SFB researchers Dr. Catharina Groß, Prof. Dr. Heinz Wiendl and their team have deciphered important processes in Susac syndrome (Photo: UKM-Fotozentrale / Monecke)

Münster. Neuroinflammation is often associated with blood-brain-barrier dysfunction, which contributes to neurological tissue damage. In a paper published in the renowned journal Nature Communications SFB 128 scientists from Mueenster 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, Dr. Catharina Gross and her team 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. The autors show that 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. Their study identifies CD8+ T-cell-mediated endotheliopathy as a key disease mechanism in SuS and highlights therapeutic opportunities.

Adapted from: Gross CC, Meyer C, Bhatia U, Yshii L, Kleffner I, Bauer J, Tröscher AR, Schulte-Mecklenbeck A, Herich S, Schneider-Hohendorf T, Plate H, Kuhlmann T, Schwaninger M, Brück W, Pawlitzki M, Laplaud DA, Loussouarn D, Parratt J, Barnett M, Buckland ME, Hardy TA, Reddel SW, Ringelstein M, Dörr J, Wildemann B, Kraemer M, Lassmann H, Höftberger R, Beltrán E, Dornmair K, Schwab N, Klotz L, Meuth SG, Martin-Blondel G, Wiendl H, Liblau R. CD8+ T cell-mediated endotheliopathy is a targetable mechanism of neuro-inflammation in Susac syndrome. Nat Commun. 2019 Dec 18;10(1):5779.

Münster. Cerebrospinal fluid (CSF) protects the central nervous system (CNS) and analyzing CSF aids the diagnosis of CNS diseases, but our understanding of CSF leukocytes remains superficial. Here, using single cell transcriptomics, SFB researchers identify a specific border-associated composition and transcriptome of CSF leukocytes. In an article published in Nature Communications, they show that multiple sclerosis (MS) – an autoimmune disease of the CNS – increases transcriptional diversity in blood, but increases cell type diversity in CSF including a higher abundance of cytotoxic phenotype T helper cells. A new analytical approach, named cell set enrichment analysis (CSEA) identifies a cluster-independent increase of follicular T helper (TFH) cells potentially driving the known expansion of B lineage cells in the CSF in MS. In mice, TFH cells accordingly promote B cell infiltration into the CNS and the severity of MS animal models. Immune mechanisms in MS are thus highly compartmentalized and indicate ongoing local T/B cell interaction.

Schafflick D, Xu CA, Hartlehnert M, Cole M, Schulte-Mecklenbeck A, Lautwein T, Wolbert J, Heming M, Meuth SG, Kuhlmann T, Gross CC, Wiendl H, Yosef N, Meyer Zu Horste G . 2020. Integrated single cell analysis of blood and cerebrospinal fluid leukocytes in multiple sclerosis. Nat Commun 11(1):247.

Muenster. For the first time scientists from the University of Münster could show that multiple sclerosis (MS) alters the energy metabolism of T cells during acute phases of disease exacerbation. Therapeutic interventions targeting the metabolism of activated T cells display new potential avenues for treatment of patients with MS affecting around 250,000 people in Germany. The results of the study have recently been published in the renowned journal Science Translational Medicine. In a clinical trial, the authors investigated the effects of the MS drug teriflunomide in patients and analyzed its effects on immune cells. They could reveal that the drug specifically interferes with the energy metabolism of T cells and thereby preferentially affects highly active immune cells. “The drug specifically interferes with the activation of these cells already in the early initiation phase”, explains Luisa Klotz, first author of the article and principal investigator at the DFG-funded collaborative research centre 128 “Multiple Sclerosis”. Science Translational Medicine doi: 10.1126/ scitranslmed. aao5563.

Munich.  Here SFB researchers from Munich use in vivo calcium imaging in a multiple sclerosis model to show that cytoplasmic calcium levels determine the choice between axon loss and survival. Calcium can enter the axon through nanoscale ruptures of the axonal plasma membrane that are induced in inflammatory lesions. Neuron doi: 10.1016/ j.neuron.2018.12.023

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