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

Abstract

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 proteolysis-sensitive immunodominant myelin oligodendrocyte glycoprotein (MOG) epitope (residues 40-48) against destructive processing. This facilitates its cross-presentation to autoaggressive cytotoxic MHC-E-restricted CD8CD56 T cells. The present study extends these observations to intact human B cells and identifies a key role of autophagy. EBV infection upregulated APC-related 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 and MOG Inhibition of cathepsin G or citrullination of the arginine residue within an LC3-interacting 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.

Epstein–Barr Virus in Multiple Sclerosis: Theory and Emerging Immunotherapies

“…Latently infected cells accumulate in lymphoid tissues in the MS brain, resulting in prolonged exposure to local antigens (such as myelin). Reports of EBV-infected autoreactive plasma cells in the synovium of rheumatoid arthritis patients and in salivary 106]. EBV also upregulated the antigen-presenting machinery of infected B cells and facilitated cross-presentation of immunogenic MOG peptides to CD8 + T cells [107].…”

Differences of basic and induced autophagic activity between K562 and K562/ADM cells

“…Abnormal basal autophagy can lead to various human diseases including cancer, neurodegenerative disorders, autoimmunity disease and inflammation (12)(13)(14)(15). Autophagy can be induced in response to several stressors including: nutrient deprivation, chemotherapeutics, hypoxia, pathogen infection and endoplasmic reticulum stress (16)(17)(18).…”

Infections, Vaccines and Autoimmunity: A Multiple Sclerosis Perspective

“…Multiple experimental and histopathological studies have proposed potential mechanisms which can explain the interactions between EBV and the immunopathophysiolocal MS cascade. EBV infection significantly activates B-cells and upregulates their ability to present antigens [38]. Now as potent antigen-presenting cells, the infected B-cells will more efficiently process the relevant myelin autoantigen, attach it to their major histocompatibility complex II (MHC-II) receptors and cross-present them to the pathogenic CD8 + T-cells [38,39].…”