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    B-cell response during HIV/SIV infection and in Multiple Sclerosis: Role of BAFF and dendritic cells.

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    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.


    A collaborative project with the group of Armelle Prevost-Blondel  aims to evaluate the role of IL4I1 in the B-cell physiology (Bod et al., J. Immunol, in press) and its ability to control autoimmune disease

     

    The group

    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.

     

    Main publications and patents

    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. 200:1027-1038. *corresponding authors.

    Borhis, G., M. Trovato, N. Chaoul, H. Ibrahim, and Y. Richard. 2017. B-cell-Activating Factor and the B-cell compartment in HIV/SIV infection Front. Immunol. 8:1338-1352 (Review)

    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

    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

     

    Financial supports

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

     

     

     

     

     

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