H. J. Kim, Mika Schneider, Yakine Raach, Panajotis Karypidis, Julien Roux, Georgios A. Perdikaris, Sebastian Holdermann, Laila Kulsvehagen, Anne-Catherine Lecourt, Kerstin Narr, Roman Sankowski, Martin Diebold, Ewelina Bartoszek-Kandler, Josef P. Kapfhammer, Gert Zimmer, Anne-Katrin Pröbstel, Marco Prinz, Ludwig Kappos, Nicholas S.R. Sanderson, Tobias Derfuss
The efficacy of B cell depletion therapies, and their association with Epstein-Barr virus (EBV), implicate B cells in the pathogenesis of multiple sclerosis (MS). In mice, we observed that viral infections induce infiltration of B cells into the brain, independent of phenotype and specificity, and that myelin-reactive B cells then capture antigens directly from parenchyma. Trafficking of these antigen-loaded B cells to draining lymph nodes was not observed, and without T cell help, antigen-capturing B cells die rapidly. CD40L signaling or EBV latent membrane protein 1 (LMP1) can override this checkpoint, leading to B cell-receptor- and/or antibody-dependent inflammatory demyelination. Myelin-reactive B cells were identified in the healthy human B cell repertoire, and expression of LMP1 was observed in the brains of a subset of MS patients. These observations can explain the dependency of disease incidence on prior EBV infection, and the increased risk associated with brain infections, and suggest possible treatment strategies.