Kaufmann M, Evans H, Schaupp AL, Engler JB, Kaur G, Willing A, Kursawe N, Schubert C, Attfield KE, Fugger L, Friese MA.

MS is a chronic autoimmune disease of the CNS associated with serious physical and cognitive disability. MS manifests most commonly in young adults with a relapsingremitting disease course (RRMS), in which recurrent episodes (relapses) of neurological symptoms are followed by clinical remission. The majority of MS patients develop a progressive form of the disease, in which an irreversible buildup of disability occurs, regardless of relapses, either from its clinical onset (primary progressive MS [PPMS]) or after approximately 10–20 years of RRMS (secondary progressive MS [SPMS]).1 Mechanistically, the relapses observed in RRMS have been linked to episodic bouts of CNS invasion by peripheral immune cells that cause demyelinating lesions in the white matter.1 therefore, targeting of the peripheral immune system can suppress RRMS disease activity as exemplified by the anti-integrin alpha 4 (ITGA4, CD49d) antibody natalizumab.2 Natalizumab blocks the extravasation of immune cells in the CNS, preventing their migration beyond the BBB and strongly suppressing relapses. Notably, in contrast to RRMS, the same treatment strategies, including natalizumab, are not effective in progressive MS, pointing to a subsequent uncoupling of disease activity from the peripheral immune system.3 Thus, there is a major unmet clinical need to understand the sequence of events that eventually leads to continuous neurodegeneration and disability progression. The best starting point would be to explore the basis for the uncoupling of the peripheral immune response and disability progression. Although it remains largely unknown and might partly be attributed to primary neurodegeneration, it could be explained by chronic organization of peripheral immune cells behind the BBB, beyond the reach of many common therapeutic strategies. This is suggested by the observation that the onset of progressive MS is best correlated with cortical lesions that are pathologically characterized by lymphocyte collections adjacent to the graymatter. 4–6 However, it is enigmatic whether such colonization of the CNS begins during the RRMS phase and therefore could be prevented at an early stage of disease. Here, we interrogated the basis of progressive MS by designing a study to (1) systematically identify immune cells homing to the CNS in RRMS, (2) test whether these cells become resident in the CNS of progressive MS patients, and (3) investigate them as a potential therapeutic target. For this purpose, we determined the signature of CNShoming cells trapped in the blood of natalizumab-treated RRMS patients using a high-dimensional readout of combined single-cell RNA sequencing (scRNA-seq) and protein surface marker profiling. We then tracked these cells in independent cohorts of both untreated RRMS and untreated progressive MS patients and investigated their localization directly in the CNS of progressive patients using spatial RNA sequencing of MS brains. Finally, we describe their detailed characteristics and suggest a strategy for specific targetingwith a view to delay or prevent the progressive phase ofMS that drives irreversible disability and is untreatable to this day.

Med (N Y). 2021 Mar 12;2(3):296-312

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