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    Effector and regulatory B-cells during HIV/SIV infection and in Multiple Sclerosis, team Y. Richard

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    Effector and regulatory B-cells during HIV/SIV infection and in Multiple Sclerosis : role of BAFF and dendritic cells 

    Principal investigator: Yolande Richard
    Contact : yolande.richard@inserm.fr         Phone : 33 1 40 51 65 85

     

    Objectives

    B-cells produce antibodies in response to infections or vaccines and/or exert immunoregulatory functions on T-cells and monocytes. My group is interested in B-cell dysfunctions in inflammatory settings associated with pathogenic infections by HIV-1 or SIV (topic 1) and Multiple Sclerosis (topic 2).

    Topic 1. During pathogenic infections with HIV-1 or SIV, B-cell impairments result in: (i) the loss of conventional (resting) memory B-cells but the expansion of atypical memory B-cells (ie: activated and/or tissue-like memory B-cells). The latter population preferentially archives virus-specific antibodies but are unable to achieve its terminal differentiation; (ii) the late and transient production of broadly neutralizing antibodies only in a minority of individuals. A fraction of these antibodies are derived from self/poly-reactive B-cells, possibly generated during germinal center (GC) reaction. Broadly neutralizing antibodies play an unique role in the virus clearance, a better knowledge of mechanisms orchestrating their developmment and controlling the generation of atypical memory B-cell is mandatory.


    BAFF (B-cell activating Factor belonging to the TNF family), a mandatory cytokine for B-cell physiology and humoral response, is overexpressed during acute SIV infection (Chaoul et al., 2012) and in primary HIV-1 infected patients (Borhis et al., 2016). In these patients, we have shown that HIV-1 differentially modulates membrane BAFF expression and its cleavage into its soluble form in myeloid cells and plasmacytoid dendritic cells. Assuming a deleterious role of BAFF excess on the virus-specific response, we are currently studying the impact of BAFF blockade (by the soluble BAFF-R antagonist, BR3-Fc of Biogen Idec) on the generation of memory B-cells and humoral response in the model of SIV infection in macaques. We pay a particular attention to the CG reaction, where plasma cells producing neutralizing/protective antibodies and conventional memory B-cells are generated. We will compare frequencies and functions of CG B-cells and follicular helper T-cells (TFH) in BR3-Fc treated and placebo macaques as well as their capacity to efficiently interact. The second part of the project focuses on comparing B-cells and TFH in macaques infected with SIV or vaccinated with a T-dependent antigen, tetanus toxoid. For each part of the project, we wil search for correlation between B-cell dysfunctions and activation of dendritic cells or monocytes.

    Topic 2. Several subsets of regulatory B-cells were shown to dampen self-reactive responses in autoimmune diseases. Accordingly, our group aims to characterize the phenotype and functions of regulatory B-cells present in patients with Multiple Sclerosis and determine whether BAFF expands them or potentiates their immunosuppressive functions. Indeed, worsening of the disease was reported in patients treated with a BAFF antagonist. We will examine whether the frequency of regulatory B-cells correlates with that of pathogenic TH1/TH17 or that of activated dendritic cells or monocytes.

     

    Resarch interests

    Topic 1. The comparison between SIV infected macaques treated or not with a BAFF antagonist will allow us to determine whether BAFF: (i) contributes to the generation of atypical memory B-cells; (ii) impairs the expansion of CG B-cells and/or TFH or their dialog; (iii) affects the recruitment of regulatory TFH in GC; and (iv) contributes to the activation of monocytes and / or dendritic cells. The comparison between SIV infected and vaccinated macaques aims to better understand CG dysfunctions, particularly in terms of B-cells and TFH interaction and generation of effector B-cells.

    For the topic 2, PBMCs from 30 patients with various forms of Multiple Sclerosis (Coll Pr Laplaud, Department of Neurology, CHU-Nantes) are available as well as PBMC of healthy donors matched for age and gender. Using these samples, we are determining the frequencies and phenotypes of regulatory B-cells for each of the forms of MS (remitting-relapsing or progressives). Next, we will examine whether the frequency of these regulatory B-cells correlates with the frequencies of pathogenic TH1/TH17, of TFH or of activated monocytes and dendritic cells. In vitro, we will determine which are the optimal stimuli for expanding regulatory B-cells from the various blood B-cell subsets of healthy donors. Indeed, we do not know whether any B-cell subset can acquire regulatory functions and by what mechanisms.

