Multiple sclerosis (MS) is a highly heterogeneous disease with large inter-individual differences in disease course. MS lesion pathology shows considerable heterogeneity in localization, cellular content and degree of demyelination between patients. In this study, we investigated pathological correlates of disease course in MS using the autopsy cohort of the Netherlands Brain Bank (NBB), containing 182 MS brain donors. Using a standardized autopsy procedure including systematic dissection from standard locations, 3188 tissue blocks containing 7562 MS lesions were dissected. Unbiased measurements of lesion load were made using the tissue from standard locations. Lesion demyelinating and innate inflammatory activity were visualized by immunohistochemistry for proteolipid protein and human leukocyte antigen. Lesions were classified into active, mixed active/inactive (also known as chronic active), inactive or remyelinated, while microglia/macrophage morphology was classified as ramified, amoeboid or foamy. The severity score was calculated from the time from first symptoms to EDSS-6. Lesion type prevalence and microglia/macrophage morphology were analyzed in relation to clinical course, disease severity, lesion load and sex, and in relation to each other. This analysis shows for the first time that (1) in progressive MS, with a mean disease duration of 28.6 ± 13.3 years (mean ± SD), there is substantial inflammatory lesion activity at time to death. 57% of all lesions were either active or mixed active/inactive and 78% of all patients had a mixed active/inactive lesion present; (2) patients that had a more severe disease course show a higher proportion of mixed active/inactive lesions (p = 6e−06) and a higher lesion load (p = 2e−04) at the time of death, (3) patients with a progressive disease course show a higher lesion load (p = 0.001), and a lower proportion of remyelinated lesions (p = 0.03) compared to patients with a relapsing disease course, (4) males have a higher incidence of cortical grey matter lesions (p = 0.027) and a higher proportion of mixed active/inactive lesions compared to females across the whole cohort (p = 0.007). We confirm that there is a higher proportion of mixed active/inactive lesions (p = 0.006) in progressive MS compared to relapsing disease. Identification of mixed active/inactive lesions on MRI is necessary to determine whether they can be used as a prognostic tool in living MS patients.Electronic supplementary materialThe online version of this article (10.1007/s00401-018-1818-y) contains supplementary material, which is available to authorized users.

Tertiary lymphoid tissues (TLTs) have been observed in the meninges of multiple sclerosis (MS) patients, but the stromal cells and molecular signals that support TLTs remain unclear. Here, we show that T helper 17 (Th17) cells induced robust TLTs within the brain meninges that were associated with local demyelination during experimental autoimmune encephalitis (EAE). Th17-cell-induced TLTs were underpinned by a network of stromal cells producing extracellular matrix proteins and chemokines, enabling leukocytes to reside within, rather than simply transit through, the meninges. Within the CNS, interactions between lymphotoxin αβ (LTαβ) on Th17 cells and LTβR on meningeal radio-resistant cells were necessary for the propagation of de novo interleukin-17 responses, and activated T cells from MS patients expressed elevated levels of LTβR ligands. Therefore, input from both Th17 cells and the lymphotoxin pathway induce the formation of an immune-competent stromal cell niche in the meninges.

These data support a role for the C1q-C3 complement axis in synaptic alterations in the MS hippocampus.