Systemic lupus erythematosus is an autoimmune disease with multiple causes that can affect the skin, joints, or kidneys. It affects approximately 50 per 100,000 individuals, predominantly young women. The breakdown of immune tolerance leads to the production of autoantibodies directed primarily against nuclear components of the cell. Together with these antigens and complement proteins, they form immune complexes that deposit in tissues and sustain chronic inflammation there; renal involvement is the leading cause of morbidity and mortality. Follicular helper T cells, which are more abundant in the blood of patients, amplify this response by organizing the germinal centers of lymphoid organs, where B cells differentiate into antibody-producing cells, notably under the influence of interleukin 21.
This News article focuses on basophil granulocytes, known for their role in type 2 immunity directed against parasites and allergens. Previous work had shown that during lupus, these cells are activated, notably by IgE contained in immune complexes, and migrate to the spleen and lymph nodes, where they promote autoantibody production. The mechanisms involved remained to be clarified.
In two murine models of lupus, one spontaneous and the other pristane-induced, the accumulation of follicular helper T cells depends on basophils. Their depletion reduces these cells, germinal center B cells, autoantibodies, and immune complex deposits in the kidneys. In the spleen, basophils position themselves at the boundary between T and B zones, in contact with the precursors of these helper cells, and primarily support those of the type 2 subset, which produce interleukin 4. In patients, these type 2 cells are more abundant in the blood, and their number correlates with disease severity. Two molecules carried by basophils prove decisive: the ligand PD-L1, whose expression increases in lupus in both humans and mice under the influence of interleukin 3 and IgE, and interleukin 4. Their specific deletion in basophils limits the accumulation of helper cells and of autoreactive IgG. In culture, basophils direct naive T cells toward this profile through the interaction between PD-L1 and PD-1 and through interleukin 4, by activating the factor GATA3 and repressing BACH2.
In mice, antibodies neutralizing interleukin 3 or interleukin 4 rapidly and markedly reduce the number of follicular helper T cells and autoantibody-producing cells. Basophils, together with interleukins 3 and 4, thus emerge as promising therapeutic targets in systemic lupus erythematosus.