Alemtuzumab treatment exemplifies discordant immune effects of blood and cerebrospinal fluid in multiple sclerosis

Background and objectives: Immune responses in the central nervous system (CNS) are highly compartmentalized and cerebrospinal fluid (CSF) in particular often reflects CNS pathology better than peripheral blood. While CSF leukocytes are known to be distinct from blood, the immediate effects of peripheral leukocyte depletion on CSF leukocytes have not been studied in humans.Methods: We here analyzed CSF and blood from two relapsing-remitting multiple sclerosis (RRMS) patients early after peripheral leukocyte depletion with the anti-CD52 antibody alemtuzumab compared to untreated RRMS and control patients using single cell RNA-sequencing.Results: As expected for alemtuzumab, most leukocyte lineages including T cells were synchronously depleted from CSF and blood, while - surprisingly - pDCs were maintained in CSF but depleted from blood by alemtuzumab. Transcriptionally, genes associated with migration were elevated only in the CSF after alemtuzumab. Predicted cellular interactions indicated a central role of pDCs and enhanced migration signaling in the CSF after alemtuzumab.Discussion: The CSF and blood compartments are thus partially uncoupled, emphasizing that the CNS is only partially accessible even for treatments profoundly affecting the blood.

Automated summary

This study aims to investigate the immediate effects of peripheral leukocyte depletion on cerebrospinal fluid (CSF) leukocytes. Using single cell RNA-sequencing, the researchers found that after peripheral leukocyte depletion with alemtuzumab, pDCs were still present in the CSF but depleted from the blood. This suggests partial decoupling between the CSF and blood compartments, highlighting the limited accessibility of the CNS to peripheral treatments.