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

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.

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.

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.

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