Institut für Neuropathologie  
       

 

Arbeitsgruppe Prof. Dr. Martin S. Weber

Professor für Translationale Neuroinflammation


Kontakt:

Prof. Dr. Martin S. Weber

Institut für Neuropathologie, Klinik für Neurologie
Universitätsmedizin Göttingen
Robert-Koch-Str. 40, 37099 Göttingen
Tel. +49 551 39-7706, Fax +49 551 39-10800
email:

Forschungsschwerpunkte und Projekte:

 

Die Arbeitsgruppe für Translationale Neuroimmunologie ist mit Hilfe des Pro Futura Programmes der Universitätsmedizin Göttingen am Institut für Neuropathologie entstanden. Sie widmet sich vorrangig dem Verständnis pathologischer aber auch regulatorischer Mechanismen im Tiermodell der Multiplen Sklerose (MS) sowie in der Erkrankung selbst. Vorrangiges Ziel ist es diese Erkenntnisse möglichst effizient auf zukünftige Therapieansätze zu übertragen.

Im Einzelnen werden folgende Projekte bearbeitet:

  • Die funktionelle Charakterisierung regulatorischer Antigenpräsentation in der experimentellen autoimmunen Enzephalomyelitis (EAE; Förderung durch die Deutsche Forschungsgemeinschaft, Industrie).
  • Die Rolle von B Zellen in Progression und Regulation autoimmuner Entzündung des Zentralen Nervensystems (Förderung durch die Else Kröner-Fresenius Stiftung).
  • Die immunologischen Auswirkungen anti-CD20 vermittelter B Zell Depletierung in EAE und MS (Förderung durch die US National Multiple Sclerosis Society, Industrie).

figure1

Fig. 1

Glatiramer acetate (GA) fosters regulatory properties of antigen presenting cells (APC). GA treatment promotes development of anti-inflammatory type II APC predominantly producing interleukin (IL)-10 and transforming growth factor ? (TGF?). Upon encounter of naïve CD4+ T cells, type II APC deviate T cell differentiation towards preferential development of T helper (Th)-2 cells and Foxp3+ regulatory T cells (Treg). Type II APC and Th2/Treg cells may facilitate each other's development in a positive feedback mechanism, as T cell-derived anti-inflammatory cytokines may in return foster type II differentiation of APC. GA-promoted anti-inflammatory CD4+ T cells may cross the blood-brain-barrier (BBB) and are thought to be locally reactivated within the CNS. In response, these cells may secrete anti-inflammatory cytokines and neurotrophic factors. Another feedback loop between APC and T cells may develop within the CNS itself, as T cell-derived cytokines could also promote type II differentiation of resident or recruited CNS APC. Furthermore, GA treatment is associated with induction of GA-reactive CD8+ T cells and most recent findings indicate that GA may also exert an immunomodulatory effect on B cells promoting secretion of anti-inflammatory cytokines. TCR = T cell receptor; TNF = tumour necrosis factor; indicates decrease.

Fig. 2 The role of B cells in MS

B cells act as a) potent producers of regulating cytokines, b) as antigen-presenting cells (APC) for the activation of T cells and c) as precursors of antibody-secreting plasma cells. B = B cell, T = T cell, mAPC = myeloid APC, IL-6/10 = Interleukin 6/10, TNF = tumor necrosis factor, IFN-g = interferon-gamma, FcR = Fc-receptor.

Fig. 3 Anti-CD20 treatment depletes B cells from established central nervous system (CNS) lesions.

C57BL/6 hCD20 Tg mice received 200 ?g anti-hCD20 or isotype control (IgG2a) weekly after experimental autoimmune encephalomyelitis (EAE) was fully established. After three injections, presence of B cells within spinal cord sections was evaluated B220-immunohistochemistry. Shown are representative spinal cord sections and the number of B220+ cells per square mm of total (left panel), meningeal (middle panel) or parenchymal (right panel) spinal cord tissue.

 

 

 
 :
 Workgroup M. Weber
 

Current staff, from left to right, front row: Eva Habedank, Leila Husseini, Silke Kinzel, Sarah Traffehn;
middle row: Julian Koch, Hannah Pellkofer, Martin Weber, Mareike Gloth, Katja Grondey
back row: Sebastian Torke, Darius Häusler (Linda Feldmann and Hanna Eisenberg not pictured)

 

Former staff (not pictured): Elena Arconada, Jan Einar Albin, Lukas Faiss, Mahboobeh Fereidan Esfahani, Cathrin Gudd,
Caroline Jaß, Sadmann Sakib

 

 

 

Für einen Überblick über das Forschungsgebiet:

  1. Levy M., Wildemann B., Jarius S., Orellano B., Sasidharan S., Weber M.S., Stuve O. Immunopathogenesis of Neuromyelitis Optica. Adv Immunol. 2014;121:213-42
  2. Weber M.S. Is intrathecal anti-CD20 an option to target compartmentalized CNS inflammation in progressive MS? Neurol Neuroimmunol Neuroinflamm 2015 Mar 12;2(2):e84.

  3. Fereidan-Esfahani M., Brück W., Weber M.S. Targeting CNS B cells in progression of MS – is intrathecal anti-CD20 a therapeutic option? JAMA Neurol. 2015 Oct 12:1-2.

  4. Kretzschmar B., Pellkofer H., Weber M.S. The use of oral disease modifying therapies in multiple sclerosis. Curr Neurol Neurosci Rep., 2016 Apr;16(4):38.


