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Multiple Sclerosis: Studies of the Interferon system and search for infectious agents

Bergkvist, My LU (2005)
Abstract
Multiple sclerosis (MS) is a chronic disease of the central nervous system, characterized by focal inflammatory lesions with demyelination and axonal loss. It is believed that MS is an immune-mediated disorder with both genetic and environmental contributions to the pathogenesis. Interferons (IFNs) are naturally occurring proteins known to have antiviral, antiproliferative and immunoregulatory effects. Treatment with IFN beta has a favourable effect in MS while IFN gamma was found to precipitate exacerbations. We have investigated whether polymorphisms in the IFN system influenced susceptibility to MS, but found no linkage between any of the investigated loci and MS. Approximately 70% of monozygotic twins are discordant for MS indicating... (More)
Multiple sclerosis (MS) is a chronic disease of the central nervous system, characterized by focal inflammatory lesions with demyelination and axonal loss. It is believed that MS is an immune-mediated disorder with both genetic and environmental contributions to the pathogenesis. Interferons (IFNs) are naturally occurring proteins known to have antiviral, antiproliferative and immunoregulatory effects. Treatment with IFN beta has a favourable effect in MS while IFN gamma was found to precipitate exacerbations. We have investigated whether polymorphisms in the IFN system influenced susceptibility to MS, but found no linkage between any of the investigated loci and MS. Approximately 70% of monozygotic twins are discordant for MS indicating that environmental factors contribute to the development of the disease. We investigated, in 3 pairs of monozygotic twins discordant for MS, serological differences that could be important for the development of MS. Two MS affected twins had serological evidence of a previous infection with Borrelia burgdorferi respective Toxoplasma gondii. In general the serum titers were strikingly similar in the twins, indicating no major disturbances of the humoral immune system in MS. Many types of viruses induce IFN production, but it is unclear whether IFN is produced in MS lesions. We searched for the expression of MxA, a cytoplasmic protein induced by IFNA/B, with the capability to inhibit the replication of several viruses. No anti-MxA staining was found in MS brain tissue indicating that MxA, and consequently IFNA/B, probably is not produced in these lesions. Oligoclonal bands (OCBs) are detected in the CSF in majority of patients with MS. They are believed to result from continuous immunization against unknown antigens. We investigated if antibodies in CSF from MS patients bound to structures in MS brain lesions and control brain tissue and found that brain lesions from secondary progressive MS patients contain a unique structure that binds IgG antibodies from the patients. Preincubation of brain sections with CSF from MS patients enhanced the IgG staining. Direct fluorescence labelled CSF antibodies from an MS patient showed similar binding pattern as with anti-IgG in MS lesions. No binding of fluorescence labelled antibodies was detected in control brain tissue. This indicates that the antigens/target structures are absent from normal brain. Double staining showed that the IgG was bound to the axons and was observed both in myelinated axons and in totally or partially demyelinated axons suggesting that the antibody binding may be an early event in myelin and axon destruction. (Less)
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author
supervisor
opponent
  • Professor Hillert, Jan, Neurotec department, Division of Neurology,Karolinska Institutet at Karolinska University Hospital,
organization
publishing date
type
Thesis
publication status
published
subject
keywords
neurophysiology, Neurologi, neuropsykologi, neurofysiologi, neuropsychology, Neurology, Axon and myelin damage, IgG, Virus, Interferon, Multiple Sclerosis, Genetic linkage
pages
100 pages
publisher
Department of Clinical Neuroscience, Lund University
defense location
Segerfalksalen Wallenberg Neurocentrum Lund
defense date
2005-06-03 13:00:00
ISBN
91-628-6353-3
language
English
LU publication?
