OX40/OX40L axis: not a friend in autoimmunity

Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease characterized by a loss of tolerance toward nuclear components, and multiple organs such as kidney, brain, vessels or skin are affected. SLE presents a waxing and waning course, rendering its outcome hardly predictable. A better understanding of human SLE pathogenesis is direly needed because only few effective treatments are available. While the precise immunological events that trigger the onset of SLE remain unknown, chronic activation of the dendritic cell (DC) system plays an important role for the activation of autoreactive T and B lymphocytes while overwhelming natural regulatory mechanisms. Generation of autoantibodies targeting broad repertoire of self antigens and formation of immune complexes are the hallmark of SLE. Central to antibody production is the interactions between CD4+ T cells and B cells particularly in germinal centers (GCs), the site of affinity maturation and the subsequent generation of memory B cells and long-lived plasma cells. In SLE, a majority of IgG class autoantibody-producing B cells are somatically mutated indicating that they are derived from GCs [1]. Consistently, recent data in humans and mice show that overrepresentation of T follicular helper cells (Tfh), a CD4+ T cell subset specialized in helping B cells in GCs, is associated with autoimmunity including SLE [2]. However, the mechanism that leads to the exaggerated Tfh response in SLE was largely unknown. Our recent study demonstrated that the OX40-OX40 ligand (OX40L) axis contributes to the lupus pathogenesis in this context [3].