EBV reprograms autoreactive anti-CNS B cells as antigen presenting cells in multiple sclerosis

Area of Science:

• Neuroimmunology
• Virology
• Immunology

Background:

• Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS).
• Epstein-Barr virus (EBV) infection is strongly associated with MS development, but the precise mechanisms remain unclear.
• The role of EBV-infected B cells in MS pathogenesis requires further elucidation.

Purpose of the Study:

• To investigate the direct effects of EBV infection on B cells in MS patients.
• To characterize the functional and transcriptional changes in EBV-infected B cells within the CNS.
• To explore the potential of EBV-infected B cells to drive autoreactive immune responses in MS.

Main Methods:

• Analysis of EBV-infected B cells from MS patients' blood and cerebrospinal fluid (CSF).
• Characterization of B cell subsets, transcriptional programs, and antigen-presenting cell (APC) function.
• Generation and testing of recombinant antibodies from EBV-infected B cells for CNS antigen binding.
• In vitro co-culture experiments to assess T cell stimulation by EBV-infected B cells.

Main Results:

• EBV directly infects autoreactive anti-CNS antigen B cells in MS, reprogramming them into pro-inflammatory APCs.
• EBV-infected B cells in MS are enriched in the CD27+CD21low memory subset, showing upregulated activation and APC programs.
• Antibodies from EBV-infected B cells bind brain tissue and cross-react with CNS autoantigens and EBV nuclear antigen-1 (EBNA1).
• In vitro, EBV-infected B cells stimulate T peripheral helper cells and activate other B cells.

Conclusions:

• EBV infection reprograms autoreactive B cells into APCs, establishing a mechanistic link between EBV and MS pathogenesis.
• These EBV-driven APCs promote pathogenic T cell and B cell responses targeting the CNS in MS.
• Targeting EBV-infected autoreactive B cells may offer a novel therapeutic strategy for MS.