Dr. Joost Smolders & Dr. Cheng-Chih Hsiao

Novel insights in MS lesion pathology and immune surveillance of the human brain

16:00-16:30: Dr. Joost Smolders – Broad rim lesions are a new biomarker for rapid disease progression in MS

Current MS treatments reduce relapse activity but have limited impact on disease progression. Clinical trials targeting progression often fail because of insufficient understanding of its underlying mechanisms. This study analyzed a clinically wellcharacterized MS autopsy cohort from the Netherland Brain Bank (186 individuals) from which we selected donors exhibiting opposite disease trajectories of slow versus rapid progression. We performed extensive unbiased histology and spatial transcriptomics, which unveiled a distinct MS lesion type marked by an extensive myeloid cell rim with cellular and transcriptional signatures of innate immune activation, inflammatory cytokine production, and apoptosis. Presence of this particular lesion type was linked to rapid disease progression. An independent TSPO-PET study (114 individuals) validates the association between lesions with a broad myeloid cell rim and disease progression in individuals with MS. Our findings offer crucial insights into the mechanisms behind MS progression, identifying broad rim lesions as a biomarker for rapid disease progression and potentially guiding patient selection for future therapeutic trials targeting central nervous system intrinsic inflammation. Nat. Med. May 2025. https://doi.org/10.1038/s41591-025-03625-7

16:30-17:00: Dr. Cheng-Chih Hsiao – Acquisition of residency programs by T cells entering the human brain

Surveillance by T cells is mandatory for maintaining a healthy state of the CNS, while aberrant accumulation of T cells is linked to neuroinflammatory diseases. We previously showed that the human brain gives home to resident T cells with distinctive gene expression and functional capacity. We postulate that circulating T cells stepwise acquire these properties when entering the human brain. To test this hypothesis, we isolated CD8+ and CD4+ T cells from CNS border compartments (choroid plexus and meninges), intrathecal compartments (cerebrospinal fluid (CSF) and subcortical white matter (WM)), and paired peripheral blood of human brain donors. Flow-cytometric analyses revealed that T cells in all CNS compartments show an effector memory phenotype that is acquired by circulating memory T cells upon interaction with brain endothelium. In contrast to border compartments, intrathecal T cells expressed tissue residency markers. Despite similar gene and protein expression, T cells from WM showed reduced expression of molecules associated with migration, co-stimulation, and recent activation compared to T cells from CSF, yet generated a similar cytokine response upon activation. This work demonstrates the versatility of T-cell phenotypes across CNS compartments and provides insight into the programs regulating their recruitment and maintenance within the CNS.