Mechanisms for Targeted Multiple Sclerosis Treatment Strategy

Researchers have revealed how Epstein-Barr virus (EBV)-infected B cells can lead to a harmful inflammatory condition that contributes to multiple sclerosis (MS). They have also identified a method to selectively target these problematic B cells, potentially reducing the damaging autoimmune response in MS patients.

The study, conducted by Paul M. Lieberman, Ph.D., at The Wistar Institute, and led by senior scientist Samantha Soldan, Ph.D., has been published in Nature Microbiology. The paper, titled "Multiple sclerosis patient derived spontaneous B cells have distinct EBV and host gene expression profiles in active disease," outlines these findings.

EBV, a herpesvirus, is present in over 90% of the human population as an often symptomless, latent infection. Despite its typically benign nature, EBV has been connected to various diseases, including MS—a chronic autoimmune condition where the body's immune system attacks the myelin sheath surrounding neurons in the brain and nervous system. This myelin sheath is crucial for rapid nerve signaling, and its degradation can result in an array of symptoms, from motor control issues to sensory problems and speech difficulties.

While it is known that EBV plays a role in the onset of MS, the exact mechanisms have remained unclear. Lieberman's lab worked in collaboration with Steven Jacobson, Ph.D., from the Neuroimmunology Branch at the National Institute of Neurological Disorders and Stroke, using cell samples from MS patients and healthy controls. The samples included spontaneous lymphoblastoid cell line (SLCL) cells from healthy individuals, patients with active MS, and patients with stable MS.

B cells are an essential part of the immune system, regulating immune responses. When infected with EBV, these cells become immortalized as lymphoblastoid cell lines (LCLs), meaning they can divide indefinitely. This state can spontaneously emerge as a result of EBV infection, allowing researchers to extract SLCL samples from various patient groups for analysis.

Through genetic analysis of the SLCLs, the researchers found that MS-positive samples exhibited higher expressions of genes linked to lytic EBV. "Lytic" refers to the active phase of the virus. These samples also showed increased inflammatory signaling and higher expression of the FOXP1 protein, which promotes lytic EBV gene expression. These findings suggest that lytic EBV activity in MS patients is linked to increased inflammation and disease progression.

Further investigation by Lieberman's team involved testing several antiviral compounds on the SLCL samples. They discovered that one compound, TAF, effectively reduced lytic EBV gene expression without killing the cells. Additionally, TAF significantly lowered the expression of inflammatory cytokines, such as IL-6, in SLCLs from active MS patients. When SLCLs from active MS, stable MS, and control groups were treated with TAF and exposed to antiviral T cells, the T cell response was reduced in MS patient SLCLs but not in control SLCLs. This indicates that TAF could act as a selectively cytotoxic anti-lytic treatment for MS.

Dr. Lieberman highlighted the importance of their findings: "Our work with these SLCLs shows that the problematic inflammation signaling from lytic EBV can be selectively targeted, reducing damaging immune responses. We are excited about the potential to further explore TAF or other EBV inhibitors as viable treatments for multiple sclerosis, aiming to halt autoimmune damage without causing widespread cell death."

This research offers a promising new direction in understanding and potentially treating multiple sclerosis by targeting the specific EBV-related mechanisms that drive the disease's progression.