    A collaborative project with the group of Armelle Prevost-Blondel which has established the role of IL4I1 in B-cell physiology (Bod et al., 2018), now aims to evaluate whether B cells, expressing or not IL4I1, have pro- or anti-tumoral effect in melanoma in mouse models and in patients. 

    I will also collaborate with the group of Flore Rozenberg to determine which subsets of dendritic cells and B-cells home pathogenic variants of JC virus in patients with progressive Multifocal leukoencephalopathies.

     

    Financial supports

    These programs are supported by ANRS (topic 1) and ARSEP/FRC (topic 2)

     

     

    Publications (2009-2019)

      • Prévost-Blondel A, Richard Y. IL4-induced gene 1 as an emerging regulator of B-cell biology and its role in cutaneous melanoma. Crit Rev Immunol, 2019; 39: 39.
      • Smith N, Rodero MP, Bekaddour N, Bondet V, Ruiz-Blanco YB, Harms M, Mayer B, Badder-Meunier B, Pierre Quartier P, Bodemer C, Baudouin V, Dieudonné Y, Kirchhoff F, Sanchez Garcia E, Charbit B, Nicolas Leboulanger N, Jahrsdörfer B, Richard Y, Korganow AS, Münch J, Nisole S, Duffy D, Herbeuval JP. 2019. Control of TLR7-mediated type I IFN signaling in pDCs through CXCR4 engagement-A new target for lupus treatment.  Sci Adv. 5 (7):eaav9019
      • Audemard-Verger, A., E. Pillebout, A. Jamin, L. Berthelot, C. Aufray, B. Martin, A. Sannier, E. Daugas, J. Dechanet-Merville, Y. Richard, R. Monteiro, and B. Lucas. 2019. Recruitment of CXCR3(+) T cells into injured tissues in adult IgA vasculitis patients correlates with disease activity. J Autoimmun 99: 73-80.
      • Ramspott JP, Bekkat F., Bod L., Favier M., Terris B., Salomon A., Djerroudi L., Zaenker KS, Richard Y, Molinier-Frenkel V, Castellano F, Avril MF and Prévost-Blondel A. 2018. Emerging role of IL4-induced gene 1 as a prognostic biomarker affecting the local T-cell response in human cutaneous melanoma.
      • J Invest. Dermatol. 138 (12): 2625-2634
      • Bod L., Douguet L., Auffray C., Lengagne R., Bekkat F., Rondeau E., Molinier-Frenkel V., Castellano F., Richard* Y. and Prévost-Blondel* A. 2018. IL4-induced gene 1 : a negative immune checkpoint controlling  B cell differentiation and activation. J. Immunol. 200(3), 1027-1038 *corresponding authors.
      • Borhis G, Trovato M, Chaoul N, Ibrahim H, and Richard Y. 2017. B-cell Activating Factor and the B-cell compartment in HIV/SIV infection.  Front. Immunol. 8:1338-1352
      • Borhis G, Burelout C, Chaoul N, Smith N, Goujard C, Meyer L, Paul S, Saoudin H, Hosmalin A, Gilbert C, Herbeuval JP, Richard Y. 2016. Plasmacytoid dendritic cells and myeloid cells differently contribute to BAFF over-expression during primary HIV infection. AIDS 30:365-76
      • Borhis, G., and Y. Richard. 2015. Subversion of the B-cell compartment during parasitic, bacterial, and viral infections. BMC Immunol 16: 15.
      • Borhis G & Richard Y. 2015. Marginal Zone B-cell responses to antigens. Ratcliffe, M.J.H. (Editor in Chief), Encyclopedia of Immunobiology, Vol. 3, pp. 216–226. Oxford: Academic Press.
