Chapter 4. DISCUSSION
4.6 Final remarks
The present study describes the activation of genes in the deep cervical lymph nodes and spleen, and relates the expression profiles to the disease progression in TME.
The use of techniques such as microarray technologies helped to elucidate the role of genes involved in the immune response during the initiation and progression of TME. Pathway analysis provided detailed information about the pathogenesis of this MS model (Ulrich et al., 2009). The present study reveals that several genes are associated with the peripheral immune response in early TME. Obtained results demonstrate the activation of B-cells in the CNS-draining lymph node, which might represent a requisite for subsequent intrathecal antibody generation within the spinal cord during disease progression. Regarding B-cells, it is interesting to highlight the divergent role of humoral immune responses in immune-mediated disorders, such as MS, including immunomodulatory effects by IL-10-producing regulatory B-cells as well as antibody-dependent cell-mediated cytotoxicity (Anderton, 2008). Future studies are planned to investigate the distribution of different B-cell and plasma cell subsets in the CNS and peripheral lymphoid organs in TMEV-infected mice.
Equivalent to the hypothesis of a closed BBB in progressive MS, reduced transcription of genes at later time points is indicative of a compartmentalization during lesion development in infected animals. However, partial reactivation of immunity related genes during the late chronic phase might represent a consequence of a leaky BBB or polyphasic process, respectively. Future experiments have to focus on the dynamics of neurovascular permeability and the interaction between CNS and the peripheral immune response during disease initiation and progression in this model for human MS.
Summary 67
SUMMARY
María José Navarrete Talloni – Gene expression profiling of peripheral lymphoid organs in a murine model for multiple sclerosis
Theiler’s murine encephalomyelitis virus-induced demyelination represents an important animal model to study the chronic-progressive form of multiple sclerosis.
The aim of the present study was to identify specific genes and pathways in peripheral lymphoid organs such as the deep cervical lymph node and spleen in experimentally infected SJL-mice, using DNA microarray techniques. Associated phenotypical changes in the lymph node have been characterized by immunohistochemistry and pathological alterations in the brain and spinal cord have been classified by histology. In addition, viral dissemination in the central nervous system (CNS) and lymphoid organs was determined by immunohistochemistry and in situ-hybridization. Molecular analyses identified 387 differentially expressed genes in the deep cervical lymph node and only six genes in the spleen of infected animals. In the lymph node, 27.4% of genes presented fold changes +/- 1.5 at 14 days post infection (dpi), followed by a reduced gene transcription at later time points. K-means clustering analyses resulted in five clusters. Accordingly, functional annotation revealed pathways associated with immune regulation, including B-cell immune responses as the most up-regulated cluster at the early disease phase. In addition, transcriptional changes in the deep cervical lymph node were associated with an increase of CD68- and lysozyme-positive cells by immunohistochemistry, suggestive of CNS-derived antigen presentation. Polioencephalitis was most intense at 14 dpi, gradually declining at 42, 98 and 196 dpi. In contrast, demyelinating leukomyelitis in the spinal cord started at 42 dpi and progressively increased until 196 dpi.
In summary, early gene expression is indicative of virus trigged immune responses in the peripheral lymphoid organs. The decreased gene transcription in the deep cervical lymph node during the chronic disease phase and the low number of
68 Summary
differentially expressed genes in the spleen supports the hypothesis of a compartmentalized inflammation within the CNS, as described in progressive multiple sclerosis.
Zusammenfassung 69
ZUSAMMENFASSUNG
María José Navarrete Talloni – Genexpressionsanalyse peripherer lymphatischer Organe in einem Mausmodell für Multiple Sklerose
Die durch das Theilersche murine Enzephalomyelitis Virus (TMEV) hervorgerufene Demyelinisierung dient als wichtiges Tiermodell zur Erforschung der chronisch-progressiven Verlaufsform der Multiplen Sklerose des Menschen. Ziel der vorliegenden Untersuchung war die Identifizierung spezifischer Gene und deren Signalwege in den tiefen zervikalen Lymphknoten und der Milz von experimentell infizierten SJL-Mäusen unter Verwendung der DNA Microarray-Analyse.
Phänotyische Veränderungen in den lymphatischen Organen wurden zusätzlich mittels Immunhistologie charakterisiert und die Läsionen im Gehirn und Rückenmark der Mäuse histologisch untersucht. Außerdem wurde die Virusverteilung im Zentralen Nervensystem (ZNS) und in den peripheren lymphatischen Organen der Tiere mittels Immunhistologie und in situ-Hybridisierung erfasst. Mittels der molekularen Analysen wurden 387 exprimierte Gene in den tiefen zervikalen Lymphknoten und sechs Gene in den Milzen von TMEV-infizierten Mäusen identifiziert. Am 14. Tag nach der Infektion (dpi) wiesen 27,4% der Gene im Lymphknoten einen „fold change“ von ± 1,5 auf, gefolgt von einer reduzierten Genexpression an den darauffolgenden Untersuchungstagen (42., 98. und 196. dpi). Die exprimierten Gene wurden mittels der „k-mean-cluster“-Analyse in fünf Gruppen eingeteilt. Die Analysen der funktionellen Gruppen verdeutlichten das Auftreten von immunregulatorischen Mechanismen und einer humoralen Immunantwort in der frühen Krankheitsphase der Tiere. Als Hinweis auf eine Migration von antigenpräsentierenden Zellen konnte eine zeitgleiche Zunahme von CD68- und Lysozym-positiven Zellen im tiefen zervikalen Lymphknoten mittels Immunhistologie nachgewiesen werden. Die Polioenzephalitis war am stärksten am 14. dpi nach der Infektion. Im Gegensatz hierzu begann die
70 Zusammenfassung
demyelinisierende Leukomyelitis im Rückenmark am 42. dpi und nahm bis zum 196.
dpi progressiv zu.
Zusammenfassend lässt sich feststellen, dass die frühe Genexpression charakteristisch für eine Virus-bedingte Immunantwort in den regionären Lymphknoten des ZNS ist. Vergleichbar mit den Prozessen bei der Multiplen Sklerose, spricht die verminderte Transkription im Lymphknoten während der chronischen Krankheitsphase und die geringe Genexpression in der Milz für die Hypothese einer Kompartimentalizierung der Entzündung innerhalb des ZNS von TMEV-infizierten Mäusen.
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