EBV Infection Empowers Human B Cells for Autoimmunity: Role of Autophagy and Relevance to Multiple Sclerosis

Elena Morandi, S. Anwar Jagessar, Bert A. 't Hart, Bruno Gran*

*Bijbehorende auteur voor dit werk

OnderzoeksoutputAcademicpeer review

46 Citaten (Scopus)
25 Downloads (Pure)

Samenvatting

The efficacy of B cell depletion therapy in multiple sclerosis indicates their central pathogenic role in disease pathogenesis. The B lymphotropic EBV is a major risk factor in multiple sclerosis, via as yet unclear mechanisms. We reported in a nonhuman primate experimental autoimmune encephalomyelitis model that an EBV-related lymphocryptovirus enables B cells to protect a proteolysissensitive immunodominant myelin oligodendrocyte glycoprotein (MOG) epitope (residues 40-48) against destructive processing. This facilitates its cross-presentation to autoaggressive cytotoxic MHC-E-restricted CD8(+) CD56(+) T cells. The present study extends these observations to intact human B cells and identifies a key role of autophagy. EBV infection upregulated APCrelated markers on B cells and activated the cross-presentation machinery. Although human MOG protein was degraded less in EBV-infected than in uninfected B cells, induction of cathepsin G activity by EBV led to total degradation of the immunodominant peptides MOG(35-55) and MOG(1-20). Inhibition of cathepsin G or citrullination of the arginine residue within an LC3interacting region motif of immunodominant MOG peptides abrogated their degradation. Internalized MOG colocalized with autophagosomes, which can protect from destructive processing. In conclusion, EBV infection switches MOG processing in B cells from destructive to productive and facilitates cross-presentation of disease-relevant epitopes to CD8(+) T cells.

Originele taal-2English
Pagina's (van-tot)435-448
Aantal pagina's14
TijdschriftJournal of Immunology
Volume199
Nummer van het tijdschrift2
DOI's
StatusPublished - 15-jul.-2017

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