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Understanding the mechanisms controlling the chronicity and severity of autoimmune and infectious diseases

from basic science:
  • innate and adaptive immunity
  • immune regulation
to the translational research:
  • infectious diseases
  • autoimmune diseases
Simon Fillatreau
Immunity in health and disease
S. Fillatreau studied biology at Ecole Normale Supérieure de la rue d’Ulm, Paris, France. He then did his PhD in the laboratory of Prof. David Gray at The University of Edinburgh, UK. He was appointed in 2003 as the head of the Immune Regulation group at the Deutsches Rheuma-Forschungszentrum, a Leibniz Institute Berlin, Germany. Since 2015, he is Professor of Immunology at the Faculté de Médecine de l’Université Paris Descartes. He is AXA professor in Translation Immunology since 2016. In 2015, he received the prestigious European Research Council consolidator award, and GlaxoSmithKline Stiftung Wissenschaftspreise. His work investigates the role of B and T cells in autoimmune and infectious diseases. He discovered regulatory plasma cells, and demonstrated that endogenous self-antigens select thymic-derived autoreactive CD4+Foxp3+ T regulatory cells in a highly specific manner.

Focus

Our group investigates the role of B and T cells in autoimmune and infectious diseases with particular emphasis on the characterization of novel pro-inflammatory and anti-inflammatory B cell as well as plasma cell subsets.

Introduction

The adaptive immune system plays a critical role in the defense against pathogens. Patients presenting with genetic deficiencies resulting in abnormal development or function of T or B lymphocytes are highly susceptible to infectious diseases, and the vast majority of successful vaccines provides protection through the generation of memory lymphocytes including in particular memory B cells and memory plasma cells. However, the adaptive immune system can also cause severe immunopathology when inappropriately reacting against self-antigens or components of the environment, which can lead to autoimmune diseases or allergies, respectively. The activation of such unwanted immune responses is normally controlled by the indexation of lymphocyte activation on signals produced upon the detection of pathogen-associated molecules through the innate immune system, and by the continuous activity of regulatory lymphocytes preventing the activation of potentially pathogenic lymphocytes. These include CD4+Foxp3+ T regulatory cells, and regulatory plasma cells producing the anti-inflammatory cytokines IL-10 and IL-35. Our group studies the antigen-recognition properties of these cells, their ontogeny, their life-span, and their mode of action in health and disease. Our long-term goal is to develop novel strategies to manipulate these cells therapeutically based on the knowledge gained from our basic studies.

Research objectives

Our objectives are to contribute to the identification of the distinctive features controlling the development, maintenance, activation, and function of selected lymphocyte subsets of possible importance in health and disease. We are currently aiming at the characterization of cytokine-producing B cells, with a focus on those expressing the pro-inflammatory mediator IL-6, which have a key role as drivers of autoimmune pathology in diseases such as multiple sclerosis (MS), and those secreting the anti-inflammatory cytokines IL-10 and IL-35, which are impaired in autoimmune disorders, for instance in MS. Our goals are to clarify the development of these cells, their distinctive phenotypic features and antigen-recognition properties, the molecular mechanisms controlling their expression of cytokine, and their life-span as well as potential contribution to immunological memory. In a second project, we are aiming at identifying the molecular mechanisms controlling the life-span of plasma cells in the bone marrow where they can persist for a lifetime in particular immune responses. Finally, we are pursuing our work on the distinctive antigen recognition properties of autoreactive CD4+Foxp3+ T regulatory cells in comparison to autoreactive CD4+Foxp3- T cells, and on the molecular mechanisms controlling the protective value of the former in adoptive cell therapy against autoimmune diseases.

5 main publications

  • Kieback E, et al. (2016) Thymus-Derived Regulatory T Cells Are Positively Selected on Natural Self-Antigen through Cognate Interactions of High Functional Avidity. Immunity 44(5):1114-1126.
  • Li R, et al. (2015) Proinflammatory GM-CSF-producing B cells in multiple sclerosis and B cell depletion therapy. Sci Transl Med 7(310):310ra166.
  • Shen P & Fillatreau S (2015) Antibody-independent functions of B cells: a focus on cytokines. Nat Rev Immunol 15(7):441-451.
  • Shen P, et al. (2014) IL-35-producing B cells are critical regulators of immunity during autoimmune and infectious diseases. Nature 507(7492):366-370.
  • Barr TA, et al. (2012) B cell depletion therapy ameliorates autoimmune disease through ablation of IL-6-producing B cells. J Exp Med 209(5):1001-1010.
Last 30 publications

