A new study has reported that the molecular and immune profile of slowly expanding lesions (SEL) in progressive multiple sclerosis is distinct from that of active demyelinating lesions that occur in the relapsing phase of MS (Jackle et al. Brain 2020;143:2073-2088; free full text at https://academic.oup.com/brain/article-pdf/143/7/2073/33502654/awaa158.pdf). SELs are considered the pathological correlate of MS disease progression.

The post-mortem study examined 21 SELs (mixed active/inactive and demyelinating lesions) from 13 patients with progressive MS aged 30-74 years. Additional tissue samples (chronic inactive lesions, normal-appearing white matter) were also examined. SELs were completely demyelinated and had a rim of macrophages/microglia at the lesion edge; this rim of macrophages/microglia was absent from chronic inactive lesions. Immunofluorescence studies demonstrated that there were acutely damaged axons and ongoing myelin breakdown at the edge of the lesion. Interestingly, at the lesion rim there were few T cells and B cells were only marginally detected, indicating that inflammatory infiltrates do not play a key role in the slowly expanding lesions that are the hallmark of progressive MS.

For SELs and chronic inactive lesions, the predominant phagocyte was CNS-resident microglia. At the rim, there was a higher number of M1-differentiated macrophages/microglia, which are activated by pro-inflammatory cytokines (e.g. TNF-alpha) and cause tissue damage (Kroner et al. Neuron 2014;83:1098-1116). There were lesser numbers of M2 macrophages/microglia, which produce growth and neurotrophic factors. SELs and chronic inactive lesions could not be distinguished as M1 or M2 subtypes, however, SELs showed more of an M1 profile; this was supported by increased CD40 at the lesion rim, which is preferentially expressed by M1 macrophages/microglia. CD206, which is preferentially expressed by M2 macrophages/microglia, showed a primarily perivascular localization.

Kuhlmann and colleagues recently proposed an updated histological classification system based on the presence and distribution of macrophages/microglia and ongoing demyelination (Kuhlmann et al. Acta Neuropathol 2017;133:13-24). According to this scheme, active lesions have macrophages/microglia throughout the lesion; mixed active/inactive lesions have macrophages/microglia only at the lesion border; and inactive lesions lack macrophages/microglia.

The present study looked at the second type, mixed active/inactive lesions, often characterized as SELs or ‘smouldering’ lesions (Frischer et al. Ann Neurol 2015;78:710-721). A prior autopsy study reported that 57% of all lesions in progressive MS patients were either active or mixed active/inactive lesions; 78% of patients had at least one mixed active/inactive lesion (Luchetti et al. Acta Neuropathol 2018;135:511-528).

The current findings support prior observations that the leading edge of these mixed active/inactive lesions appears to expand due to the action of M1 microglia. In contrast, the active demyelinating lesions seen in RRMS are primarily due to macrophages from the periphery that have crossed the blood-brain barrier. Microglia in active lesions in RRMS have been shown to express molecules involved in antigen presentation and T cell activation (Zrzavy et al. Brain 2017;140:1900-1913), indicating the importance of T and B cells to lesion formation during the relapsing phase of MS.