Study identifies mechanisms for selective MS treatment strategy

June 07, 2024
A new study suggests B cells infected with the Epstein-Barr virus can influence a pathogenic, inflammatory phenotype that contributes to multiple sclerosis. The study’s authors show how these problematic B cells can be selectively targeted in a way to reduce the damaging autoimmune response of MS. 

EBV — a usually inactive herpesvirus — affects most of the human population; more than 90 percent of people carry the virus as a passive, typically symptomless infection. However, EBV infection has been linked to several diseases, including MS — an incurable, chronic autoimmune disease which causes the body’s immune system to attack the myelin sheath of neurons in the brain and nervous system. Because myelin sheathing facilitates fast nervous system signaling (the fatty insulation of myelin along a neuron’s axon allows electrical impulses to travel through neuronal networks faster), its degradation can cause a wide variety of symptoms in both type and severity that may include motor control disruption, sensory issues, and speech difficulties.

Though researchers know that EBV can contribute to the development of MS, the exact mechanisms by which it does so are not completely understood. In seeking to understand how EBV contributes to the development of MS, Wistar Institute researchers collaborated with the Neuroimmunology Branch at the National Institute of Neurological Disorders and Stroke, which contributed cell line samples from patients. The research team analyzed spontaneous lymphoblastoid cell line cell samples from a healthy control group and a group of patients with MS. 

B cells are crucial cells of the immune system that help regulate the body’s immune responses. They have also been implicated in autoimmune conditions because of their role as mediators of which biological signals warrant immune response. And B cells, when infected with EBV, become immortalized — that is, the cells are no longer constrained by senescence, so they can continue to divide an indefinite number of times — as “lymphoblastoid cell lines,” or LCLs. This immortalized B cell state can occur spontaneously within the body as a result of EBV infection, which is how researchers were able to extract immortalized spontaneous lymphoblastoid cell line samples for study from the different patient groups. 

Having obtained the matched samples, researchers conducted genetic analyses of the spontaneous lymphoblastoid cell lines and confirmed the MS-positive sample group showed greater expression of genes linked to lytic EBV (“lytic” describes when latent viruses like EBV become active). They also saw increased inflammatory signaling and expression of the FOXP1 protein, the latter of which was shown to promote lytic EBV gene expression. The findings suggested a mechanism of lytic EBV in MS that promoted inflammation and disease. 

Diving further, researchers tested several antiviral compounds on all spontaneous lymphoblastoid cell line groups and found that one, TAF, reduced lytic EBV gene expression without killing the cells. TAF also significantly reduced the expression of inflammatory cytokines such as IL-6 in the SLCLs from the patients with active MS. Finally, when cultured SLCLs from multiple sclerosis and controls were administered TAF in the presence of antiviral T cells, the T cell response (a major factor in the autoimmune dysfunction of MS) was reduced in SLCLs from patients with MS but not reduced in the control spontaneous lymphoblastoid cell lines — an indication that TAF treatment has potential as a selectively cytotoxic antilytic treatment for MS.

The study’s authors said their work with spontaneous lymphoblastoid cell lines shows the problematic inflammation signaling from lytic EBV can be selectively targeted in a way that demonstrably reduces damaging immune responses. They’re interested in expanding this concept further. They have the potential to see whether TAF or other inhibitors of EBV might be a viable treatment for MS that can stop the autoimmune damage without causing wide-ranging and dangerous cell death.

The findings were published in the journal Nature Microbiology.

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