      • Aloui, C., A. Prigent, C. Sut, S. Tariket, H. Hamzeh-Cognasse, B. Pozzetto, Y. Richard, F. Cognasse, S. Laradi, and O. Garraud. 2014. The signaling role of CD40 ligand in platelet biology and in platelet component transfusion. Int J Mol Sci 15: 22342-22364.      
      • Dutertre, C. A., J. P. Jourdain, M. Rancez, S. Amraoui, E. Fossum, B. Bogen, C. Sanchez, A. Couedel-Courteille, Y. Richard, M. Dalod, V. Feuillet, R. Cheynier, and A. Hosmalin. 2014. TLR3-responsive, XCR1+, CD141(BDCA-3)+/CD8alpha+-equivalent dendritic cells uncovered in healthy and simian immunodeficiency virus-infected rhesus macaques. J Immunol 192: 4697-4708.
      • Garraud, O., G. Borhis, G. Badr, S. Degrelle, B. Pozzetto, F. Cognasse, and Y. Richard. 2012. Revisiting the B-cell compartment in mouse and humans: more than one B-cell subset exists in the marginal zone and beyond. BMC Immunol 13: 63.
      • Dutertre, C. A., S. Amraoui, A. DeRosa, J. P. Jourdain, L. Vimeux, M. Goguet, S. Degrelle, V. Feuillet, A. S. Liovat, M. Muller-Trutwin, N. Decroix, C. Deveau, L. Meyer, C. Goujard, P. Loulergue, O. Launay, Y. Richard, and A. Hosmalin. 2012. Pivotal role of M-DC8(+) monocytes from viremic HIV-infected patients in TNFalpha overproduction in response to microbial products. Blood 120: 2259-2268.
      • Chaoul, N., C. Burelout, S. Peruchon, B. N. van Buu, P. Laurent, A. Proust, M. Raphael, O. Garraud, R. Le Grand, S. Prevot, and Y. Richard. 2012. Default in plasma and intestinal IgA responses during acute infection by simian immunodeficiency virus. Retrovirology 9: 43.
      • Borhis, G., M. Viau, G. Badr, Y. Richard*, and M. Zouali*. 2012. Corruption of human follicular B-lymphocyte trafficking by a B-cell superantigen. Mol Med 18: 636-646. Corresponding auhors
      • Badr, G., O. Garraud, M. Daghestani, M. S. Al-Khalifa, and Y. Richard. 2012. Human breast carcinoma cells are induced to apoptosis by samsum ant venom through an IGF-1-dependent pathway, PI3K/AKT and ERK signaling. Cell Immunol 273: 10-16.
      • Zouali, M., and Y. Richard. 2011. Marginal zone B-cells, a gatekeeper of innate immunity. Front Immunol 2: 63.
      • Lafarge, S., H. Hamzeh-Cognasse, Y. Richard, B. Pozzetto, M. Cogne, F. Cognasse, and O. Garraud. 2011. Complexes between nuclear factor-kappaB p65 and signal transducer and activator of transcription 3 are key actors in inducing activation-induced cytidine deaminase expression and immunoglobulin A production in CD40L plus interleukin-10-treated human blood B cells. Clin Exp Immunol 166: 171-183.
      • Richard, Y., C. Amiel, V. Jeantils, D. Mestivier, A. Portier, G. Dhello, J. Feuillard, R. Creidy, J. C. Nicolas, and M. Raphael. 2010. Changes in blood B cell phenotypes and Epstein-Barr virus load in chronically human immunodeficiency virus-infected patients before and after antiretroviral therapy. J Infect Dis 202: 1424-1434.
      • Peruchon, S., N. Chaoul, C. Burelout, B. Delache, P. Brochard, P. Laurent, F. Cognasse, S. Prevot, O. Garraud, R. Le Grand, and Y. Richard. 2009. Tissue-specific B-cell dysfunction and generalized memory B-cell loss during acute SIV infection. PLoS One 4: e5966.

