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Department of… Research Neuroimmunology Molecular… Multiple…

MULTIPLE SCLEROSIS

Relevance of peripheral immune tolerance mechanisms for the immunopathogenesis of MS

Multiple sclerosis (MS) is caused by a predominantly T cell-mediated autoimmune reaction against myelin antigens initiated by systemic activation of autoreactive T lymphocytes. Our work focuses on elucidating the mechanisms relevant for maintaining peripheral immune tolerance such as homeostasis of naive T cells and for the functioning of regulatory T cells (Treg). We investigate the impact of T cell neogenesis on these parameters in MS in both adult patients and children and adolescents, the effector mechanisms of Treg, the susceptibility of Treg to pharmacological therapy, and the distribution and activation of Treg in inflammatory lesions of the brain.

 

Alterations of B cell homeostasis in patients with MS

The role of B lymphocytes in the pathogenesis of MS is currently being revisited. Clinical studies demonstrating a beneficial effect of B cell-depleting drugs such as rituximab indicate that B cells contribute substantially to disease progression in MS. This project focuses on the composition and interaction of B cell subpopulations in blood and cerebrospinal fluid in different disease stages, as well as on the effects on B cells of long-term treatment with immunomodulatory agents.

Selected publications

  • Ruprecht K, Wildemann B, Jarius S. The paradoxically low frequency of intrathecal antibody production to Epstein-Barr virus in multiple sclerosis: a structured review of the literature. J Neurol 2017 Nov 2; epub ahead of print (doi: 10.1007/s00415-017-8656-z).
  • Jarius S, König F, Metz I, Ruprecht K, Paul F, Brück W, Wildemann B. Pattern II and pattern III MS are entities distinct from pattern I MS: evidence from cerebrospinal fluid analysis. J Neuroinflammation 2017 Aug 29; 14:171.
  • Hahn S, Trendelenburg G, Scharf M, Denno Y, Brakopp S, Teegen B, Probst C, Wandinger KP, Buttmann M, Haarmann A, Szabados F, Vom Dahl M, Kümpfel T, Eichhorn P, Gold H, Paul F, Jarius S, Melzer N, Stöcker W, Komorowski L. Identification of the flotillin-1/2 heterocomplex as a target of autoantibodies in bona fide multiple sclerosis. J Neuroinflammation 2017 Jun 23;14(1):123.
  • Jarius S, Eichhorn P, Franciotta D, Petereit HF, Akman-Demir G, Wick M, Wildemann B. The MRZ reaction as a highly specific marker of multiple sclerosis: re-evaluation and structured review of the literature. J Neurol 2017 Mar;264(3):453-466. [FREE PDF].
  • Breckwoldt MO, Gradl J, Hähnel S, Hielscher T, Wildemann B, Diem R, Platten M, Wick W, Heiland S, Bendszus M. Increasing the sensitivity of MRI for the detection of multiple sclerosis lesions by long axial coverage of the spinal cord: a prospective study in 119 patients. J Neurol 2017 Feb;264(2):341-349.
  • Haas J, Schwarz A, Korporal-Kuhnke M, Jarius S, Wildemann B. Myeloid Dendritic Cells exhibit Defects in Activation and Function in Patients with Multiple Sclerosis. Journal of Neuroimmunology 2016 Dec 15;301:53-60.
  • Schwarz A, Balint B, Korporal-Kuhnke M, Jarius S, von Engelhardt K, Fuerwentsches A, Bussmann C, Ebinger F, Wildemann B*, Haas J*. B-cell populations discriminate between pediatric- and adult-onset multiple sclerosis. Neurol Neuroimmunol Neuroinflamm 2016 Dec 15;4(1):e309.