yes
additional info
My Bergkvist, Tommy Martinsson, Pierre Åman and Magnhild Sandberg-Wollheim. 1996. No genetic linkage between multiple sclerosis and the interferon alpha/beta locus Journal of neuroimmunology, vol 65 pp 163-165. Elsevier
My Bergkvist, Marita Olsson and Magnhild Sandberg-Wollheim. 2004. No evidene for a genetic linkage between development of multiple slerosis and components of the JAK-STAT pathway Multiple Sclerosis, vol 10 pp 87-88. Department of Clinial Neuroscience Lund University Sweden
My Bergkvist and Magnhild Sandberg-Wollheim. 2001. Serological differences in monozygotic twin pairs discordant for multiple sclerosis Acta Neurologica Scandinavica, vol 104 pp 262-265. Blackwell
My Bergkvist, Claes Nordborg and Pierre Åman. . Immunohistochemical analysis of MxA, p53 and CHOP expression in brain tissue from patients with multiple sclerosis (manuscript)
My Bergkvist, Claes Nordborg, Anders Oldfors and Pierre Åman. . Identification of target structures for autoantibodies in brain tissue from patients with multiple sclerosis (manuscript)
id
bf64e59c-9b6a-485a-b657-08d25400960e (old id 544940)
date added to LUP
2016-04-01 16:27:20
date last changed
2018-11-21 20:41:32
@phdthesis{bf64e59c-9b6a-485a-b657-08d25400960e,
  abstract     = {{Multiple sclerosis (MS) is a chronic disease of the central nervous system, characterized by focal inflammatory lesions with demyelination and axonal loss. It is believed that MS is an immune-mediated disorder with both genetic and environmental contributions to the pathogenesis. Interferons (IFNs) are naturally occurring proteins known to have antiviral, antiproliferative and immunoregulatory effects. Treatment with IFN beta has a favourable effect in MS while IFN gamma was found to precipitate exacerbations. We have investigated whether polymorphisms in the IFN system influenced susceptibility to MS, but found no linkage between any of the investigated loci and MS. Approximately 70% of monozygotic twins are discordant for MS indicating that environmental factors contribute to the development of the disease. We investigated, in 3 pairs of monozygotic twins discordant for MS, serological differences that could be important for the development of MS. Two MS affected twins had serological evidence of a previous infection with Borrelia burgdorferi respective Toxoplasma gondii. In general the serum titers were strikingly similar in the twins, indicating no major disturbances of the humoral immune system in MS. Many types of viruses induce IFN production, but it is unclear whether IFN is produced in MS lesions. We searched for the expression of MxA, a cytoplasmic protein induced by IFNA/B, with the capability to inhibit the replication of several viruses. No anti-MxA staining was found in MS brain tissue indicating that MxA, and consequently IFNA/B, probably is not produced in these lesions. Oligoclonal bands (OCBs) are detected in the CSF in majority of patients with MS. They are believed to result from continuous immunization against unknown antigens. We investigated if antibodies in CSF from MS patients bound to structures in MS brain lesions and control brain tissue and found that brain lesions from secondary progressive MS patients contain a unique structure that binds IgG antibodies from the patients. Preincubation of brain sections with CSF from MS patients enhanced the IgG staining. Direct fluorescence labelled CSF antibodies from an MS patient showed similar binding pattern as with anti-IgG in MS lesions. No binding of fluorescence labelled antibodies was detected in control brain tissue. This indicates that the antigens/target structures are absent from normal brain. Double staining showed that the IgG was bound to the axons and was observed both in myelinated axons and in totally or partially demyelinated axons suggesting that the antibody binding may be an early event in myelin and axon destruction.}},
  author       = {{Bergkvist, My}},
  isbn         = {{91-628-6353-3}},
  keywords     = {{neurophysiology; Neurologi; neuropsykologi; neurofysiologi; neuropsychology; Neurology; Axon and myelin damage; IgG; Virus; Interferon; Multiple Sclerosis; Genetic linkage}},
  language     = {{eng}},
  publisher    = {{Department of Clinical Neuroscience, Lund University}},
  school       = {{Lund University}},
  title        = {{Multiple Sclerosis: Studies of the Interferon system and search for infectious agents}},
  url          = {{https://lup.lub.lu.se/search/files/4677838/544950.pdf}},
  year         = {{2005}},
}