Ausgewählte Publikationen:

  1. Molnarfi N., Schulze-Topphoff U., Weber M.S., Patarroyo J.C., Prod’homme T., Varrin-Doyer M., Shetty A., Linington C., Slavin A.J., Hidalgo J., Jenne D.E., Wekerle H., Sobel R.A., Bernard C.C.A., Shlomchik M.J., Zamvil S.S. MHC class II-dependent B cell APC function is required for induction of CNS autoimmunity independent of myelin-specific antibodies; J Exp Med., 2013 Dec 16;210(13):2921-37.
  2. Kowarik M.C., Grummel V., Wemlinger S., Buck D., Weber M.S., Berthele A., Hemmer B. Immune cell subtyping in the cerebrospinal fluid of patients with neurological diseases. J Neurol. 2014 Jan;261(1):130-43.

  3. Weber M.S., Prod'homme T., Youssef S., Dunn S.E., Steinman L., Zamvil S.S. Neither Th2, nor Foxp3+ regulatory T cells appear necessary for therapeutic benefit of atorvastatin in treatment of central nervous system autoimmunity. J Neuroinflammation, 2014 Feb 6;11(1):29. doi: 10.1186/1742-2094-11-29

  4. Lehmann-Horn K., Kinzel S., Feldmann L., Radelfahr F., Hemmer B., Traffehn S., Bernard C., Stadelmman-Nessler C., Brück W., Weber M.S. Intrathecal anti-CD20 efficiently depletes meningeal B-cells in CNS autoimmunity. Ann Clin Trans Neurol. 2014 Jul;1(7):490-6.

  5. Shetty A., Gupta S.G., Varrin-Doyer M., Weber M.S., Prod'homme T., Molnarfi N., Ji N., Nelson P.A., Patarroyo J.C., Schulze-Topphoff U., Fogal S., Forsthuber T., Sobel R.A. Bernard C.C.A., Slavin A.J., Zamvil S.S. Immunodominant T cell epitopes of MOG reside in its transmembrane and cytoplasmic domains in EAE. Neurol Neuroimmunol Neuroinflamm. 2014 Aug 14;1(2):e22.

  6. Varrin-Doyer M, Shetty A, Spencer CM, Schulze-Topphoff U, Weber MS, Bernard CC, Forsthuber T, Cree BA, Slavin AJ, Zamvil SS. MOG transmembrane and cytoplasmic domains contain highly stimulatory T-cell epitopes in MS. Neurol Neuroimmunol Neuroinflamm. 2014 Aug 14;1(2):e20.

  7. Menzfeld C., John M., van Rossum D., Regen T., Scheffel J., Janova H., Götz A., Ribes S., Nau R., Borisch A., Boutin P., Neumann K., Bremes V., Wienands J., Reichardt H.M., Lühder F., Tischner D., Waetzig V., Herdegen T., Teismann P., Greig I., Müller M., Pukrop T., Mildner A., Kettenmann H., Brück W., Prinz M., Rotshenker S., Weber M.S., Hanisch U.-K. Tyrphostin AG126 exerts neuroprotection in CNS inflammation by a dual mechanism. GLIA, 2015 Jun;63(6):1083-99.

  8. Metz I., Traffehn S., Straßburger-Krogias S., Keyvani K., Bergmann M., Nolte K., Weber M.S., Bartsch T., Gold R., Brück W. Glial Cells Express Nuclear Nrf2 After Fumarate Treatment for Multiple Sclerosis and Psoriasis. Neurol Neuroimmunol Neuroinflamm., 2015 Apr 2;2(3):e99.

  9. Molnarfi N., Prod’homme T., Schulze-Topphoff U., Spencer C.M., Weber M.S., Patarroyo J.C. Lalive P.H. and Zamvil S.S. Glatiramer acetate modulates innate immunity by negatively regulating type I interferon signaling Neurol Neuroimmunol Neuroinflamm. 2015 Nov 9;2(6):e179.

  10. Janova H., Böttcher C., Holtman I.R., Regen T., van Rossum D., Götz A., Ernst A.S., Fritsche C., Gertig U., Saiepour N., Gronke N., Wrzos C., Ribes S., Rolfes S., Weinstein J., Ehrenreich H., Pukrop T., Kopatz J., Stadelmann C., Salinas-Riester G., Weber M.S., Prinz M., Brück W., Eggen B.J.L., Boddeke H.W.G.M., Priller J., Hanisch U.K. CD14 is a key organizer of microglial responses to CNS infection and injury. Glia., 2016 Apr;64(4):635-49

  11. Kleiter I., Gahlen A., Borisow N., Fischer K., Wernecke K.D., Wegner B., Hellwig K., Pache F., Ruprecht K., Havla J., Krumbholz M., Kümpfel T., Aktas O., Hartung H.P., Ringelstein M., Geis C., Kleinschnitz C., Berthele A., Hemmer B., Angstwurm K., Stellmann J.P., Schuster S., Stangel M., Lauda F., Tumani H., Mayer C., Zeltner L., Ziemann U., Linker R., Schwab M., Marziniak M., Then Bergh F., Hofstadt-van Oy U., Neuhaus O., Winkelmann A., Marouf W., Faiss J., Wildemann B., Paul F., Jarius S., Trebst C., Neuromyelitis Optica Study Group. Neuromyelitis optica: Evaluation of 871 attacks and 1,153 treatment courses. Ann Neurol. 2016 Feb;79(2):206-16

  12. Kinzel S., Lehmann-Horn K., Torke S., Häusler D., Feldmann L., Winkler A., Stadelmann C., Payne N., Saiz A., Reindl M., Bernard C.C., Lalive P.H., Brück W., Weber M.S. Myelin-reactive antibodies initiate T cell-mediated CNS autoimmune disease by opsonization of endogenous antigen. Acta Neuropathol. 2016 Mar 29. [Epub ahead of print]