  • Haas J, Schneider K, Schwarz A, Korporal-Kuhnke M, Faller S, Glehn von F, Jarius S, Wildemann B. Th17 cells: a prognostic marker for MS rebound after natalizumab cessation? Mult Scler 2017 Mar;264(3):453-466.Breckwoldt MO, Gradl J, Hähnel S, Hielscher T, Wildemann B, Diem R, Platten M, Wick W, Heiland S, Bendszus M. Increasing the sensitivity of MRI for the detection of multiple sclerosis lesions by long axial coverage of the spinal cord: a prospective study in 119 patients. J Neurol. 2017 Feb;264(2):341-349.
  • Biller A, Pflugmann I, Badde S, Diem R, Wildemann B, Nagel AM, Jordan J, Benkhedah N, Kleesiek J. Sodium MRI in Multiple Sclerosis is Compatible with Intracellular Sodium Accumulation and Inflammation-Induced Hyper-Cellularity of Acute Brain Lesions. Sci Rep. 2016 Aug 10;6:31269.
  • Huss AM, Halbgebauer S, Öckl P, Trebst C, Spreer A, Borisow N, Harrer A, Brecht I, Balint B, Stich O, Schlegel S, Retzlaff N, Winkelmann A, Roesler R, Lauda F, Yildiz Ö, Voß E, Muche R, Rauer S, Bergh FT, Otto M, Paul F, Wildemann B, Kraus J, Ruprecht K, Stangel M, Buttmann M, Zettl UK, Tumani H. Importance of cerebrospinal fluid analysis in the era of McDonald 2010 criteria: a German-Austrian retrospective multicenter study in patients with a clinically isolated syndrome. J Neurol 2016 Dec;263(12):2499-2504.
  • Andlauer TF, Buck D, Antony G, Bayas A, Bechmann L, Berthele A, Chan A, Gasperi C, Gold R, Graetz C, Haas J, Hecker M, Infante-Duarte C, Knop M, Kümpfel T, Limmroth V, Linker RA, Loleit V, Luessi F, Meuth SG, Mühlau M, Nischwitz S, Paul F, Pütz M, Ruck T, Salmen A, Stangel M, Stellmann JP, Stürner KH, Tackenberg B, Then Bergh F, Tumani H, Warnke C, Weber F, Wiendl H, Wildemann B, Zettl UK, Ziemann U, Zipp F, Arloth J, Weber P, Radivojkov-Blagojevic M, Scheinhardt MO, Dankowski T, Bettecken T, Lichtner P, Czamara D, Carrillo-Roa T, Binder EB, Berger K, Bertram L, Franke A, Gieger C, Herms S, Homuth G, Ising M, Jöckel KH, Kacprowski T, Kloiber S, Laudes M, Lieb W, Lill CM, Lucae S, Meitinger T, Moebus S, Müller-Nurasyid M, Nöthen MM, Petersmann A, Rawal R, Schminke U, Strauch K, Völzke H, Waldenberger M, Wellmann J, Porcu E, Mulas A, Pitzalis M, Sidore C, Zara I, Cucca F, Zoledziewska M, Ziegler A, Hemmer B, Müller-Myhsok B. Novel multiple sclerosis susceptibility loci implicated in epigenetic regulation. Sci Adv. 2016 Jun 17;2(6):e1501678.
  • Laible M, Jarius S, Mackensen F, Schmidt-Bacher A, Platten M, Haas J, Albrecht P, Wildemann B. Adding papillomacular bundle measurements to standard optical coherence tomography does not increase sensitivity to detect prior optic neuritis in patients with multiple sclerosis. PLoS One 2016 May 12;11(5):e0155322.
  • Haas J, Schwarz A, Korporal-Kuhnke M, Faller S, Jarius S, Wildemann B. Hypovitaminosis D upscales B-cell immunoreactivity in multiple sclerosis. J Neuroimmunol 2016 May;294:18–26.
  • Dankowski T, Buck D, Andlauer TF, Antony G, Bayas A, Bechmann L, Berthele A, Bettecken T, Chan A, Franke A, Gold R, Graetz C, Haas J, Hecker M, Herms S, Infante-Duarte C, Jöckel KH, Kieseier BC, Knier B, Knop M, Kümpfel T, Lichtner P, Lieb W, Lill CM, Limmroth V, Linker RA, Loleit V, Meuth SG, Moebus S, Müller-Myhsok B, Nischwitz S, Nöthen MM, Paul F, Pütz M, Ruck T, Salmen A, Stangel M, Stellmann JP, Strauch K, Stürner KH, Tackenberg B, Then Bergh F, Tumani H, Waldenberger M, Weber F, Wiendl H, Wildemann B, Zettl UK, Ziemann U, Zipp F, Hemmer B, Ziegler A; German Competence Network for Multiple Sclerosis (KKNMS). Successful Replication of GWAS Hits for Multiple Sclerosis in 10,000 Germans Using the Exome Array. Genet Epidemiol 2015 Dec;39(8):601-8.
