Investigations of APRIL, its receptors TACI and BCMA, and EBI2, in the deregulation of B cells and plasma cells in a lupus animal model.
Systemic lupus erythematosus (SLE) is a disorder of systemic autoimmunity characterized by the production of a variety of autoantibodies (antibodies directed against self-components) and subsequent development of immune complex glomerulonephritis. Several mouse strains with different genetic backgrounds spontaneously develop an autoimmune syndrome resembling human SLE. This allows to study the immunological and genetic basis underlying the pathogenesis of SLE and to evaluate various therapeutic approaches. In SLE, B cell (B lymphocyte, the plasma cell precursor. Plasma cells produce autoantibodies) hyperactivity leads to the production of various autoantibodies mainly directed against nuclear constituents such as chromatin, double-stranded and single-stranded DNA (dsDNA and ssDNA), and RNA-related antigens. B cell defects encountered in lupus mice may originate from several altered pathways, such as B cell differentiation and plasma cell survival. We herein propose to study the potential implication of molecules involved in B cells and plasma cell generation that would be relevant in B cell and antibody-mediated autoimmunity such as SLE.
Among these molecules, APRIL (A proliferation inducing ligand), is known to play a crucial role for the control of plasma-cell survival and for the late stages of B-cell differentiation. In this respect, we have shown a beneficial effect on anti-APRIL therapy in a mouse lupus model. In addition, lymphocytes mobility is modulated by the chemoattractant receptor EBI2 (Epstein-Barr virus (EBV)-induced gene 2) which is upregulated during B cell maturation in the bone marrow. EBI2 increases in expression early after activation, before being downregulated during plasma cell differentiation for antibody secretion.
In order to understanding the combined effect of APRIL-receptors TACI and BCMA on B cells and plasma cells during SLE, we plan to study the effect of APRIL-deficiency and APRIL-receptors (BCMA and TACI)-deficiency on the development of the disease in a lupus mice.
The important role for EBI2 in positioning B cells appropriately in order to mount T-dependent antibody response makes it an interesting receptor to be studied in murine lupus context where altered T-dependant autoantibody response is observed. For this reason we intend to investigate the effect of EBI2 deficiency in a spontaneous murine lupus model.
The proposed studies should clarify the potential contribution of APRIL and its receptors, and of EBI2 in deregulated development and/or activation of B cells and plasma cells in the pathogenesis of SLE, thus providing a possible explanation for the mechanism responsible for the break of self-tolerance in SLE. It will be then legitimate to consider these signaling pathways as potential new targets for therapeutic approaches in B cells and antibody-mediated autoimmunity.