Broader anti-EBV TCR repertoire in multiple sclerosis: disease specificity and treatment modulation - Report - MDSpire

Broader anti-EBV TCR repertoire in multiple sclerosis: disease specificity and treatment modulation

  • By

  • Tilman Schneider-Hohendorf

  • Christian Wünsch

  • Simon Falk

  • Catarina Raposo

  • Florian Rubelt

  • Hamid Mirebrahim

  • Hosseinali Asgharian

  • Ulrich Schlecht

  • Daniel Mattox

  • Wenyu Zhou

  • Eva Dawin

  • Marc Pawlitzki

  • Sarah Lauks

  • Sven Jarius

  • Brigitte Wildemann

  • Joachim Havla

  • Tania Kümpfel

  • Miriam-Carolina Schrot

  • Marius Ringelstein

  • Markus Kraemer

  • Carolin Schwake

  • Thomas Schmitter

  • Ilya Ayzenberg

  • Katinka Fischer

  • Sven G Meuth

  • Orhan Aktas

  • Martin W Hümmert

  • Julian R Kretschmer

  • Corinna Trebst

  • Ilka Kleffner

  • Jennifer Massey

  • Paolo A Muraro

  • Haiyin Chen-Harris

  • Catharina C Gross

  • Luisa Klotz

  • Heinz Wiendl

  • Nicholas Schwab

  • July 18, 2024

  • 0 min

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Expanded TCR Repertoire Targeting EBV in Multiple Sclerosis

Overview

This study demonstrates that multiple sclerosis (MS) patients exhibit a broader MHC-I-restricted Epstein-Barr virus (EBV)-specific T-cell receptor beta chain (TRB) repertoire compared to healthy controls and other CNS inflammatory diseases. MS therapies such as ocrelizumab, teriflunomide, and dimethyl fumarate selectively reduce EBV-specific TRB sequence matches, indicating modulation of the aberrant EBV-directed T-cell response in MS.

Background

Epstein-Barr virus infection has been strongly linked to the development of multiple sclerosis, with elevated EBV-specific antibodies and CNS damage observed post-infection. Prior research identified an expanded and potentially dysfunctional CD8+ T-cell response to EBV in MS patients, characterized by a broader TRB repertoire. It remains unclear whether this altered EBV-specific T-cell response is unique to MS or shared with other CNS inflammatory diseases, and how it is affected by MS treatments. This study investigates these questions by analyzing peripheral blood TRB repertoires across multiple patient cohorts.

Data Highlights

GroupNumber of SamplesEBV-specific TRB Repertoire Breadth
Healthy Donors409Baseline (Narrower)
MS Patients710Broader than controls
Neuromyelitis Optica Spectrum Disorder87No broadening observed
MOG Antibody-Associated Disease64No broadening observed
Susac’s Syndrome47No broadening observed
MS Patients Post-AHSCTSubsetEBV reactivation coincided with elevated EBV-specific TRB matches

Key Findings

  • MS patients have a significantly broader MHC-I-restricted EBV-specific TRB repertoire compared to healthy controls and patients with NMOSD, MOGAD, or Susac’s syndrome.
  • Other CNS inflammatory diseases evaluated did not show this broadened EBV-specific TRB repertoire, indicating disease specificity to MS.
  • Autologous hematopoietic stem-cell transplantation (AHSCT) in MS patients revealed EBV reactivation coinciding with increased EBV-specific TRB sequence matches.
  • MS therapies including ocrelizumab, teriflunomide, and dimethyl fumarate selectively reduced EBV-specific TRB sequence matches without affecting CMV-specific TRB matches.
  • The expanded EBV-specific T-cell response in MS may reflect an aberrant or ineffective immune reaction contributing to disease pathogenesis.

Clinical Implications

The specificity of the expanded EBV-specific T-cell response to MS suggests that targeting this aberrant immune reaction could be a viable therapeutic strategy. Monitoring EBV-specific TRB repertoires may provide insights into disease activity and treatment response. MS therapies that reduce EBV-specific T-cell clones may help modulate pathogenic immune responses and improve clinical outcomes.

Conclusion

This study confirms that an expanded MHC-I-restricted EBV-specific T-cell repertoire is a distinctive immunological feature of MS, modifiable by current MS therapies. These findings support the role of EBV in MS pathogenesis and highlight potential avenues for targeted therapeutic intervention.

References

  1. Giovannoni 2024 -- Expanded TCR repertoire targeting EBV in multiple sclerosis

Original Source(s)

Broader anti-EBV TCR repertoire in multiple sclerosis: disease specificity and treatment modulation

  • by Tilman Schneider-Hohendorf, Christian Wünsch, Simon Falk, Catarina Raposo, Florian Rubelt, Hamid Mirebrahim, Hosseinali Asgharian, Ulrich Schlecht, Daniel Mattox, Wenyu Zhou, Eva Dawin, Marc Pawlitzki, Sarah Lauks, Sven Jarius, Brigitte Wildemann, Joachim Havla, Tania Kümpfel, Miriam-Carolina Schrot, Marius Ringelstein, Markus Kraemer, Carolin Schwake, Thomas Schmitter, Ilya Ayzenberg, Katinka Fischer, Sven G Meuth, Orhan Aktas, Martin W Hümmert, Julian R Kretschmer, Corinna Trebst, Ilka Kleffner, Jennifer Massey, Paolo A Muraro, Haiyin Chen-Harris, Catharina C Gross, Luisa Klotz, Heinz Wiendl, Nicholas Schwab

  • July 18, 2024

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