A pre-relapse immune signature implicates EBV reactivation in MS relapse

A Boston-based group of scientists found a pro-inflammatory transcriptional signature in patients with MS, up to 3 months before relapse. They identified a monocyte/dendritic cell response to Epstein-Barr virus (EBV) reactivation in B cells as one of the earliest events in the development of MS relapse.

Dr Devin King (Brigham and Women’s Hospital, MA, USA) and colleagues set out to catalogue peripheral immune cells around a relapse, establish a timeline of transcriptomic mechanisms prior to a relapse, and identify and validate novel blood-based biomarkers of relapse [1]. They presented a time-resolved single-cell atlas of the peripheral immune cells in MS relapse. This was based on single-cell RNA sequencing (scRNA-seq) of 30 clinical blood samples from 15 patients with MS and 21 age- and sex-matched healthy controls. The specimens were drawn within 90 days before relapse or during relapse, and paired with remission samples. “Ultimately, we generated 42 scRNA seq-libraries, as well as 36 whole-genome sequencing (WGS) libraries, to better understand the genetic risk factors for MS,” said Dr King. The researchers expanded this to 71 more patients with MS and generated CD3-, CD14-, and CD19-positive cell populations.

From the 15 patients with MS, Dr King and colleagues generated a single-cell reference of 302,874 cells. Peripheral immune cells were found to exhibit widespread transcriptomic perturbations between 7 and 90 days before relapse. The strongest perturbations were found in naïve B cells and intermediate B cells, followed by mucosal-associated invariant T (MAIT) and CD16 monocytes. “Interestingly, these cell perturbations have dampened considerably within 7 days after a relapse,” Dr King added.

A pathway analysis highlighted a fairly unified set of viral processes that precede relapse: responses to the virus, regulation of viral processes, and regulation of viral genome replication. The pre-relapse immune signature was consistent with a host-cell response to EBV activity, including both latent and lytic programmes.

Dr King said the multi-omic cellular atlas offers a wealth of new blood-based biomarkers predictive of disease activity. Several pre-relapse mechanisms are potentially targetable with new and existing therapies. This could contribute to more specific, personalised treatments for patients with MS.

1. King D, et al. A pre-relapse immune signature implicates EBV reactivation in multiple sclerosis attacks. CE1.2, ACTRIMS 2025, 27 February–01 March 2025, West Palm Beach, FL, USA.

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Posted on 28 March 202528 March 2025