     

    Alumni

    Visiting Scientist and Post-Doctoral fellows.

    Hany M. Ibrahim. Japanese PhD (2010). Lecturer at the University of Minufiya (Egypt). Visiting Scientist with a short-term fellowship from the French Institute in Egypt (2014). Current position (from 2015): Associate Professor at the University of Minufiya (Egypt).

    Maria Trovato, Italian PhD (2013). Fellowship from ANRS (2016-2018). Current position (from 2018): Science Teacher in high-School (Napoli, Italy)

    Gwenoline Borhis. M2 (2005) & PhD (2005-2008) under the supervision of Y. Richard, with a fellowship from University Paris-Sud.  Three years of post-doctorate in the Laboratory of S. Khakoo (Imperial College, London). Four years of post-doctorate at the Cochin Institute (2011-2015) with fellowships from ANRS and ARSEP. Current position (from 2015): Research Scientist 2 in Onco-Immunology therapeutics area at KYMAB Ltd (Cambridge, UK).

    Chantal Burelout. French Doctorate in Pharmacy. Canadian PhD (2007). Fellowship from European Project (EP7) (2008-2009). Current position (from 2012): Drug Safety Officer at Mayoly Spindler (Paris)

     

    PhD Fellows

    Nada Chaoul. M2 (2006) and PhD University Paris-sud (2006-2010). Fellowships from Lebanese University St-Joseph and CNRS (2006-2007), and Europrise Network of Excellence (EP7)(2007-2010). Post-doctoral fellow in Onco-Immunology at the French Pasteur Institute (C. Leclerc’ s Lab)(2011-2014). Current position from 2016: Research Scientist at University of Bari (Italy).

    Sandrine Peruchon. PhD University of St-Etienne (2003-2007). Fellowships from EFS, ANRS and Sidaction. Recruited as Research Associate in the Retrovirology Unit (CRP-santé, Luxembourg)(2008-2010).

    Gamal Badr. M2 (2001) and PhD University Paris-Sud (2005). Fellowships from Egyptian government (2001-2004) and Sidaction (2004-2005). Post-doctoral fellow at Montreal (Lab N Shoukry, 2007-2008), Assistant Professor in Immunology at King Saud University (2011-2013) and at Assiut University (Egypt) (2013-2016) Current position (from 2016: Full Professor of Immunology at the Faculty of Science of Assiut.

    Jerôme Bernard. M2 (1997) and PhD at University Paris-Sud (1998-2002). Fellowships from Ligue Nationale Contre le Cancer (1999-2000) and ARC (2001-2002). Positions at EuroScreen (Brussels, 2002-2013), Inventiva (2014-17). Current position (from 2017): General Manager at DIAFIR.

    Eric Lefevre. M2 (1996) and PhD at University Paris-Sud (1996-2000). Fellowships from ANRS and Sidaction. Post-doctoral fellow (2001-2004) then Research Associate at the Jenner Institute for Animal Health (Compton, UK) (2004-2014). Current position (from 2014): Research engineer at R&D systems (Abingdon, UK).

    Roman Krzysiek. Polish MD. M2 (PAI Tempus, 1996) and PhD at University Paris-Sud (1996-99). Associate Assistant at University Paris-Sud (1996-98) and fellowship from ARC (1998-99). Clinical Research Assistant at CHU-Bicêtre (2000-2003). MCU at University Paris-Sud (2004-2012). Current position (from 2012): MCU-PH at CHU-Bicêtre.

    Christine Rolling. M2 (1992) and PhD at University Paris-Sud (1992-96). Positions at GSK (1996-97), Wyeth (1999-2001) and LFB (2005-18). Current position (from 2019): Business Manager at Azanta (France)

    Cheikh Momar Nguer. PhD at University Paris-Sud (1995-99). Research Assistant at the Pasteur Institute of Dakar (1995-99). MCU at University of Dakar (1999-present)

    Corinne Leprince. PhD at University Paris-Sud (1985-88). Post-doctoral fellow at University of Washington (Seattle, Pr Ed Clark’ s lab, 1989-1992) with a Fogerty fellowship. Recruited at CRCN at INSERM in 1992 (INSERM u131). CRCN at INSERM-UMR 248 (Curie Institute, 1995-2005), CNRS-UMR5088 (Toulouse, 2006-10) and UMR1056 (Toulouse, 2011- present).

     

    Undergraduate Students (20011-2019 at the Cochin Institute)

    Marine Sirerol (2019). Brevet de Technicien supérieur, 4 months

    Angelique Lubin (2018). Ecole de Techniciens supérieurs ESTBA, 6 months

    Yael Wilkie (2017). Licence professionnelle in Biotechnology and Bioindustry, 6 months

    Yannis Zalagh-Achari (2017). Ecole de Techniciens supérieurs ESTBA, 6 months

    Nassim Djerroud. MD. (2016). M2 in Immunology (Univ Paris XII), 6 months

    Benjamin Morin (2015). Ecole de Techniciens supérieurs ESTBA, 6 months

    Alexandre Lubin (2013). Ecole de Techniciens supérieurs ESTBA, 6 months

    Ezgi Yildiz (2013). M2 in Cellular and Molecular Biology (Univ. Paris VI), 6 months

    Nicolas Brard (2013). M1 in Cellular and Molecular Biology (Univ. Paris VI), 2 months

    Humberto Alzima-Cortes (2014). M1 in Cellular and Molecular Biology (Univ. Paris VI), 2 months 

     

     

     

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