Several experimental and clinical observations have suggested the presence of elevated inflammation, diffuse or organized in lymphoid structures that resemble secondary lymphoid organs, tertiary lymphoid structures (TLS), in the leptomeninges of either experimental animal model or post-mortem multiple sclerosis (MS) central nervous system (CNS), both in the brain and in the spinal cord. This feature, named lymphoid neogenesis, has been suggested to have a relevant role in maintaining intrathecal immune response in MS, as well as previosly shown in other chronic inflammatory diseases.
MS meningeal inflammation, particularly enriched in B cells and compartmentalized within cerebral sulci, is specifically linked to elevated demyelination and damage of the adjacent subpial cortical grey matter. In particular, elevated meningeal inflammationis associated with substantial “surface-in” gradient of cortical neuronal loss and microglia activation highest in the outer cortical layers, close to the cerebrospinal fluid (CSF)/pia boundary, compared to the inner ones.
The strict correlation between meningeal molecular profiling and paired CSF protein one in post-mortem MS cases with elevated cortical lesion load and aggressive disease course has suggested that meningeal infiltrates may represent one of the main intrathecal sources of inflammatory and cytotoxic factors that released in the CSF might orchestrate and/or exacerbate chronic local inflammation and following cortical pathology.
Similar intrathecal inflammatory pattern detected in naïve MS patients was able to predict 89% of the variance in cortical lesion volume and number at time of diagnosis and to distinguish patients at high risk of disease activity after 4 years follow-up.