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Single-cell profiling of myasthenia gravis identifies a pathogenic T cell signature

Authors: Ingelfinger, Florian; Krishnarajah, Sinduya; Kramer, Michael; Utz, Sebastian G.; Galli, Edoardo; Lutz, Mirjam; Zwicky, Pascale; Akarca, Ayse U.; Jurado, Nicole Puertas; Ulutekin, Can; Bamert, David; Widmer, Corinne C.; Piccoli, Luca; Sallusto, Federica; Núñez, Nicolás G.; Marafioti, Teresa; Schneiter, Didier; Opitz, Isabelle; Lanzavecchia, Antonio; Jung, Hans H.; De Feo, Donatella; Mundt, Sarah; Schreiner, Bettina; Becher, Burkhard

Online: https://doi.org/10.1007/s00401-021-02299-y

Issue: Acta Neuropathol . 2021 Jun;141(6):901-915.


Myasthenia gravis (MG) is an autoimmune disease characterized by impaired neuromuscular signaling due to autoantibodies targeting the acetylcholine receptor. Although its auto-antigens and effector mechanisms are well defined, the cellular and molecular drivers underpinning MG remain elusive. Here, we employed high-dimensional single-cell mass and spectral cytometry of blood and thymus samples from MG patients in combination with supervised and unsupervised machine-learning tools to gain insight into the immune dysregulation underlying MG. By creating a comprehensive immune map, we identified two dysregulated subsets of inflammatory circulating memory T helper (Th) cells. These signature ThCD103 and ThGM cells populated the diseased thymus, were reduced in the blood of MG patients, and were inversely correlated with disease severity. Both signature Th subsets rebounded in the blood of MG patients after surgical thymus removal, indicative of their role as cellular markers of disease activity. Together, this in-depth analysis of the immune landscape of MG provides valuable insight into disease pathogenesis, suggests novel biomarkers and identifies new potential therapeutic targets for treatment.