Basophils in Lupus: Mechanisms and Therapy – BALUMET

Systemic Lupus Erythematosus (SLE) is a rare autoimmune disease characterized by autoreactive antibodies (autoAb) mainly raised against nuclear antigens. These autoAb will form some immune complexes that will deposit in target organs where they induce inflammatory flares that can ultimately lead to a loss of function. SLE can affect several organs such as skin, joints or kidneys (Lupus Nephritis, LN). LN affects 30 to 50% of SLE patients who are treated with high doses of corticoids and non-specific immunosuppressors. Developing specific treatment is mandatory in order to ameliorate SLE patient care. SLE evolves by flares of the disease. These flares can be induced and/or amplified by cells from the innate immune system. Basophils are innate immune cells known for their involvement in allergies and parasitic diseases. We recently demonstrated that basophils were activated in the blood of SLE patients by autoreactive IgEs, and more specifically in LN patients. By a translational approach, we demonstrated that basophils were recruited and accumulated in secondary lymphoid organs (SLO) during SLE development where they amplify autoAb production. We also identified the mechanisms by which basophils were recruited in SLO during lupus. These studies led to a very promising clinical trial. However, some key questions still need to be addressed in order to understand how basophils amplify autoAb production once they are in SLOs. The BALUMET project aims at answering these questions by a translational approach and at developing innovative therapeutic modalities, which may prevent LN development in SLE patients. BALUMET (Basophils in LUpus: Mechanisms and Therapy) is a collaborative research project between two teams perfectly complementary for the project’s tasks completion. The first task aims at analyzing SLE patients basophils. Our goal is to evaluate the diagnostic and prognostic values of recently identified surface biomarkers on SLE patient basophils. These new biomarkers suggest that basophils may interact with some T cell subsets that are specialized in the induction of antibody production by B cells. This first task will aim as well at evaluating a new therapeutic approach in SLE-like animal models that may fully prevent the development of LN in SLE patients. The second task of the BALUMET project is based on strong preliminary results showing, in mouse models, a functional relationship between basophils and the aforementioned T cell subset. In SLE-like mouse models, we will demonstrate and decipher molecularly this functional relationship with the help of new mouse strains in which the basophil surface markers identified in SLE patients will be genetically deleted specifically in the basophil compartment. By innovative imaging techniques, we will precisely describe the localization of basophils in SLOs during SLE development. Finally, the third task of the BALUMET project will characterize molecular and functional interactions between the two concerned cell compartments in ex vivo co-culture experiments and in experiments where the identified surface markers of basophils will be engaged. Based on strong preliminary data, the BALUMET project will identify and develop innovative diagnostic, prognostic and therapeutic approaches to ameliorate SLE patient care.