Research
B cell differentiation is a highly regulated process. At every step of B cell activation and maturation, mechanisms exist for eliminating or inhibiting autoreactive clones. Deficient control of autoreactive B cells has been implicated in the development and maintenance of several autoimmune diseases. My work focuses on the different mechanisms controlling selection and survival of germinal centre B cells and plasma cells.
1- Survival and homeostasis of plasma cells in the bone marrow depend on soluble factors provided by the microenvironment. The control of long-lived plasma cell survival is a critical goal for the treatment of autoimmune diseases characterized by the production of auto-antibodies. I have recently showed that in lupus nephritis, autoreactive plasma cells mostly home and survive in the inflamed kidneys, suggesting that the renal plasma cell niche may constitute a new therapeutic target. The identification of this cellular niche is in progress.
2- The germinal centre reaction is crucial for the development of switched and high-affinity plasma cells and memory B cells following T-dependent immunisation. Potentially autoreactive clones might also be generated or expanded during the germinal centre reaction and need to be counter-selected. Using a knock-in mouse system where the FcgammaRIIb promoter from wild mice was introduced in a C57BL6 background, I have demonstrated that natural variants of FcgammaRIIb control the up-regulation of this inhibitory receptor upon B cell activation. Accordingly, these knock-in mice failed to up-regulate FcgammaRIIb on germinal centre B cells. Using this model, we were able to demonstrate that FcgammaRIIb up-regulation on germinal centre B cells constitutes an important mechanism controlling the counter-selection of autoreactive B cell clones and the affinity maturation.
Publications
Mancini SJ, Elantak L, Boned A, Espéli M, Guerlesquin F, Schiff C. Examination of galectin-induced lattice formation on early B-cell development.
Methods Mol Biol. 2015;1207:169-84.
Wallin EF, Jolly EC, Suchánek O, Bradley JA, Espéli M, Jayne DR, Linterman MA, Smith KG.Human T follicular helper and T follicular regulatory cell maintenance is independent of germinal centers. Blood. 2014 Sep 15. pii: blood-2014-07-585976.
BSiglec-G deficiency leads to more severe collagen-induced arthritis and earlier onset of lupus-like symptoms in MRL/lpr mice.ökers S, Urbat A, Daniel C, Amann K, Smith KG, Espéli M, Nitschke L.
J Immunol. 2014 Apr 1;192(7):2994-3002. JC, Espéli M, Anderson CA, Linterman MA, Pocock JM, Williams NJ, Roberts R, Viatte S, Fu B, Peshu N, Tran TH, Nguyen HP, Wesley E, Edwards C, Ahmad T, Mansfield JC, Gearry R, Dunstan S, Williams TS, Barton A, Vinuesa CG, UK IBD Genetics Consortium, Parkes M, Lyons PA, Smith KGC. Human SNP links differential outcomes in inflammatory and infectious disease to a FOXO3-regulated pathway”. Cell 2013: in press.
Anginot A, Espéli M, Chasson L, Mancini SJ, Schiff C. Galectin 1 modulates plasma cell homeostasis and regulates the humoral immune response. J Immunol. 2013 Jun 1;190(11):5526-33.
Elantak L, Espéli M, Boned A, Bornet O, Bonzi J, Gauthier L, Feracci M, Roche P, Guerlesquin F, Schiff C. Structural basis for galectin-1-dependent pre-B cell receptor (pre-BCR) activation. J Biol Chem. 2012 Dec 28;287(53):44703-13.
Marion Espéli, Menna R. Clatworthy, Susanne Bökers, Kate E. Lawlor, Antony J. Cutler, Frank Köntgen, Paul A. Lyons, Kenneth G. C. Smith. Analysis of a wild mouse Fcgr2b promoter variant reveals a novel role for FcgRIIb in the control of the germinal center and autoimmunity. J Exp Med. 2012 Nov 19;209(12):2307-19.
Espéli M, Bökers S, Giannico G, Dickinson HA, Bardsley V, Fogo AB, Smith KGC. Local renal autoantibody production in lupus nephritis. JASN, 2011 Feb;22(2):296-305.
Espéli M, Niederer HA, Traherne JA, Trowsdale J, Smith KGC. Genetic variation, Fcγ receptors, KIRs and infection: the evolution of autoimmunity. Curr Opin Immunol. 2010 22(6):715-22.
Espéli M, Mancini SJ, Breton C, Poirier F, Schiff C. Impaired B-cell development at the pre-BII-cell stage in galectin-1-deficient mice due to inefficient pre-BII/stromal cell interactions. Blood. 2009 Jun 4;113(23):5878-86.