  • Helling B, König M, Dälken B, Engling A, Krömer W, Heim K, Wallmeier H, Haas J, Wildemann B, Fritz B, Jonuleit H, Kubach J, Dingermann T, Radeke HH, Osterroth F, Uherek C, Czeloth N, Schüttrumpf J. A specific CD4 epitope bound by tregalizumab mediates activation of regulatory T cells by a unique signaling pathway. Immunol Cell Biol 2015 Apr;93(4):396-405.
  • Haas J, Schwarz A, Korporal-Kunke M, Jarius S, Wiendl H, Kieseier BC, Wildemann B. Fingolimod does not impair T-cell release from the thymus and beneficially affects Treg function in patients with multiple sclerosis. Mult Scler 2015 Oct;21(12):1521-32.
  • Grützke B, Hucke S, Gross CC, Herold MV, Posevitz-Fejfar A, Wildemann BT, Kieseier BC, Dehmel T, Wiendl H, Klotz L. Fingolimod treatment promotes regulatory phenotype and function of B cells. Ann Clin Transl Neurol 2015 Feb;2(2):119-30.
  • Kolber P, Luessi F, Meuth SG, Klotz L, Korn T, Trebst C, Tackenberg B, Kieseier B, Kümpfel T, Fleischer V, Tumani H, Wildemann B, Lang M, Flachenecker P, Meier U, Brück W, Limmroth V, Haghikia A, Hartung HP, Stangel M, Hohlfeld R, Hemmer B, Gold R, Wiendl H, Zipp F. [Current aspects of therapy conversion for multiple sclerosis]. Nervenarzt 2015 Oct;86(10):1236-47.
  • Balint B, Haas J, Schwarz A, Jarius S, Fürwentsches A, Engelhardt K, Bussmann C, Ebinger F, Fritzsching B, Paul F, Seidel U, Vlaho S, Huppke P, Gärtner J, Wildemann B. T-cell homeostasis in pediatric multiple sclerosis: Old cells in young patients. Neurology 2013;81(9):784-92.
  • Schwarz A, Schumacher M, Pfaff D, Schumacher K, Jarius S, Balint B, Wiendl H, Haas J, Wildemann B. Fine-Tuning of Regulatory T Cell Function: The Role of Calcium Signals and Naive Regulatory T Cells for Regulatory T Cell Deficiency in Multiple Sclerosis. J Immunol 2013 May;190(10):4965-70.
  • Trinschek B, Luessi F, Haas J, Wildemann B, Zipp F, Wiendl H, Becker C, Jonuleit H. Kinetics of IL-6 production defines T effector cell responsiveness to regulatory T cells in multiple sclerosis. PLOS One 2013 Oct 14;8(10):e77634.
  • Schwab N, Schneider-Hohendorf T, Posevitz V, Breuer J, Göbel K, Windhagen S, Brochet B, Vermersch P, Lebrun-Frenay C, Posevitz-Fejfár A, Capra R, Imberti L, Straeten V, Haas J, Wildemann B, Havla J, Kümpfel T, Meinl I, Niessen K, Goelz S, Kleinschnitz C, Warnke C, Buck D, Gold R, Kieseier BC, Meuth SG, Foley J, Chan A, Brassat D, Wiendl H. L-selectin is a possible biomarker for individual PML risk in natalizumab-treated MS patients. Neurology. 2013 Sep 3;81(10):865-71.
  • Elliott C, Lindner M, Arthur A, Brennan K, Jarius S, Hussey J, Chan A, Stroet A, Tomas Olsson, Willison H, Barnett SC, Meinl E, Linington C. Functional identification of pathogenic autoantibody responses in patients with multiple sclerosis. Brain 2012 Jun;135(Pt 6):1819-33.
  • Comi G, Jeffery D, Kappos L, Montalban X, Boyko A, Rocca MA, Filippi M; ALLEGRO Study Group. Placebo-controlled trial of oral laquinimod for multiple sclerosis. N Engl J Med 2012 Mar 15;366(11):1000-9.
