The Primate EAE Model Points at EBV-Infected B Cells as a Preferential Therapy Target in Multiple Sclerosis

Area of Science:

• Immunology
• Neuroscience
• Primate Models

Background:

• Anti-CD20 monoclonal antibodies (mAb) show clinical efficacy in relapsing-remitting multiple sclerosis (MS), highlighting B cell involvement.
• The precise pathogenic role of B cells in MS remains incompletely understood.
• Rodent experimental autoimmune encephalomyelitis (EAE) models do not fully recapitulate MS pathology.

Purpose of the Study:

• To investigate the role of CD20+ B cells in a unique primate model of EAE.
• To explore the relevance of these findings for human MS.
• To examine the impact of B cell-targeted therapies in this model.

Main Methods:

• Utilized a novel EAE model in common marmosets (Callithrix jacchus).
• Analyzed disease progression independent of autoantibodies.
• Investigated the role of MHC class Ib-restricted cytotoxic T cells activated by herpesvirus-infected B cells.
• Assessed the effects of anti-CD20, anti-BLyS, and anti-APRIL therapies.
• Monitored depletion of the marmoset gamma-herpesvirus (CalHV3), analogous to Epstein-Barr virus (EBV).

Main Results:

• Marmoset EAE progression occurred independently of autoantibodies, mirroring MS.
• Progressive disease was mediated by cytotoxic T cells activated by gamma-herpesvirus-infected B cells, leading to demyelination.
• B cell-directed therapies showed variable efficacy, correlating with CalHV3 depletion from lymphoid organs.
• Epstein-Barr virus (EBV)-like gamma-herpesvirus CalHV3 infection in B cells was implicated in pathogenesis.

Conclusions:

• CD20+ B cells, especially those infected with EBV, play a significant pathogenic role in MS.
• The marmoset EAE model offers valuable insights into MS mechanisms distinct from rodent models.
• Targeting specific B cell subsets, particularly those harboring gamma-herpesviruses, may be a therapeutic strategy for MS.