Sumanta Barman, Saskia Räuber, Katharina Eisenhut, Daniela Esser, M. L. van Duijn, Madeleine Scharf, Marisol Herrera-Rivero, Paul Disse, Lara-Maria Preuth, Valeria Gulyaeva, Ilja Schwan, Eliza vom Stein, Marius Jonas, Duygu Pul, Michael Heming, Louisa Müller-Miny, Manuela Paunovic, Christine Strippel, Ebru Haholu, Jan Bartosch, Elisabeth Kaufmann, Justina Dargvainiene, S. Kahl, Marius Ringelstein, Eric M. Bindels, Heinz Wiendl, Nikolas H. Stoecklein, Johannes Fischer, Norbert Goebels, Lars Komorowski, Michael Roden, Andrea Rossi, Monika Stoll, A. Becker, Motaz Hamed, Christian G. Bien, Romana Höftberger, J Bauer, Sven G. Meuth, Maarten J. Titulaer, Frank Leypoldt, G Meye. z. Hörste, Franziska Thaler, Nico Melzer, Juna M. de Vries, Mariska M. P. Nagtzaam, Suzanne C. Franken, Yvette S. Crijnen, Juliëtte Brenner, Robin W. van Steenhoven, Jeroen Kerstens, Marienke A. A. M. de Bruijn, Anna E.M. Bastiaansen, Remco M. Hoogenboezem, Sharon Veenbergen, Peter A.E. Sillevis Smitt, Marwa Al-Dubai, Luise Appeltshauser, Ilya Ayzenberg, Carolin Baade-Büttner, Andreas van Baalen, Sebastian Baatz, Oliver Bähr, Bettina Balint, Iason Bartzokis, Sebastian Bauer, Annette Baumgartner, Tobias Baumgartner, Antonios Bayas, Stefanie Becker, Sonka Benesch, Robert Berger, Birgit Berger, Martin Berghoff, Sarah Bernsen, Achim Berthele, Christian G. Bien, Corinna Bien, Julia Bierwith, Andreas Binder, Stefan Bittner, Daniel Bittner, Franz Blaes, Astrid Blaschek, Amelie Bohn, Moritz Philipp Böhringer, Marie Braun, Sergio Castro-Gomez, Justina Dargvainiene, Timo Deba, Julia Maren Decker, Johanna-Maria Dietmaier, Andre Dik, Julian Dominik, Kathrin Doppler, Mona Dreesmann, Lena Edelhoff, Laura Ehrhardt, Sven Ehrlich, Katharina Eisenhut
The immunopathogenesis of autoimmune neurological syndromes (AINS) with antibodies against the 65 kDa isoform of glutamic acid decarboxylase (anti-GAD65 AINS) remains poorly understood. To elucidate underlying disease mechanisms and identify relevant cell populations, we performed single-cell RNA and immune repertoire sequencing of cerebrospinal fluid (CSF) and peripheral blood mononuclear cells (PBMCs) of eight anti-GAD65 AINS individuals compared to eight noninflammatory controls. In addition, PBMCs from 19 anti-GAD65 AINS individuals and 20 healthy controls were analyzed by multidimensional flow cytometry, and brain tissue specimens from four anti-GAD65 AINS individuals were examined histologically. We detected higher frequencies of stem cell–like memory T cells (TSCM) within the PBMCs and a marked enrichment and clonal expansion of activated CD4 + TSCM in the CSF of anti-GAD65 AINS individuals. Expanded T cells exhibited increased expression of proinflammatory genes. Histological analyses confirmed intraparenchymal CD8 + TSCM in three of four anti-GAD65 AINS individuals and rare meningeal/intraparenchymal CD4 + TSCM in one person. Although CSF B cell receptors (BCRs) displayed little to no clonal expansion, recombinant expression of 40 CSF BCRs revealed that 25% were GAD65-reactive with increased somatic hypermutations compared to non-GAD65-reactive BCRs. These findings further support the concept of an antigen-specific intrathecal immune response. In summary, we characterize the immune landscape of anti-GAD65 AINS at single-cell resolution and identify clonally expanded TSCM with cytotoxic properties as a hallmark of this disease.