Author Of 1 Presentation
P0976 - Lymphotoxin alpha overexpression in the meninges causes lymphoid-like tissue development and subsequent neurodegeneration (ID 1450)
Abstract
Background
Lymphotoxin alpha (LTa) plays a role in both lymphoid organ development and in cell cytotoxicity mechanisms in the immune system. Levels of LTa expression are increased in the post-mortem meninges and CSF from MS patients with high levels of meningeal inflammation and subpial cortical pathology. Tertiary lymphoid-like structures (TLS) are discrete, structured organisations of infiltrating immune cells that form in nonlymphoid tissue and share structural and functional characteristics with secondary lymphoid structures such as lymph nodes.
Objectives
Here we aimed to study whether chronically increased levels of LTa in the cortical meninges in a rat model could give rise to tertiary lymphoid-like structures in the meninges and subsequent underlying cortical pathology.
Methods
To do this we stereotactically injected HIV-1 based VSV-g pseudotyped lentiviral (LV) transfer vectors into the sagittal sulcus (SS) of MOG peptide immunised DA rats to deliver continuous transgene expression (LTα + IFNγ) in the meninges. A neuropathological analysis was conducted at chronic time points up to 3 months.
Results
In LTα/IFNγ LV injected animals accumulation of meningeal inflammation in the midline subarachnoid space and lateral surface of the cortex was found at 28 and 90 days post injection. Meningeal aggregates were formed of CD4 and CD8+ T-cells and CD79a+ B-cells. CD4+ and CD8+ cells were evenly distributed throughout the space whilst CD79a+ B-cells formed into densely, packed focal clusters, lacking T-cells but containing IgG plasma cells. Within CD79a+ B-cell clusters a proportion co-expressed the proliferation marker Ki67.Throughout the infiltrates we identified the formation of channels similar to lymphatic vessels or that stained for a marker of high endothelial venules (HEVs), mucosal addressin cell adhesion molecule ((MAdCAM)-1). Within T-cell rich zones staining for laminin and podoplanin revealed a dense network of stromal cells that are most likely fibroblastic reticular cells (FRC). A population of follicular dendritic cells (FDC) could be stained with the marker ED5. Immunostaining showed high levels of lymphoid chemokines CCL19, CCL21, CXCL13 and CXCL12 and their receptors CCR7 and CXCR4, which organise lymphocyte compartmentalisation. The lymphotoxin beta receptor, through which LTa could induce chemokine and MAdCAM-1 production, was highly expressed throughout the infiltrates. In the underlying cortical parenchyma there were expansive regions that demonstrated marked neuronal loss (40% loss neun+ cells) extending from the pial surface into deeper cortical layer V.
Conclusions
The segregation of meningeal infiltrates into discrete T-cell and B-cell regions, the presence of FRC and FDC cell networks, HEVs and lymphoid chemokine production show LTα overexpression is sufficient to induce formation of meningeal TLS. The loss of subpial neurons shows TLS formation can lead to underlying cortical pathology.