The tremendous heterogeneity of the human population presents a major obstacle in understanding how autoimmune diseases like multiple sclerosis (MS) contribute to variations in human peripheral immune signatures. To minimize heterogeneity, SFB researchers from Munich and Muenster made use of a unique cohort of 43 monozygotic twin pairs clinically discordant for MS and searched for disease-related peripheral immune signatures in a systems biology approach covering a broad range of adaptive and innate immune populations on the protein level. Results of their work were published in the latest issue of the prestigious journal PNAS.
Despite disease discordance, the immune signatures of MS-affected and unaffected cotwins were remarkably similar. Twinship alone contributed 56% of the immune variation, whereas MS explained 1 to 2% of the immune variance. Notably, distinct traits in CD4+ effector T cell subsets emerged when Lisa Ann Gerdes, Claudia Janoschka and colleagues focused on a subgroup of twins with signs of subclinical, prodromal MS in the clinically healthy cotwin. Some of these early-disease immune traits were confirmed in a second independent cohort of untreated early relapsing-remitting MS patients. Early involvement of effector T cell subsets thus points to a key role of T cells in MS disease initiation.

Adapted from.
Gerdes LA° Janoschka C°, Eveslage M, Mannig B, Wirth T, Schulte-Mecklenbeck A, Lauks S, Glau L, Gross CC, Tolosa E, Flierl-Hecht A, Ertl-Wagner B, Barkhof F, Meuth SG, Kümpfel T, Wiendl H°, Hohlfeld R*, Klotz L*. Immune signatures of prodromal multiple sclerosis in monozygotic twins. Proc Natl Acad Sci U S A 117(35):21546-21556. (°,*= equal contribution)

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. Although the CNS is immune privileged, continuous search for pathogens and tumours by immune cells within the CNS is indispensable. Thus, distinct immune-cell populations also cross the blood–brain barrier independently of inflammation/under homeostatic conditions. It was previously shown that effector memory T cells populate healthy CNS parenchyma in humans and, independently, that CCR5-expressing lymphocytes as well as CCR5 ligands are enriched in the CNS of patients with multiple sclerosis. Apart from the recently described CD8+ CNS tissue-resident memory T cells, CRC researchers from Muenster identified a population of CD4+CCR5high effector memory cells as brain parenchyma-surveilling cells. In an interview with the German radio news channel NDR info they explain these latest insights. Listen to the radio report (in German):

Adapted from: Herich S, Schneider-Hohendorf T, Rohlmann A, Khaleghi Ghadiri M, Schulte-Mecklenbeck A, Zondler L, Janoschka C, Ostkamp P, Richter J, Breuer J, Dimitrov S, Rammensee HG, Grauer OM, Klotz L, Gross CC, Stummer W, Missler M, Zarbock A, Vestweber D, Wiendl H, Schwab N. Human CCR5high effector memory cells perform CNS parenchymal immune surveillance via GZMK-mediated transendothelial diapedesis. Brain.142(11):3411-3427.

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.

92. Congress of the German Society of Neurology in Stuttgart Foto: Claudius Pflug

Münster. For the third time the renowned neuroscience award “Heinrich Pette prize” goes to Münster, as this year Luisa Klotz was rewarded with the prestigious award for neuroscience researchers and clinicians at the congress of the German Society of Neurology in Stuttgart.

Neurologist and Neuroscientist Luisa Klotz received the award for her outstanding research in the field of Multiple Sclerosis and related neuroinflammatory disorders. She succeeds the director of the department of neurology Prof. Heinz Wiendl (2009) and the director of the institute of translational neurology Prof. Sven Meuth (2014). Read more . . .

 

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

In a large multi-cohort study, performed by the International Multiple Sclerosis Genetics Consortium (IMSGC) and published in Cell Magazine, unexplained heritability for multiple sclerosis (MS) is detected in low-frequency coding variants that are missed by genome-wide association study (GWAS) analyses, further underscoring the role of immune genes in MS pathology. The IMSGC was formed in 2003 with funding from the National Multiple Sclerosis Society and published results from the first GWAS in 2007 that identified the second and third susceptibility genes known to predispose people to developing MS. IMSGC later expanded to include more research groups from more countries, receiving grants to conduct larger GWAS studies. IMSGC brings together researchers from 15 different countries, among them scientists from the SFB-CRC 128 member organizations Technische Universität München and Universitätsmedizin Mainz. A pdf of the article may be found here (restricted access)

Munich. The Cluster for Systems Neurology (SyNergy) by LMU and TUM will receive funding from 2019 on. Currently SFB PIs Prof. Reinhard Hohlfeld, Prof. Martin Kerschensteiner, Prof. Mikael Simons are also PIs of SyNergy projects.

Münster. On January 31, Prof. Roland  Liblau,  Director of the Pathophysiology Research Center at Toulouse Purpan, gave a lecture on “Immune targeting of CNS neurons: from mouse models to human diseases”. Prof. Liblau is one of the most visible neuroimmunologists worldwide which is why the SFB 128 is proud to make his lecture also available online. Just click here to see his presentation.

News

Tue, 08/09/2020
Study with identical twins shows that the early form of multiple sclerosis has a specific pattern
The tremendous heterogeneity of the human population presents a major obstacle in understanding how autoimmune diseases like multiple sclerosis (MS) contribute to variations in human peripheral immune signatures. To minimize heterogeneity, SFB researchers from Munich and Muenster made use of a unique cohort of 43 monozygotic twin pairs clinically discordant for MS and searched for […]...more
Mon, 09/03/2020
Breakthrough: SFB scientsists explain pathomechanism of Susac Syndrome
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, […]...more
Wed, 04/03/2020
The brain is less immune-priviledged than we thought
Münster. Although the CNS is immune privileged, continuous search for pathogens and tumours by immune cells within the CNS is indispensable. Thus, distinct immune-cell populations also cross the blood–brain barrier independently of inflammation/under homeostatic conditions. It was previously shown that effector memory T cells populate healthy CNS parenchyma in humans and, independently, that CCR5-expressing lymphocytes […]...more