Pathogenicity of cytotoxic T cells lead to the development of microvascular endotheliopathy in Susac syndrome Urvashi Bhatia1*, Ilka Kleffner1*, Lidia Yshii2*, Céline Meyer2*, Markus Schwaninger3, Anna Tröscher4, Jan Bauer4, Guillaume Martin-Blondel2, Sebastian Herich1, Luisa Klotz1, Wolfgang Brück5, Marius Ringelstein6, Jan Dӧrr7, Brigitte Wildemann8, Tilman Schneider-Hohendorf1, Nicholas Schwab1, Klaus Dornmair9, Hans Lassmann4, Roland Liblau2*, Sven Meuth1*, Heinz Wiendl1*, Catharina Gross1* *Authors contributed equally 1Department of Neurology, University of Muenster, 48149 Muenster, Germany; 2INSERM UMR U1043 - CNRS U5282, Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan, Toulouse, France; 3Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Lübeck, Germany; 4Center for Brain Research, Medical University of Vienna, Vienna, Austria; 5Department of Neuropathology, University Hospital Göttingen, Georg-August University Göttingen, Germany, Munich, Germany; 6Department of Neurology, Medical Faculty, Heinrich Heine University, 40225, Düsseldorf, Germany; 7NeuroCure Clinical Research Center, Charité - Universitaetsmedizin Berlin, Berlin, Germany; 8Clinical and Experimental Multiple Sclerosis Research Center, Charité - Universitätsmedizin Berlin, Berlin, Germany; 9Institute of Clinical Neuroimmunology, University Hospital and Biomedical Center, Ludwig-Maximilians University Munich, 80539
Susac syndrome (SuS) is an orphan disease that clinically manifests as branch retinal arterial occlusions (BRAO), encephalopathy and sensorineural hearing loss. Although current studies have postulated an antibody-mediated autoimmune pathogenesis, the etiology of SuS remains unknown. To elucidate the immunopathology of SuS, an in-depth, comparative study of a cohort of 41 patients with clinically defined SuS, 86 healthy individuals, 23 patients with somatoform disorders, and 118 MS patients was performed. Multi-parameter flow cytometry revealed altered CD4/CD8 T cell ratio and proportions of HLA-DR expressing activated CD8 T cells in SuS, indicating that CD8 T cells seem to be important in both systemic and intrathecal pathology of SuS. These cells acquire a distinctive increase in cytotoxicity particularly in cells at a late state of differentiation in the periphery. Detailed analyses of the CD8 T-cell repertoires of these patients, using high throughput sequencing of the CDR3-Vβ region of T-cell receptors further revealed highly clonal repertoires in these patients. Characterization of expanded clones suggests a possible antigenic response in SuS. Additionally, SuS-derived CD8 T cells were found to strongly degranulate in response to TCR-triggering. In vitro functional assays and biopsies of CNS lesions demonstrated that cytotoxic CD8 T cells appear to target microvascular endothelial cells in SuS patients. Collectively, our findings have led to the efficacious treatment of a small cohort of patients with α4-integrin blocking monoclonal antibodies. We speculate that SuS may represent a paradigm of a CD8 T cell-mediated endotheliopathy that is associated with neuro-inflammation.
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