Myelin-Reactive TCR/IgM Dual-Expresser Lymphocytes in Multiple Sclerosis: Linking Pathogenesis to Anti-CD20 Therapy.

Abstract

Background: Multiple sclerosis (MS) is an autoimmune disorder driven by myelin autoantigen-specific autoreactive T cells, yet the most effective disease-modifying therapies (DMTs) target B cells. The mechanism underlying this paradox remains unclear. Here, we identify dual-expressor cells (DEs) -a novel lymphocyte population with hybrid T and B cell characteristics, including co-expression of the T cell receptors (TCRαβ) and surface B cell receptors (BCRs), primarily IgM-as potential contributors to MS pathogenesis and inadvertent targets of anti-CD20 DMTs.

Methods: DEs were examined in the peripheral blood and cerebrospinal fluid (CSF) of patients with relapsing-remitting MS (RRMS) compared to healthy controls. Their phenotype and functional properties were characterized, including responses to myelin autoantigens and susceptibility to depletion in a pilot cohort of seven RRMS patients treated with ocrelizumab.

Results: DEs were found at significantly higher frequencies in the peripheral blood of patients with RRMS compared to healthy controls and were further enriched in CSF, where up to 95% expressed CD20, versus ~60% in blood. Furthermore, most of DEs in CSF express CXCR3, indicating involvement of CXCR3-CCL-9, 10 and 11 in their recruiting and maintenance in the CSF of MS patients. Functionally, DEs exhibited robust responses to myelin autoantigens, supporting their relevance in disease. In a pilot cohort of seven RRMS patients, ocrelizumab significantly reduced circulating DE frequencies, confirming their susceptibility to CD20-mediated depletion.

Conclusions: These findings implicate DEs in MS and provide insight into the efficacy of anti-CD20 therapies in a traditionally T cell-driven disease.