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Title: Tertiary lymphoid organ neogenesis in grey matter pathology in multiple sclerosis
Author: Browne, Eleanor
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2015
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Chronic meningeal inflammation is suggested to contribute to the progression of secondary progressive multiple sclerosis (SPMS) in part by driving cortical grey matter pathology. The presence of tertiary lymphoid organ-like (TLO) structures in a large proportion of SPMS cases is associated with faster clinical progression and more severe cortical pathology, suggesting that TLO neogenesis and chronic meningeal inflammation contribute to progression. Gene expression of the cytokine lymphotoxin-alpha (LTα), implicated in TLO formation and cytotoxicity, and the lymphoid chemokines CXCL13 and CCL21, was determined in post-mortem SPMS meninges by qPCR. LTα was increased in SPMS, while substantially increased CXCL13 expression was associated with the presence of TLOs in SPMS. As LTα induces CXCL13 during inflammation, we investigated the hypothesis that LTα drives TLO formation and exacerbates cortical pathology in SPMS, using an animal model of cortical demyelination driven by meningeal inflammation. Subclinical experimental autoimmune encephalomyelitis was induced in female dark agouti rats by immunisation with 5-10μg of recombinant mouse myelin oligodendrocyte glycoprotein (rmMOG) in incomplete Freund's adjuvant. Injection of LTα and the cytokine interferon-γ into the subarachnoid space 21 days post-immunisation induced substantial meningeal infiltration with B cell-rich areas, T cells, macrophages and channel formation reminiscent of early TLOs, accompanied by microglial activation, extensive demyelination, and remyelination within 21 days. To study chronic meningeal cytokine expression we injected a VSV-G pseudotyped lentiviral vector (LV) expressing green fluorescent protein (GFP) or human LTα (LVLTα) into the subarachnoid space. Meningeal GFP expression was induced up to 90 days post-injection. Human LTα expression was detected in rat brain and CSF, with widespread microglial activation and meningeal infiltrates of macrophages, B and T cells resembling TLOs, in naïve and rmMOG-immunised rats at 90 days post-LVLTα, while extensive demyelination was present only in rmMOG-immunised rats. This suggests that chronic meningeal LTα expression is sufficient for widespread microglial activation, but demyelination requires an anti-myelin response in this model. These findings support the hypothesis that chronic meningeal inflammation drives cortical pathology, and LTα/TLO neogenesis may represent a novel therapeutic target for SPMS.
Supervisor: Reynolds, Richard Sponsor: Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral