Myelin antigen capture in the CNS by B cells expressing EBV latent membrane protein 1 leads to demyelinating lesion formation
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.
HIGHLIGHTS
• Naive myelin-reactive B cells enter the brain and capture antigen
• B cells capturing antigen in the brain die by activation-induced cell death
• EBV protein LMP1 can rescue B cells from activation-induced cell death
• B cells rescued after antigen capture induce multiple-sclerosis-like demyelinated lesions
Web | DOI | PDF | Cell | Open Access
Hyein Kim; Mika Schneider; Yakine Raach; Panajotis Karypidis; Julien Roux; Georgios 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 Sr 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.
HIGHLIGHTS
• Naive myelin-reactive B cells enter the brain and capture antigen
• B cells capturing antigen in the brain die by activation-induced cell death
• EBV protein LMP1 can rescue B cells from activation-induced cell death
• B cells rescued after antigen capture induce multiple-sclerosis-like demyelinated lesions
Web | DOI | PDF | Cell | Open Access