Susac syndrome (SuS) as a paradigm of a CD8 T-cell mediated endotheliopathy

• Applicant: Dr. Catharina C. Groß
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Immunology ; Clinical Neurology; Neurosurgery and Neuroradiology
• Term: from 2017 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 385011349

Susac syndrome (SuS) is an orphan disease with approximately 300 cases worldwide that manifest with a clinical triad of branch retinal artery occlusions, sensorineural hearing loss, and encephalopathy. Although it has been postulated that the disease is caused by an autoimmune-mediated occlusion of microvessels of the affected organs, the role of the immune system in its pathogenesis still needs to be elucidated. A comparative study by our own group including 34 patients with definite SuS, the largest cohort in Europe, revealed a crucial role of cytotoxic CD8+ T cells in the pathology of SuS. Enhanced frequencies of HLA-DR expressing activated CD8+ T cells in both the peripheral blood and cerebrospinal fluid indicates systemic SuS related changes. SuS patients showed increased frequencies of circulating terminally differentiated effector memory CD8+ TEMRA cells as well as bona fide cytotoxic T lymphocytes (CTL). CD8+ T effector cells derived from SuS patients evaded regulatory T-cell mediated suppression in vitro, expressed higher amounts of granzyme B and perforin, and exhibited a higher cytolytic activity upon T-cell receptor (TCR) triggering. Moreover, SuS patients showed a higher degree of alterations in the CD8+ TCR repertoire when compared to healthy individuals, but more importantly also to MS patients. CDR3 sequencing revealed strong clonal expansions of CD8+ T-cell clones with a significant number of shared clones between SuS patients. Occurrence of cytotoxic CD8+ T cells close to the vessel wall in CNS specimen of SuS patients suggests a CD8-mediated endotheliopathy. The efficacy of Natalizumab treatment interfering with lymphocyte transmigration at the blood/brain/barrier in a pilot study of SuS patients further highlights the potential significance of immune-endothelial cell interaction in this disease. Based on our findings, we propose that SuS shows the hallmark of a CD8+ T-cell driven microvascular endotheliopathy associated with neuroinflammation. Using biomaterial (peripheral blood, CSF, and brain biopsies) from SuS patients we will (i) investigate potential causes driving CD8+ T-cell differentiation in SuS, (ii) reveal the mechanism of CD8+ T-cell mediated endotheliopathy in SuS in vitro, and (iii) study the functional impact of SuS-derived CD8+ T cells in vivo using a humanized mouse model. Comparison of our findings with data from patients with multiple sclerosis (MS) and Rasmussen Encephalitis (RE) will obtain insight into similarities and differences between SuS and both its important differential diagnosis (MS) and another CD8+-mediated encephalopathy targeting neuronal structures within the CNS (RE), respectively. A better understanding of the role of CD8+ T cells in the pathophysiology of SuS will help to find new and more specific treatment options and broaden our knowledge on T-cell mediated neurological diseases.

• DFG Programme: Research Grants
• Co-Investigator: Dr. Ilka Kleffner