  • Haas J, Bekeredjian-Ding I, Milkova M, Balint B, Schwarz A, Korporal M, Jarius S, Fritz B, Lorenz HM, Wildemann B. B cells undergo unique compartmentalized redistribution in multiple sclerosis. J Autoimmun 2011 Dec;37(4):289-99.
  • Filippi M, Rocca MA, Pagani E, De Stefano N, Jeffery D, Kappos L, Montalban X, Boyko AN, Comi G; ALLEGRO Study Group. Placebo-controlled trial of oral laquinimod in multiple sclerosis: MRI evidence of an effect on brain tissue damage. J Neurol Neurosurg Psychiatry. 2014 Aug;85(8):851-8.
  • Tumani H, Deisenhammer F, Giovannoni G, Gold R, Hartung HP, Hemmer B, Hohlfeld R, Otto M, Stangel M, Wildemann B, Zettl UK. Revised McDonald criteria: the persisting importance of cerebrospinal fluid analysis. Ann Neurol 2011 Sep;70(3):520.
  • Fritzsching B, Haas J, König F, Kunz P, Fritzsching E, Pöschl J, Krammer PH, Brück W, Suri-Payer E, Wildemann B. Intracerebral Human FOXP3+ T Cells: Analysis of CD4+CD25+FOXP3+ T cells in Brain Lesions and Cerebrospinal Fluid of Multiple Sclerosis Patients. PLoS One 2011;18:e17988.
  • Haas J, Korporal M, Schwarz A, Balint B and Wildemann B. The interleukin-7 receptor alpha chain contributes to altered homeostasis of regulatory T-cells in multiple sclerosis. Eur J Immunol 2011;41:845-53.
  • Haas J, Korporal M, Balint B, Fritzsching B, Schwarz A and Wildemann B. Glatiramer acetate improves regulatory T-cell function by expansion of naive CD4(+)CD25(+)FOXP3(+)CD31(+) T-cells in patients with multiple sclerosis. J Neuroimmunol 2009;216:113-7.
  • Multiple Sclerosis Therapy Consensus Group (MSTCG), Wiendl H, Toyka KV, Rieckmann P, Gold R, Hartung HP, Hohlfeld R. Basic and escalating immunomodulatory treatments in multiple sclerosis: current therapeutic recommendations. J Neurol. 2008 Oct;255(10):1449-63.
  • Korporal M, Haas J, Balint B, Fritzsching B, Schwarz A, Moeller S, Fritz B, Suri-Payer E and Wildemann B. Interferon beta-induced restoration of regulatory T-cell function in multiple sclerosis is prompted by an increase in newly generated naive regulatory T cells. Arch Neurol 2008;65:1434-9.
  • Haas J, Fritzsching B, Trübswetter P, Korporal M, Milkova L, Fritz B, Vobis D, Krammer PH, Suri-Payer E and Wildemann B. Prevalence of Newly Generated Naïve Regulatory T-Cells is Critical for Treg Suppressive Function and Determines Treg Dysfunction in Multiple Sclerosis. J Immunol 2007;179:1322-30.
  • Fritzsching B, Korporal M, Haas J, Krammer PH, Suri-Payer E, Wildemann B. Similar sensitivity of regulatory T cells towards CD95L-mediated apoptosis in patients with multiple sclerosis and healthy individuals. J Neurol Sci 2006;251:91-7.
  • Haas J, Hug A, Viehöver A, Fritzsching B, Falk CS, Filser A, Vetter T, Milkova L, Korporal M, Fritz B, Storch-Hagenlocher B, Krammer PH, Suri-Payer E, Wildemann B. Reduced suppressive effect of CD4+CD25high regulatory T cells on the T cell immune response against myelin oligodendrocyte glycoprotein in patients with multiple sclerosis. Eur J Immunol 2005;35:3343-52.
  • Fritzsching B, Oberle N, Eberhardt N, Quick S, Haas J, Wildemann B, Krammer PH, Suri-Payer E. In contrast to effector T cells, CD4+CD25+FoxP3+ regulatory T cells are highly susceptible to CD95 ligand- but not to TCR-mediated cell death. J Immunol 2005;175:32-6.
  • Hug A, Korporal M, Schröder I, Haas J, Glatz K, Storch-Hagenlocher B, Wildemann B. Thymic export function and T cell homeostasis in patients with relapsing remitting multiple sclerosis. J Immunol 2003;171:432-7.