Abstract
Multiple sclerosis (MS) is caused by a combination of genetic and environmental factors. It is believed that previous infection with Epstein Barr Virus (EBV) plays an important role in the development of MS. Previously, we developed a murine model where latent infection with gamma herpesvirus 68 (γHV-68), a murine homolog to EBV, enhanced the symptoms of experimental autoimmune encephalomyelitis (EAE), resulting in disease that more closely resembles MS in humans. Here, we explored the conditions that were necessary for EAE enhancement. We showed that latently infected CD19+IgD− B cells were capable of enhancing EAE symptoms when transferred from mice previously infected with γHV-68 into uninfected mice. We also observed a prevention of enhancement when B cells were depleted before infection. However, depletion after the establishment of latency only partially reduced EAE. This indicated the existence of a mechanism where B cells play an important role as antigen presenting cells (APCs) prior to EAE induction for the priming of Th1 cells. It is possible that these signals persist even after B cell depletion, strongly suggesting a paracrine signaling modulation of non-B cell APCs. These results strongly support the concept that EBV contributes to the development of autoimmunity and highlights the need for a vaccine against EBV that could limit or prevent multiple sclerosis development.
Highlights
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) that affects more than 2.2 million people worldwide [1]
When we compared the level of T cell infiltration into the CNS of mice receiving gamma herpesvirus 68 (gHV-68) B cells compared to MEM B cells we found that there was a significant increase in CD8+ T cells in the brain (p < 0.05) and spinal cord (p < 0.05) of mice that received gHV-68 B cells (Figure 1C)
Similar to what we had previously reported [25], there was no statistically significant difference in the infiltration of CD4+ T cells between mice that received gHV-68 B cells and MEM B cells in both the brain and spinal cord (Figure 1D). This confirms that CD19+IgD− B cells from gHV-68 mice are able to drive an increase in CD8+ T cell infiltrates into the CNS
Summary
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) that affects more than 2.2 million people worldwide [1]. As with many autoimmune diseases, the etiology of MS is largely unknown, a combination of genetic elements [2,3,4,5] and environmental factors, including vitamin D deficiency, early-life obesity, gut dysbiosis, smoking, and infections have been associated with MS development [6,7,8,9,10,11]. Previous infection with Epstein-Barr Virus (EBV) is amongst the most prominent viral infections associated with contributing to the development of MS or the worsening of MS progression [12,13,14,15]. This discrepancy has caused a surge in the study of the antigen presentation ability of B cells [19,20,21,22,23,24]
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