Spatial transcriptomics of compartmentalised inflammation in a natural disease multiple sclerosis cohort.

Compartmentalised inflammation is a poorly understood aspect of multiple sclerosis (MS) that is associated with worse outcomes and represents an important therapeutic target. To gain deep insight into compartmentalised inflammation, we have taken the approach of digital spatial profiling of the whole human transcriptome in areas of Central Nervous System (CNS) perivascular and meningeal inflammation and tertiary lymphoid-like structures (TLS) in MS. Critically, we had access to rare archival tissue obtained before the era of disease-modifying therapies, representing the natural history of disease. This analysis has identified differentially expressed genes in TLS compared to meningeal or perivascular inflammation. Pathway analysis highlighted that TLS signalling is dominated by B cell activity including active antibody secretion. Our data demonstrated the diversity of immunoglobulins and the prominence of IgG3-and IgG4-secreting cells in TLS. Intriguingly, our analyses suggest pathways of active viral mRNA translation and associated-cellular responses within TLS immune cells, suggesting TLS may be hubs for viral (re)activation. These findings provide insight into the function of TLS in MS disease pathogenesis and reveal unique immune signatures that may support biomarker development to predict which patients harbour TLS in life.