CSF single-cell RNA sequencing reveals clonally expanded CD4+stem cell-like memory T cells in GAD65-antibody associated neurological syndromes

  1. Sumanta Barman
  2. Saskia Räuber
  3. Katharina Eisenhut
  4. Daniela Esser
  5. Martijn van Duijn
  6. Madeleine Scharf
  7. Marisol Herrera-Rivero
  8. Paul Disse
  9. Marius Jonas
  10. Duygu Pul
  11. Michael Heming
  12. Louisa Müller-Miny
  13. Manuela Paunovic
  14. Christine Strippel
  15. Ebru Haholu
  16. Elisabeth Kaufmann
  17. Justina Dargvainiene
  18. Sabine Kahl
  19. Marius Ringelstein
  20. Eric Bindels
  21. Heinz Wiendl
  22. Nikolas H. Stoecklein
  23. Johannes Fischer
  24. Norbert Goebels
  25. Lars Komorowski
  26. Michael Roden
  27. Andrea Rossi
  28. Monika Stoll
  29. Sven G. Meuth
  30. Maarten J. Titulaer
  31. Frank Leypoldt
  32. Gerd Meyer zu Hörste
  33. Franziska Thaler
  34. Nico Melzer
  35. cooperation with the EMC-AIE Study group
  36. the German Network for Research on Autoimmune Encephalitis
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Abstract

Background

Glutamic acid decarboxylase (GAD) antibody-associated autoimmune neurological syndromes (AINS) are a spectrum of autoimmune-mediated CNS disorders. While antibodies targeting the 65 kDa isoform of GAD are of high diagnostic value, T cell mediated cytotoxicity has been identified as a key component of disease pathogenesis. The precise pathophysiological mechanisms by which the disease is triggered and maintained, however, remain incompletely understood.

Methods

We performed single-cell transcriptome and immune repertoire sequencing (sc-seq) in CSF and blood of 8 anti-GAD65 AINS patients compared to 8 non-inflammatory controls. Monoclonal antibodies (mAbs) were synthesized from B cell receptor (BCR) data to evaluate the B cellular immune response.

Findings

We identified an increase and expansion of activated CD4+stem cell-like memory T cells (TSCM) in the CSF of anti-GAD65 AINS patients. Expanded T cells showed increased expression of proinflammatory genes. The mAb analysis revealed a high frequency of GAD65-reactive BCRs in the CSF of anti-GAD65 AINS patients with increased somatic hypermutations compared to non-GAD-reactive BCRs and BCRs from controls.

Conclusions

Sc-seq identified clonally expanded CD4+TSCM in the CSF of anti-GAD65 AINS patients harboring cytotoxic properties likely contributing to disease pathogenesis. GAD-reactive B cells circulate in the CSF of anti-GAD65 AINS patients further supporting the concept of an antigen-specific intrathecal immune response. Future studies need to clarify the actual pathogenicity of these immune cells and the link between T and B cellular immune mechanisms in the pathogenesis of anti-GAD65 AINS.

Funding

German Research Foundation (ERARE18-202 UltraAIE), German Federal Ministry of Education and Research (CONNECT GENERATE (2.0); 01GM1908A and 01GM2208A).

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