2016

  • Fillatreau S. Regulatory roles of B cells in infectious diseases. Clin Exp Rheumatol. 2016 Jul-Aug;34(4 Suppl 98):1-5.
  • Korniotis S, Gras C, Letscher H, Montandon R, Mégret J, Siegert S, Ezine S, Fallon PG, Luther SA, Fillatreau S, Zavala F. Treatment of ongoing autoimmune encephalomyelitis with activated B-cell progenitors maturing into regulatory B cells. Nat Commun. 2016 Jul 11;7:12134.
  • Kieback E, Hilgenberg E, Stervbo U, Lampropoulou V, Shen P, Bunse M, Jaimes Y, Boudinot P, Radbruch A, Klemm U, Kühl AA, Liblau R, Hoevelmeyer N, Anderton SM, Uckert W, Fillatreau S. Thymus-Derived Regulatory T Cells Are Positively Selected on Natural Self-Antigen through Cognate Interactions of High Functional Avidity. Immunity. 2016 May 17;44(5):1114-26.
  • Hojyo S, Sarkander J, Männe C, Mursell M, Hanazawa A, Zimmel D, Zhu J, Paul WE, Fillatreau S, Löhning M, Radbruch A, Tokoyoda K. B Cells Negatively Regulate the Establishment of CD49b(+)T-bet(+) Resting Memory T Helper Cells in the Bone Marrow. Front Immunol. 2016 Feb 2;7:26. doi: 10.3389/fimmu.2016.00026. eCollection 2016.
  • Lino AC, Dörner T, Bar-Or A, Fillatreau S. Cytokine-producing B cells: a translational view on their roles in human and mouse autoimmune diseases. Immunol Rev. 2016 Jan;269(1):130-44. doi: 10.1111/imr.12374.
  • 2015

  • Li R, Rezk A, Miyazaki Y, Hilgenberg E, Touil H, Shen P, Moore CS, Michel L, Althekair F, Rajasekharan S, Gommerman JL, Prat A, Fillatreau S, Bar-Or A; Canadian B cells in MS Team. Proinflammatory GM-CSF-producing B cells in multiple sclerosis and B cell depletion therapy. Sci Transl Med. 2015 Oct 21;7(310)
  • Anderton SM, Fillatreau S. Editorial overview: Immunomodulation: New insights for future treatments. Curr Opin Pharmacol. 2015 Aug;23:vii-ix. doi: 10.1016/j.coph.2015.06.005.
  • Shen P, Fillatreau S. Suppressive functions of B cells in infectious diseases. Int Immunol. 2015 Oct;27(10):513-9.
  • Shen P, Fillatreau S. Antibody-independent functions of B cells: a focus on cytokines. Nat Rev Immunol. 2015 Jul;15(7):441-51. doi: 10.1038/nri3857. Review.
  • Fillatreau S. Regulatory plasma cells. Curr Opin Pharmacol. 2015 Aug;23:1-5.
  • Fillatreau S. Pathogenic functions of B cells in autoimmune diseases: IFN-γ production joins the criminal gang. Eur J Immunol. 2015 Apr;45(4):966-70.
  • 2014

