; Encephalitis Virus, Japanese; Encephalitis, Japanese; Female; Mice; Mice, Inbred ICR; Models, Animal; Myelin Basic Protein; Necrosis; T-Lymphocytes

By using an in vitro model of antibody-mediated demyelination, we investigated the relationship between tumor necrosis factor-alpha (TNF-alpha) and heat shock protein (HSP) induction with respect to oligodendrocyte survival. Differentiated aggregate cultures of rat telencephalon were subjected to demyelination by exposure to antibodies against myelin oligodendrocyte glycoprotein (MOG) and complement. Cultures were analyzed 48 hr after exposure. Myelin basic protein (MBP) expression was greatly decreased, but no evidence was found for either necrosis or apoptosis. TNF-alpha was significantly up-regulated. It was localized predominantly in neurons and to a lesser extent in astrocytes and oligodendrocytes, and it was not detectable in microglial cells. Among the different HSPs examined, HSP32 and alphaB-crystallin were up-regulated; they may confer protection from oxidative stress and from apoptotic death, respectively. These results suggest that TNF-alpha, often regarded as a promoter of oligodendroglial death, could alternatively mediate a protective pathway through alphaB-crystallin up-regulation.

Topics: 2',3'-Cyclic-Nucleotide Phosphodiesterases; Animals; Antibodies; Apoptosis; Blotting, Western; Cells, Cultured; Complement System Proteins; Crystallins; Demyelinating Diseases; Disease Models, Animal; Drug Interactions; Embryo, Mammalian; Glial Fibrillary Acidic Protein; Heme Oxygenase (Decyclizing); Heme Oxygenase-1; Immunohistochemistry; In Situ Hybridization; Myelin Basic Protein; Myelin Proteins; Myelin-Associated Glycoprotein; Myelin-Oligodendrocyte Glycoprotein; Necrosis; Neurons; Oligodendroglia; Rats; Telencephalon; Tumor Necrosis Factor-alpha; Up-Regulation

Caspase-8 is a member of the family of caspases, which are involved in the execution of apoptosis. To investigate whether caspase-8 can be used for gene therapy of gliomas, we transduced A-172 and U251 glioma cells with the caspase-8 gene via an adenoviral vector (Adv) controlled by the chicken beta-actin (CA) promoter (Advcaspase-8), and found that a similar level of caspase-8 protein induced A-172 cells to undergo necrotic cell death and U251 cells to undergo apoptotic cell death. Neither Bcl-XL nor Bcl-2, which play important roles in antiapoptotic mechanisms in gliomas, protected glioma cells from apoptosis induced by overexpression of caspase-8. Injection of Adv-caspase-8 suppressed the in vivo growth of U251 xenografts, in which apoptotic cell death remarkably increased as revealed by TUNEL analysis. Finally, we assessed whether gene therapy with a tissue-specific promoter, the myelin basic protein (MBP) promoter, is applicable to gliomas. Adv for caspase-8 controlled by the MBP promoter induced drastic apoptosis in U251 and U-373MG glioma cells, whereas it did not induce apoptosis in human endothelial cells, fibroblasts, and nerve growth factor-treated PC12 cells. These results indicate that Adv for caspase-8 effectively induced cell death in gliomas, and that this approach may be a useful modality for gene therapy of gliomas.

Topics: Actins; Adenoviridae; Animals; Apoptosis; Brain Neoplasms; Caspase 8; Caspase 9; Caspases; Cell Separation; Diploidy; DNA Fragmentation; Endothelium; Fibroblasts; Flow Cytometry; Genetic Therapy; Genetic Vectors; Glioma; Humans; In Situ Nick-End Labeling; Mice; Mice, Inbred BALB C; Mice, Nude; Microscopy, Electron; Myelin Basic Protein; Necrosis; Neoplasm Transplantation; Neoplasms, Experimental; Nerve Growth Factor; PC12 Cells; Promoter Regions, Genetic; Rats; Transduction, Genetic

We report an autopsied case of paraneoplastic necrotizing myelopathy. The patient had bilateral blindness, quadriplegia, and dyspnea of acute onset and died without remission 7 weeks later. The severe tissue necrosis and demyelination were found in the optic chiasm and from the medulla oblongata throughout the whole length of spinal cord. A papillary carcinoma was found in the thyroid gland at autopsy. In the present case IgG, myelin basic protein and activated helper T cells were increased in the CSF at onset, suggesting a mechanism of autoimmune demyelination for the condition.

Topics: Autoimmune Diseases; Autopsy; Carcinoma, Papillary; Demyelinating Diseases; Female; Humans; Immunoglobulin G; Medulla Oblongata; Middle Aged; Myelin Basic Protein; Necrosis; Optic Chiasm; Paraneoplastic Syndromes; Spinal Cord; Thyroid Neoplasms

The cytotoxic effects of CD4+ P2-specific T-cell lines on Schwann cells were examined in vitro with 51Cr-release cytotoxicity assays. Only those P2-specific T-cell lines capable of inducing EAN when injected back into adult Lewis rats were cytotoxic to the Schwann cells. The addition of exogenous P2 protein was not necessary for the cytotoxic effect. The monoclonal antibody (mAb) OX6 directed against Major histocompatibility complex (MHC) class II molecules blocked cytotoxicity, indicating an essential role for MHC class II molecules in this interaction between CD4+ T-cell lines and Schwann cells.

