BASILE

Systemic Lupus Erythematosus (SLE) is a multifactor-mediated disease affecting multiple organs that could lead to death when the kidney damage (lupus nephritis) is confirmed. Lupus nephritis is characterized by glomerular deposits of IgM, IgG and IgA autoantibodies-containing circulating immune complexes (CIC) which lead to a chronic inflammatory renal disease resulting in kidney failure. SLE has been associated with high IgE levels in patients, without a correlation with any atopic disorder suggesting a Th2 component of the disease. This Th2 component has been completely ignored in recent SLE research reports. As many chronic inflammatory diseases, SLE has no specific treatment available or early diagnostic and prognostic tools. Basophils are immune cells which have not been extensively studied since they represent less than 1% of total leukocytes and very few technical tools exist for their study. Whereas these cells have clearly been associated to allergies and to parasite clearance, they have never been associated to autoimmune disorders yet. Recently, we demonstrated that basophils could induce Th2 differentiation of CD4 T cells in vivo. Moreover, these cells have recently been shown as professional antigen-presenting cells through MHC II and as key effector cells in humoral memory responses via their direct interactions with the B cell compartment. Interestingly, our published and preliminary data on a spontaneous murine model of SLE (Lyn-/- mice) showed that basophils control autoantibody production via their interactions with the B and T cell compartments. We showed as well that lupus nephritis development depends on the Th2 environment generated by basophils, IgE and IL-4. These results have been confirmed in SLE patients whose circulating basophils are constitutively activated. Disease and especially nephritis activities are correlated with IgE autoantibody levels able to directly activate basophils. The BASILE project is subdivided into two main tasks. The first one aims to generate the tools necessary to study basophil involvement in autoimmune diseases such as SLE (inducible basophil-deficient and basophil-specific mice, monoclonal antibodies for basophil activation markers, basophil-depleting antibodies, basophil cell line, basophil primary cell culture conditions…). These tools will allow detailed mechanistic studies of basophil involvement in spontaneous murine models of SLE (MRL/lpr, BSXB, Lyn-/- mice…). The second task concerns all the clinical studies and the application of murine model results to patients samples. This task should allow the demonstration of basophil and autoreactive IgE involvements in SLE pathogenesis. In continuity with the first task, this part should lead to the generation of currently missing diagnostic, prognostic and therapeutic tools for the human pathology. In this perspective, the BASILE project will include clinical trials and studies of large cohorts of patients to validate our strong preliminary results. ANR’s support to the BASILE project will allow my team to quickly reach its cruising speed in a highly competitive research field that is under-represented in France and Europe. Indeed, this project will allow research and development of currently inexistent diagnostic, prognostic and therapeutic solutions for SLE.