Charakterisierung der humoralen Immunantwort bei der Multiplen Sklerose
Loading...
Files
Date
relationships.isAuthorOf
Publisher
Philipps-Universität Marburg
item.page.supervisor-of-thesis
Abstract
Multiple sclerosis (MS) is a chronic inflammatory
and demyelinating disease of the central nervous system (CNS)
with an yet unknown etiology. Infiltration of immune cells in
the CNS and histopathological changes are key features in MS.
Although it is likely that the immune system plays an important
role in disease process it is still unknown which immune cells
are potentially relevant in disease manifestation and
progression. Since inflammatory parameters in the cerebrospinal
fluid (CSF) correlate with the extent of CNS lesions, CSF
abnormalities could reflect lesion pathology. In this study,
the distribution of various immune cells and proteins in the
CSF and peripheral blood was compared between MS patients and
patients with non-inflammatory neurological diseases (NIND) in
order to search for CSF abnormalities in MS. The analysis
revealed no significant differences in peripheral blood between
MS and control patients. In contrast, significant changes were
observed in the CSF. In particular, MS patients showed an
activation of the humoral immune response which was reflected
by a higher percentage of B cells and plasmacells in patient?s
CSF and an increased intrathecal immunoglobulin-G
(IgG)-synthesis. Furthermore, the analyses enclosed three
distinct CSF patterns, which remained stable during different
phases of disease: 1. a B cell dominant pathology with high
percentages of B cells, low percentages of monocytes and an
increased intrathecal IgG-synthesis, 2. a monocyte-dominant
pathology with low numbers of B cells, high numbers of
monocytes and low IgG-levels and 3. an intermediate pathology
with equal numbers of B cells and monocytes and a moderate
IgG-synthesis. Further analyses revealed an association between
CSF pathology and disease progression. A predominance of B
cells was associated with a faster disease progression, whereas
a predominance of monocytes was found in patients with slower
progression. This study describes the existence of
heterogeneity in CSF cytology in MS patients and support the
idea of different pathomechanisms in MS. The different CSF
patterns may allow for the first time the stratification of MS
patients according to their CSF pathology and a prediction of
individual disease progression. A hallmark of the MS is the
presence of intrathecal antibody synthesis and the occurence of
oligoclonal IgG bands (OCB) in the CSF, which are found in 95%
of the MS patients but rarely in healthy controls (<1%).
These OCB are also found in infectious CNS diseases. In these
disorders the OCB are specific for the disease causing
pathogen. In MS, the target antigen is still unknown. The aim
of the second part of this study was to identify the antigen
specificity of the highly focused antibody response. A novel
protein-array technology based on a cDNA library of the human
brain enabled us to screen for the antibody response against
more than 37000 different proteins. Potential candidate
antigens which were identified with CSF of MS patients but not
with control CSF were selected for large ELISA-experiments to
determine the frequency of positive immunreactivities in large
MS and control groups. 10 candidate antigens showed significant
higher immunreaktivities in MS patients. Interestingly, the
different proteins showed overlappings in immunreactivity
assuming that all proteins of each group share the same
epitope. The underlying epitopes were defined by peptidescan
analysis and amino acid substitutional assays. The analyses
identified two proteins of the Epstein-Barr virus (EBV): EBNA-1
and BRRF-2. To investigate the immunreactivity against these
EBV-Proteins, the BRRF-2 protein was recombinantly expressed in
E.coli using a cloning strategy. The analyses revealed a
significant higher immunreactivity against EBNA-1 and BRRF-2 in
CSF and serum of MS patients compared to NIND patients and
patients with other inflammatory neurological diseases (OIND).
Furthermore, a BRRF-2 specific intrathecal IgG synthesis was
observed. Of significant importance, we could show that the OCB
of MS patients were specific for both EBV proteins. The data
strongly support the role of EBV in the pathogenesis of
MS.
Review
Metadata
Contributors
Supervisor:
Dates
Created: 2004Issued: 2004-04-20Updated: 2011-08-10
Faculty
Medizin
Publisher
Philipps-Universität Marburg
Language
ger
Data types
DoctoralThesis
Keywords
B-Zellen , ImmunsystemLiquor cerebrospinalisprotein-arraymultiple sclerosisCNS , immunglobulinscerebrospinal fluidZNSProtein-ArrayEpstein-Barr-Virus
DFG-subjects
ImmunglobulineMultiple Sklerose
DDC-Numbers
610
show more
Cepok, Sabine: Charakterisierung der humoralen Immunantwort bei der Multiplen Sklerose. : Philipps-Universität Marburg 2004-04-20. DOI: https://doi.org/10.17192/z2004.0113.
License
This item has been published with the following license: In Copyright