  • Sieber J, Daridon C, Fleischer SJ, Fleischer V, Hiepe F, Alexander T, Heine G, Burmester GR, Fillatreau S, Dörner T. Active systemic lupus erythematosus is associated with a reduced cytokine production by B cells in response to TLR9 stimulation. Arthritis Res Ther. 2014 Nov 11;16(6):477.
  • Grötsch B, Brachs S, Lang C, Luther J, Derer A, Schlötzer-Schrehardt U, Bozec A, Fillatreau S, Berberich I, Hobeika E, Reth M, Wagner EF, Schett G, Mielenz D, David JP. The AP-1 transcription factor Fra1 inhibits follicular B cell differentiation into plasma cells. J Exp Med. 2014 Oct 20;211(11):2199-212. doi: 10.1084/jem.20130795. Erratum in: J Exp Med. 2014 Oct 20;211(11):223.
  • Kieback E, Hilgenberg E, Fillatreau S. A method for the generation of TCR retrogenic mice. Methods Mol Biol. 2014;1193:117-26.
  • Miyazaki Y, Li R, Rezk A, Misirliyan H, Moore C, Farooqi N, Solis M, Goiry LG, de Faria Junior O, Dang VD, Colman D, Dhaunchak AS, Antel J, Gommerman J, Prat A, Fillatreau S, Bar-Or A; CIHR/MSSC New Emerging Team Grant in Clinical Autoimmunity.; MSSRF Canadian B cells in MS Team. A novel microRNA-132-sirtuin-1 axis underlies aberrant B-cell cytokine regulation in patients with relapsing-remitting multiple sclerosis [corrected]. PLoS One. 2014 Aug 19;9(8):e105421. doi: 10.1371/journal.pone.0105421. Erratum in: PLoS One. 2014;9(9):e109041.
  • Moura-Alves P, Faé K, Houthuys E, Dorhoi A, Kreuchwig A, Furkert J, Barison N, Diehl A, Munder A, Constant P, Skrahina T, Guhlich-Bornhof U, Klemm M, Koehler AB, Bandermann S, Goosmann C, Mollenkopf HJ, Hurwitz R, Brinkmann V, Fillatreau S, Daffe M, Tümmler B, Kolbe M, Oschkinat H, Krause G, Kaufmann SH. AhR sensing of bacterial pigments regulates antibacterial defence. Nature. 2014 Aug 28;512(7515):387-92.
  • Calderón-Gómez E, Fillatreau S. Utilization of a lentiviral system for the generation of B cells with regulatory properties. Methods Mol Biol. 2014;1190:105-13.
  • Hilgenberg E, Shen P, Dang VD, Ries S, Sakwa I, Fillatreau S. Interleukin-10-producing B cells and the regulation of immunity. Curr Top Microbiol Immunol. 2014;380:69-92.
  • Fillatreau S. Monocyte-derived dendritic cells identified as booster of T follicular helper cell differentiation. EMBO Mol Med. 2014 May 1;6(5):574-6
  • Fillatreau S. Sweetened antibodies against humoral autoimmunity: sialylated antibodies are required for IVIg-mediated therapy. Eur J Immunol. 2014 May;44(5):1276-80.
  • Raftery MJ, Wolter E, Fillatreau S, Meisel H, Kaufmann SH, Schönrich G. NKT cells determine titer and subtype profile of virus-specific IgG antibodies during herpes simplex virus Infection. J Immunol. 2014 May 1;192(9):4294-302.
  • Weber M, Stein P, Prüfer S, Rudolph B, Kreft A, Schmitt E, Bopp T, Roers A, Schild H, Fillatreau S, Radsak MP. Donor and host B cell-derived IL-10 contributes to suppression of graft-versus-host disease. Eur J Immunol. 2014 Jun;44(6):1857-65
  • Dang VD, Hilgenberg E, Ries S, Shen P, Fillatreau S. From the regulatory functions of B cells to the identification of cytokine-producing plasma cell subsets. Curr Opin Immunol. 2014 Jun;28:77-83.
  • Ries S, Hilgenberg E, Lampropoulou V, Shen P, Dang VD, Wilantri S, Sakwa I, Fillatreau S. B-type suppression: a role played by "regulatory B cells" or "regulatory plasma cells"? Eur J Immunol. 2014 May;44(5):1251-7.
  • Shen P, Roch T, Lampropoulou V, O'Connor RA, Stervbo U, Hilgenberg E, Ries S, Dang VD, Jaimes Y, Daridon C, Li R, Jouneau L, Boudinot P, Wilantri S, Sakwa I, Miyazaki Y, Leech MD, McPherson RC, Wirtz S, Neurath M, Hoehlig K, Meinl E, Grützkau A, Grün JR, Horn K, Kühl AA, Dörner T, Bar-Or A, Kaufmann SH, Anderton SM, Fillatreau S. IL-35-producing B cells are critical regulators of immunity during autoimmune and infectious diseases. Nature. 2014 Mar 20;507(7492):366-70.
  • 2013

  • Mensen A, Ochs C, Stroux A, Wittenbecher F, Szyska M, Imberti L, Fillatreau S, Uharek L, Arnold R, Dörken B, Thiel A, Scheibenbogen C, Na IK. Utilization of TREC and KREC quantification for the monitoring of early T- and B-cell neogenesis in adult patients after allogeneic hematopoietic stem cell transplantation. J Transl Med. 2013 Aug 14;11:188.
  • Fillatreau S, Six A, Magadan S, Castro R, Sunyer JO, Boudinot P. The astonishing diversity of Ig classes and B cell repertoires in teleost fish. Front Immunol. 2013 Feb 13;4:28. doi: 10.3389/fimmu.2013.00028.
  • Castro R, Jouneau L, Pham HP, Bouchez O, Giudicelli V, Lefranc MP, Quillet E, Benmansour A, Cazals F, Six A, Fillatreau S, Sunyer O, Boudinot P. Teleost fish mount complex clonal IgM and IgT responses in spleen upon systemic viral infection. PLoS Pathog. 2013 Jan;9(1):e1003098. doi: 10.1371/journal.ppat.1003098.
  • Shen P, Lampropoulou V, Stervbo U, Hilgenberg E, Ries S, Mecqinion A, Fillatreau S. Intrinsic Toll-like receptor signalling drives regulatory function in B cells. Front Biosci (Elite Ed). 2013 Jan 1;5:78-86. Review.
  • Fillatreau S. Cytokine-producing B cells as regulators of pathogenic and protective immune responses. Ann Rheum Dis. 2013 Apr;72 Suppl 2:ii80-4.
  • Permanent researcher
    Simon Fillatreau
    Professor Researcher
    +33(0)1 72 60 64 85
    David Alexandre Gross
    Researcher
    +33 (0)1 44 49 53 65
    Non permanent engineer
    Marylin Harinquet
    Engineer
    Post-doctoral degree
    Jelka Pohar
    Post-Doctoral Researcher
    +33(0)1 72 60 64 86
    PhD
    Cuc Bui Thi
    PhD Student
    Address

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    Support(s)
    HRH Princess Caroline of Hanover, who through the Princess Grace Foundation, already supports medical research and anything that helps to relieve the sick children in France and around the world, has agreed to commit to our side so that our Center of Molecular medicine continues to meet the current challenges and fight diseases, and in particular the ones affecting children.

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