Intrathecal CD8+CD20+ T Cells in Primary Progressive Multiple Sclerosis

Abstract

Background and objective: Despite accumulating evidence of intrathecal inflammation in patients with primary progressive multiple sclerosis (PPMS), immunomodulatory and suppressive treatment strategies have proven unsuccessful. With this study, we investigated the involvement of CD20⁺ T cells and the effect of dimethyl fumarate on CD20⁺ T cells in PPMS.

Methods: The main outcomes in this observational, case-control study were flow cytometry assessments of blood and CSF CD20⁺ T cells and ELISA measurements of myelin basic protein and neurofilament light chain in untreated patients with PPMS and patients treated for 48 weeks with dimethyl fumarate or placebo. MRI measures included new and enlarging T2-weighted lesions over 48 weeks and lesion, normal-appearing white matter, cortical, and thalamic volume.

Results: Assessing CD20⁺ T cells in patients with PPMS and controls showed an increased percentage of CD20⁺ T cells in the blood of untreated patients and a strong enrichment in the CSF. In addition, a higher frequency of CD8⁺CD20⁺ T cells in the CSF correlated with a higher concentration of myelin basic protein and T2-weighted lesion volume and with a lower normal-appearing white matter and thalamus volume. Furthermore, CD8⁺CD20⁺ T cells were associated with the development of new T2 lesions. After 48 weeks of treatment with dimethyl fumarate, total T cells in CSF were reduced; however, CD20⁺ T cells were unaffected.

Discussion: This study shows an association between intrathecal CD8⁺CD20⁺ T cells, white matter injury, and thalamic atrophy in PPMS, suggesting a role of CD8⁺CD20⁺ T cells in the immunopathogenesis of PPMS. The results also suggest that limited efficacy of dimethyl fumarate in PPMS may, at least partly, be a consequence of failure to suppress CD8⁺CD20⁺ T cells in CSF.

Trial registration: ClinicalTrials.gov NCT02959658.