Atara Biotherapeutics, Inc. lauded the second high impact study this month solidifying EBV as the primary driver of the development of MS. The paper, titled, “Clonally Expanded B Cells in Multiple Sclerosis Bind EBV EBNA1 and GlialCAM,” was published in the journal Nature. MS is a chronic neurological illness affecting an estimated 2.8 million people worldwide, including approximately 900,000 in the U.S. MS is driven by abnormally activated immune cells and subsequent inflammation which damages and ultimately destroys the protective myelin sheath surrounding nerve fibers in the central nervous system (CNS). While genetics and environmental factors play a role, it has long been postulated that EBV triggers the patient's immune cells to erroneously attack myelin.

The Nature study adds to the known EBV-MS epidemiological connection by providing a mechanistic basis for how EBV infection can trigger the patient's immune cells to attack self-tissue in the CNS. These findings validate molecular mimicry as one of the leading mechanisms of EBV-mediated MS, which occurs when fragments of the virus share sequence or structural similarities with certain brain proteins. The immune system may mistake these “self-proteins” for EBV.

These new data reveal how EBV infection can drive the development of antibodies that target both EBV and CNS proteins, potentially leading to MS. The researchers identified a type of antibody isolated from MS patients' cerebrospinal fluid (CSF), which strongly binds an EBV protein, EBNA1, and cross-reacts with the central nervous system protein GlialCAM. GlialCAM is a cell adhesion molecule expressed in a variety of brain cells, including oligodendrocytes that are responsible for producing myelin, as well as on the outside of myelin sheaths. This antibody cross-reactivity between EBV and self-proteins was found to result from molecular mimicry due to key similarities between GlialCAM and EBNA1.

The group also demonstrated that immunization with EBNA1 in a mouse model of MS exacerbated the disease and generated a strong antibody response against GlialCAM and EBNA1, enhancing immune cell infiltration and demyelination that are two hallmark features of human MS pathology. The Nature paper complements findings from a second publication, “Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis,” recently published in the journal Science, and collectively provide new epidemiological and molecular data confirming the role of EBV in triggering and driving the pathophysiology of MS. The cohort-based study provided compelling epidemiological evidence that EBV infection precedes the onset of MS. The study analyzed 62 million serum samples and followed >10 million individuals in the U.S. military over a 20-year period (1993-2013), showing a 32-fold increase in the risk of MS after EBV infection. Out of the 801 MS cases identified, 35 were EBV negative at baseline with all but one becoming EBV positive before the onset of their MS, yielding a 97% seroconversion rate versus 57% among individuals who did not develop MS. Serum concentrations of neurofilament light chain (sNfL), a sensitive biomarker for nerve fiber damage, only increased after EBV infection, indicating that EBV infection preceded not only symptom onset but also the time of the first detectable pathological mechanisms underlying MS. Other viral infections, like CMV, were not found to increase the risk of MS and were ruled out as a contributing factor in MS development.