Spatial transcriptomics of compartmentalised inflammation in multiple sclerosis

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 deeper insight into compartmentalised inflammation, we have taken the approach of digital spatial profiling of the whole human transcriptome in areas of perivascular and meningeal inflammation and tertiary lymphoid-like structures (TLS) in MS central nervous system tissue. Critically, we had access to rare archival tissue obtained before the era of disease-modifying therapies, representing a 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, pathway analysis suggests TLS may be hubs for viral (re)activation which warrants further investigation. 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.