Local antigen acquisition by B cells in the brain and its potential to cause an autoimmune response

Background and rationale
The exact pathogenesis of multiple sclerosis (MS) is still under investigation. The recent success in treatment with monoclonal antibodies – natalizumab and anti-CD20 monoclonal antibodies – suggests that infiltration of lymphocytes, particularly naïve or memory B cells, is closely related to neuroinflammation in MS. As a central nervous system (CNS)-restricted antigen acquisition by B cells is a pre-requisite of several potential mechanisms how B cells might contribute to MS, we examined the local antigen acquisition by B cells in the brain and its potential to cause an autoimmune response in the brain.
Results
We first established B cell infiltration in the brain using a viral vector, VSV∆G. The VSV infected neurons and caused B cell infiltration and accumulation in the perivascular spaces starting from day 2 post-injection. The B cells entered the brain parenchyma after day 5 post-injection. We could observe that the anti-viral B cells closely interact with the infected cells using histology and intravital imaging, yet the interactions were not significantly higher than in wildtype controls. We demonstrated that the B cells could capture their cognate antigen directly from the antigen-expressing cells in vitro, which happened within the first hour of co-culture. Due to the difficulty of controlling the dynamics of B cell infiltration in the brain, we switched the paradigm to a lung infection and showed that FluBI B cells had significantly higher intimacy of contact with their cognate antigen in the influenza-infected lung compared to wildtype B cells. Finally, we demonstrated using enzyme-linked immunospot (ELISpot) that the IgH MOG B cells could acquire their cognate antigen locally in the brain. At least on this timepoint of 7 days post-injection we did not observe the migration of antigen-loaded B cells to peripheral lymphoid tissues. The IgH MOG B cells disappeared in the brain after antigen capture due to activation-induced cell death because they lacked further survival signals. When CD40L was provided, a plasmablast-like cell population was found in IgH MOG mouse brain by single-cell transcriptomics (scTranscriptomics) and demyelination in the B cell infiltrating area in IgH MOG mouse brain was observed using confocal microscopy.
Conclusion
Our results support that virus infection of the brain facilitates the infiltration of autoimmune B cells into the brain parenchyma. The infiltrating B cells acquire their target antigen directly in the brain. Upon CD40-CD40L interaction, they can evade activation-induced cell death and thereby circumvent an important immune checkpoint. Our study provides new insights into understanding the possible mechanisms of B cell pathogenesis in MS.