Basophils As Therapeutic Target in systemic Lupus Erythematosus – BATTLE

Systemic Lupus Erythematosus (SLE) is a multifactorial autoimmune disease affecting multiple organs that could lead to death when the kidney damage (lupus nephritis, LN) is confirmed. LN 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. As for many chronic inflammatory diseases, no specific treatment, early diagnostic and prognostic tools exist for SLE. Developing innovative and specific therapeutic approaches will allow a better SLE patient care and will limit the use of invasive diagnostic tests such as kidney biopsy. Basophils, representing less than 1% of circulating leukocytes, are well known for their involvement in allergic and parasitic diseases. Recent studies, including ours, demonstrated their immune regulatory role in immune memory humoral responses, in the TH2 differentiation of CD4+ T cells and during SLE development. We demonstrated in a murine model of SLE that basophils were responsible for an amplification loop of autoantibody production by promoting the TH2 differentiation of CD4+ T cells and the production of autoantibodies by plasma B cells. These functions depend on IL-4 and both total and autoreactive IgE. These results have been confirmed in SLE patients, where basophils are activated and recruited to secondary lymphoid organs (SLOs). We demonstrated that autoreactive IgE titers (able to activate basophils) are correlated with SLE disease activity (especially LN activity) and with basophil activation status. The BATTLE project is the BASILE project follow-up which was funded by the ANR in 2011. The BASILE project confirmed basophil involvement in SLE pathogenesis in several spontaneous or inducible SLE-like mouse models and in a large cohort of over 200 SLE patients, over 300 patients with various chronic kidney diseases and over 120 healthy controls. In addition the BASILE project identified SLE-specific basophil activation profiles leading to a highly promising new therapeutic approach targeting the pathway responsible for basophil accumulation in SLOs. Finally, the BASILE project established a new transgenic mouse model allowing an inducible recombinase CRE expression only in the basophil compartment. The BATTLE project aims to develop the BASILE project results in order to provide new diagnostic, prognostic and therapeutic solutions to SLE patients. The BATTLE project is subdivided into three main tasks. The first one, translational, aims to perform i) a longitudinal follow-up of SLE patients included into the BASILE cohort, ii) a transcriptome analysis of basophils from active SLE patients and healthy controls, and iii) the identification of other chronic inflammatory diseases in which basophils may be involved. The second task corresponds to a pre-clinical strategy aiming to validate the preventive and/or curative effects of the targets identified during the BASILE project in new animal models by pharmacological and/or genetic approaches. The third task, a more basic science approach, aims to generate specific tools for human and murine basophil studies and to identify two new immunoglobulin receptors detected on SLE patient basophils during the BASILE project. ANR’s support to the BATTLE project will allow my team to keep 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.