Epigenetic Plasticity Enables CNS-Trafficking of EBV-infected B Lymphocytes

Abstract

Subpopulations of B-lymphocytes traffic to different sites and organs to provide diverse and tissue-specific functions. Here, we provide evidence that epigenetic differences confer a neuroinvasive phenotype. An EBV+ B cell lymphoma cell line (M14) with low frequency trafficking to the CNS was neuroadapted to generate a highly neuroinvasive B-cell population (MUN14). MUN14 B cells efficiently infiltrated the CNS within one week and produced neurological pathologies. We compared the gene expression profiles of viral and cellular genes using RNA-Seq and identified one viral (EBNA1) and several cellular gene candidates, including secreted phosphoprotein 1/osteopontin (SPP1/OPN), neuron navigator 3 (NAV3), CXCR4, and germinal center-associated signaling and motility protein (GCSAM) that were selectively upregulated in MUN14. ATAC-Seq and ChIP-qPCR revealed that these gene expression changes correlated with epigenetic changes at gene regulatory elements. The neuroinvasive phenotype could be attenuated with a neutralizing antibody to OPN, confirming the functional role of this protein in trafficking EBV+ B cells to the CNS. These studies indicate that B-cell trafficking to the CNS can be acquired by epigenetic adaptations and provide a new model to study B-cell neuroinvasion associated CNS lymphoma and autoimmune disease of the CNS, including multiple sclerosis (MS).

Epstein–Barr virus and multiple sclerosis

“…Studies in MS patients and animal models have identified gene variants, miRNAs and viral co-factors that exert epigenetic control to increase inflammation, immune cell differentiation and myelin breakdown 189 . Epigenetic modification of genes that promote neuroinvasion of EBV-positive B cells, including the genes encoding osteopontin and CXCR4, has been described in some experimental models, suggesting that EBV may affect epigenetic mechanisms driving MS 190 .…”

CD4+ Cytotoxic T Cells Involved in the Development of EBV-Associated Diseases

“…Thus, EBV-associated autoimmune diseases, regardless of the cellular or humoral autoreactive response, could be at an increased risk of developing cancer over the years, as is the case in MS [ 174 ] or RA [ 23 , 190 , 191 ]. Thus, the presence of B cells with EBV latency in ectopic lymphoid structures in the tissue where the autoimmune response develops could lead to the development of B-cell lymphoma, as has been observed in the salivary glands in Sjögren’s syndrome [ 258 , 259 , 260 , 261 ], in the thyroid gland in autoimmune thyroiditis [ 220 , 262 , 263 , 264 ], and in the central nervous system in MS [ 265 , 266 ]. Even first-degree relatives of patients with MS have an increased susceptibility for developing Hodgkin’s lymphoma, suggesting that the same environmental factor (EBV infection) in a family environment with similar genetic factors (HLA class II) could predispose some to develop an autoimmune disease, and for others, cancer [ 175 , 176 , 177 ].…”

Primary Peripheral Epstein-Barr Virus Infection Can Lead to CNS Infection and Neuroinflammation in a Rabbit Model: Implications for Multiple Sclerosis Pathogenesis

“…This may mechanistically implicate this chemokine in the migration of virus infected cells to the CNS. Furthermore, EBV infected B cells with phosphoprotein 1/osteopontin gene upregulation have been found to have the potential of infiltrating the CNS ( 45 ). The gene upregulation in these cells is associated with epigenetic changes including histone modification.…”