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      Expression of Neutral Glycosphingolipids in the Brain, Lymphoid Organs and Lungs of Mice Lacking β 2-Microglobulin

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          Abstract

          Objectives and Methods:Previous studies have demonstrated the involvement of glycosphingolipid (GSL) antigens in the pathogenesis of immune-mediated neurological disorders such as peripheral neuropathies and multiple sclerosis, as well as in infections of the central nervous system. We investigated the expression of neutral GSLs in the brain, thymus, spleen, and lungs of mice lacking the gene for the β<sub>2</sub>-microglobulin (β<sub>2</sub>M), an important component of the MHC class I molecule. Determination of GSL fractions in the tissues of mice homozygous (β<sub>2</sub>M–/–) or heterozygous (β<sub>2</sub>M+/–) for β<sub>2</sub>M gene knockout was performed by high performance thin layer chromatography, followed by immunostaining with specific antibodies. Results: Immunochemical analyses revealed abundant expression of globotetraosylceramide (Gb4), in the brain of β<sub>2</sub>M–/– mice, compared with undetectable expression in the control β<sub>2</sub>M+/– mice. The brain of both groups of animals was negative for Gg3, Gg4 and Gb3 immunostaining. Abundant expression of Gg3, Gg4, and Gb3 was found in the lungs of control β<sub>2</sub>M+/– mice, whereas β<sub>2</sub>M–/– mice lacked these structures. Immunostaining of Gb4 in the lungs was similar in both groups of animals. The thymus and spleen neutral GSL profiles did not significantly differ between β<sub>2</sub>M–/– and control animals. Conclusion: This study provides in vivoevidence that globo- and ganglio-series neutral GSL expression in the brain and lungs may be related to the presence of β<sub>2</sub>M or functional MHC class I molecule, and implicates different modulation of biosynthesis of globo- and ganglio-series neutral GSLs in these tissues.

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          Most cited references 13

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          Functional Requirement for Class I MHC in CNS Development and Plasticity

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            Lack of HLA-class I antigens in human neuroblastoma cells: analysis of its relationship to TAP and tapasin expression.

            We studied the constitutive and the interferon (IFN)-gamma-induced expression of HLA class I antigen heavy chain, beta2-microglobulin (beta2m), TAP-1, TAP-2 and tapasin in a panel of eleven neuroblastoma cell lines. Surface expression of HLA class I antigens was low in eight out of eight neuroblastoma cell lines bearing MYC-N amplification and/or 1p deletion, while two out of three neuroblastoma cell lines lacking these genetic alterations showed normal expression. IFN-gamma treatment restored HLA class I antigen surface expression in all neuroblastoma cell lines. Eight out of 11 neuroblastoma cell lines did not express TAP-1 mRNA and three of them also lacked TAP-2 mRNA. beta2 m mRNA was barely detectable or absent in five neuroblastoma cell lines, while tapasin mRNA was always expressed. IFN-gamma upregulated the expression of HLA class I heavy chain, beta2 m, TAP-1, TAP-2 and tapasin, as detected at mRNA or protein level. Post-transcriptional events were involved in altered TAP-1 and beta2 m expression in one peculiar neuroblastoma cell line. These data indicate that multiple mechanisms play a role in the HLA class I antigen-deficient phenotype of human neuroblastoma.
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              Cellular Reservoirs for Coronavirus Infection of the Brain in β 2 -Microglobulin Knockout Mice

              Mouse hepatitis virus (MHV) A59 infection which causes acute encephalitis, hepatitis, and chronic demyelination, is one of the experimental models for multiple sclerosis. Previous studies showed that lethal infection of β2-microglobulin ‘knockout’ (β2M(-/-)) mice required 500-fold less virus and viral clearance was delayed as compared to infection of immunocompetent C57Bl/6 (B6) mice. To investigate the mechanism of the increased susceptibility of β2M(-/-) mice to MHV-A59, we studied organ pathology and the distribution of viral antigen and RNA during acute and chronic infection. A59-infected β2M(-/-) mice were more susceptible to acute encephalitis and hepatitis, but did not have increased susceptibility to demyelination. Viral antigen and RNA distribution in the brain was increased in microglia, lymphocytes, and small vessel endothelial cells while the distribution in neurons and glia was similar in β2M(-/-) mice and B6 mice. Acute hepatitis and thymus cortical hypoplasia in β2M(-/-) mice were delayed in onset but pathologic changes in these organs were similar to those in B6 mice. The low rate of demyelination in β2M(-/-) mice was consistent with the low dose of the virus given. A less neurotropic virus MHV-2, caused increased parenchymal inflammation in β2M(-/-) mice, but without demyelination. Thus, CD8+ cells were important for viral clearance from endothelial cells, microglia and inflammatory cells, but not from neuronal and glial cells. In addition, CD8+ cells played a role in preventing the spread of encephalitis.
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                Author and article information

                Journal
                NIM
                Neuroimmunomodulation
                10.1159/issn.1021-7401
                Neuroimmunomodulation
                S. Karger AG
                1021-7401
                1423-0216
                2005
                September 2005
                21 September 2005
                : 12
                : 5
                : 310-313
                Affiliations
                Departments of aBiochemistry, Split University School of Medicine, Split, and bAnatomy, Zagreb University School of Medicine, Zagreb, Croatia; cInstitute for Medical Physics and Biophysics, University of Münster, Münster, Germany
                Article
                87110 Neuroimmunomodulation 2005;12:310–313
                10.1159/000087110
                16166811
                © 2005 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 1, Tables: 1, References: 17, Pages: 4
                Categories
                Original Paper

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