Topics: Animals; Antibodies; CD4 Antigens; Cell Communication; Cell Division; Cell Line; Cytotoxicity Tests, Immunologic; Histocompatibility Antigens Class II; Myelin Basic Protein; Myelin P2 Protein; Necrosis; Neuritis, Autoimmune, Experimental; Rats; Schwann Cells; T-Lymphocytes; T-Lymphocytes, Cytotoxic

Single-fraction, closed skull, small-volume irradiation (radiosurgery) of intact intracranial structures requires accurate knowledge of radiation tolerance. We have developed a baboon model to assess the in vivo destructive radiobiological effects of stereotactic radiosurgery. Three baboons received a single-fraction, 150-Gy lesion of the caudate nucleus, the thalamus, or the pons using the 8-mm diameter collimator of the gamma unit. Serial standard neurodiagnostic tests (neurological examination, computed tomographic scan, magnetic resonance imaging, stable xenon-enhanced computed tomographic scan of cerebral blood flow, somatosensory and brain stem evoked potentials, and myelin basic protein levels of cerebrospinal fluid) were compared with preoperative studies. Magnetic resonance imaging revealed the development of a lesion at the target site between 45 and 60 days after irradiation. Deterioration of the brain stem evoked potentials preceded imaging changes when the lesion encroached on auditory pathways. Myelin basic protein levels increased subsequent to imaging changes. Postmortem neuropathological examination confirmed a well-demarcated radionecrosis of the target volume. The baboon model appears to be an excellent method to study the in vivo biological effects of radiosurgery.

Topics: Animals; Caudate Nucleus; Cobalt Radioisotopes; Cranial Irradiation; Evoked Potentials; Hemiplegia; Magnetic Resonance Imaging; Male; Myelin Basic Protein; Necrosis; Papio; Pons; Radiation Injuries, Experimental; Radioisotope Teletherapy; Stereotaxic Techniques; Thalamus; Tomography, X-Ray Computed

Focal white matter necrosis is frequently seen in the brains of infants with perinatal cerebral hypoperfusion. Periventricular leukomalacia (PL) occurs in the deep white matter of premature and term neonates and subcortical leukomalacia (SL) in the subcortical white matter of young infants. Using immunoperoxidase methods in normal infants, glia positive for glial fibrillary acidic protein (GFAP) were found first in the deep zones of white matter and with increasing age they became more prominent in the subcortical zone. They increased diffusely in the deep or subcortical zones of the cases of PL or SL, respectively. The number of myelin basic protein-positive glia is much larger than that of GFAP-positive glia in the cases of old PL. These findings suggest that an increased number of positive glia may be a reaction to hypoxic, ischemic, or toxic insults, or this shifting, transient increase of positive glia in cerebral white matter may be one of several predisposing factors leading to perinatal leukomalacia. Furthermore, positive staining of GFAP and MBP for reactive astrocytes in old PL suggests that at a certain stage of gliogenesis both GFAP and myelin basic protein may be present within the same cell.

Topics: Bronchopulmonary Dysplasia; Cerebral Cortex; Cerebral Ventricles; Child Development; Child, Preschool; Encephalomalacia; Glial Fibrillary Acidic Protein; Humans; Immunoenzyme Techniques; Infant; Infant, Newborn; Myelin Basic Protein; Necrosis; Neuroglia; Risk; Telencephalon

Cerebrospinal fluid was examined from 70 children with acute lymphoblastic leukemia for evidence of active myelin breakdown based on the release of myelin basic protein (MBP). Fifty-three asymptomatic children were followed from diagnosis with serial MBP determinations. Eight (15.1%) of 53 children had abnormal elevations of MBP, six of eight before receiving presymptomatic central nervous system therapy. Long-term observations are in progress. For comparison, six children with clinical and radiologic findings of leukoencephalopathy had abnormal MBP determinations, whereas no abnormalities were detected in 11 children with meningeal leukemia.

Topics: Adolescent; Central Nervous System Diseases; Child; Child, Preschool; Humans; Leukemia, Lymphoid; Meningeal Neoplasms; Myelin Basic Protein; Necrosis; Prospective Studies

Topics: Adjuvants, Immunologic; Animals; Antigens; Binding Sites, Antibody; Cattle; Central Nervous System; Encephalomyelitis, Autoimmune, Experimental; Female; Fluorescent Antibody Technique; Freund's Adjuvant; Guinea Pigs; Haplorhini; Macaca; Male; Mycobacterium tuberculosis; Myelin Basic Protein; Necrosis; Papio

Topics: Animals; Brain; Brain Stem; Cerebral Cortex; Demyelinating Diseases; Disease Models, Animal; Electrophoresis, Polyacrylamide Gel; Encephalomyelitis, Autoimmune, Experimental; Haplorhini; Macaca; Multiple Sclerosis; Myelin Basic Protein; Necrosis; Nerve Tissue Proteins; Peptide Hydrolases