Selectins impair regulatory T cell function and contribute to systemic lupus erythematosus pathogenesis

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by a loss of tolerance toward self-nucleic acids, autoantibody production, interferon expression and signaling, and a defect in the regulatory T (Treg) cell compartment. In this work, we identified that platelets from patients with active SLE preferentially interacted with Treg cells via the P-selectin/P-selectin glycoprotein ligand-1 (PSGL-1) axis. Selectin interaction with PSGL-1 blocked the regulatory and suppressive properties of Treg cells and particularly follicular Treg cells by triggering Syk phosphorylation and an increase in intracytosolic calcium. Mechanistically, P-selectin engagement on Treg cells induced a down-regulation of the transforming growth factor–β axis, altering the phenotype of Treg cells and limiting their immunosuppressive responses. In patients with SLE, we found an up-regulation of P- and E-selectin both on microparticles and in their soluble forms that correlated with disease activity. Last, blocking P-selectin in a mouse model of SLE improved cardinal features of the disease, such as anti-dsDNA antibody concentrations and kidney pathology. Overall, our results identify a P-selectin–dependent pathway that is active in patients with SLE and validate it as a potential therapeutic avenue.

Systemic Lupus Erythematosus: Pathogenesis at the Functional Limit of Redox Homeostasis

Systemic lupus erythematosus (SLE) is a disease characterized by the production of autoreactive antibodies and cytokines, which are thought to have a major role in disease activity and progression. Immune system exposure to excessive amounts of autoantigens that are not efficiently removed is reported to play a significant role in the generation of autoantibodies and the pathogenesis of SLE. While several mechanisms of cell death-based autoantigenic exposure and compromised autoantigen removal have been described in relation to disease onset, a significant association with the development of SLE can be attributed to increased apoptosis and impaired phagocytosis of apoptotic cells. Both apoptosis and impaired phagocytosis can be caused by hydrogen peroxide whose cellular production is enhanced by exposure to endogenous hormones or environmental chemicals, which have been implicated in the pathogenesis of SLE. Hydrogen peroxide can cause lymphocyte apoptosis and glutathione depletion, both of which are associated with the severity of SLE. The cellular accumulation of hydrogen peroxide is facilitated by the myriad of stimuli causing increased cellular bioenergetic activity that enhances metabolic production of this toxic oxidizing agent such as emotional stress and infection, which are recognized SLE exacerbating factors. When combined with impaired cellular hydrogen peroxide removal caused by xenobiotics and genetically compromised hydrogen peroxide elimination due to enzymatic polymorphic variation, a mechanism for cellular accumulation of hydrogen peroxide emerges, leading to hydrogen peroxide-induced apoptosis and impaired phagocytosis, enhanced autoantigen exposure, formation of autoantibodies, and development of SLE.