CD8+ T cell-mediated endotheliopathy is a targetable mechanism of neuro-inflammation in Susac syndrome

Abstract

Neuroinflammation is often associated with blood-brain-barrier dysfunction, which contributes to neurological tissue damage. Here, we reveal the pathophysiology of Susac syndrome (SuS), an enigmatic neuroinflammatory disease with central nervous system (CNS) endotheliopathy. By investigating immune cells from the blood, cerebrospinal fluid, and CNS of SuS patients, we demonstrate oligoclonal expansion of terminally differentiated activated cytotoxic CD8+ T cells (CTLs). Neuropathological data derived from both SuS patients and a newly-developed transgenic mouse model recapitulating the disease indicate that CTLs adhere to CNS microvessels in distinct areas and polarize granzyme B, which most likely results in the observed endothelial cell injury and microhemorrhages. Blocking T-cell adhesion by anti-α4 integrin-intervention ameliorates the disease in the preclinical model. Similarly, disease severity decreases in four SuS patients treated with natalizumab along with other therapy. Our study identifies CD8+ T-cell-mediated endotheliopathy as a key disease mechanism in SuS and highlights therapeutic opportunities.

Increased Incidence Of Susac Syndrome: A Case Series Study

“…Elevated serum levels of antiendothelial cells antibodies are found in approximately 25% of the patients, suggestive of an antibody-mediated immunity process [28,29]. Recently a CD8+ Tcell-mediated endotheliopathy has been shown to play a key role in SuS [5]. What triggers this immune response is currently unknown.…”

“…There is a great variability in the clinical presentation of SuS and the complete triad is present in less than 20% of patients at presentation. As a result, misdiagnosis or delay in diagnosis and treatment are common [5][6][7]. Diagnostic procedures such as MRI, FA, OCT [19,20] and audiometry are crucial to enable early and accurate diagnosis since, as mentioned above, subclinical pathology may occur without clinical manifestation [5,7,18].…”

Generation of a Model to Predict Differentiation and Migration of Lymphocyte Subsets under Homeostatic and CNS Autoinflammatory Conditions

“…SuS is a CD8 + -mediated endotheliopathy affecting the microvessels of the brain, eye, and inner ear [7]. Increased proportions of HLA-DR + -expressing CD8 + T cells in both the PB and CSF is a hallmark of this disease [7].…”

“…Under autoinflammatory conditions, barrier dysfunction and/or hyperactivation of immune-cell subsets results in increased migration of pathogenic lymphocytes into the CNS [5]. Furthermore, autoinflammatory CNS diseases may drive lymphocyte activation/differentiation (e.g., differentiation of CD8 + cytotoxic T cells in Rasmussen encephalitis [6] and Susac syndrome (SuS) [7]) and/or intrathecal generation of distinct lymphocyte subsets (e.g., generation of antibody-producing plasmacytoid cells in multiple sclerosis [MS] [8][9][10]). Thus, changes in the composition and activation/differentiation status of lymphocyte subsets in the PB and CSF serve as an indicator of both CNS inflammation and response to immune-modulating therapies.…”

“…Thus, changes in the composition and activation/differentiation status of lymphocyte subsets in the PB and CSF serve as an indicator of both CNS inflammation and response to immune-modulating therapies. Immune profiling of PB and CSF by multi-parameter flow cytometry provides a deeper insight into the disease underlying pathophysiology [6,7,11,12], thereby supporting differential diagnosis, optimized treatment decisions, and monitoring of treatment-related changes (e.g., treatment responses to natalizumab in MS patients [13][14][15][16]) in autoinflammatory CNS diseases.…”