Systemic lupus erythematosus (SLE) is a complex autoimmune disease affecting multiple organ systems. Several steps forward have been made in unraveling formerly hidden steps of SLE pathogenesis, leading to the conception and testing of multiple targeted therapies against key immune checkpoints sustaining SLE development; nevertheless, the overall dysregulated process leading to a full-blown disease is far from being fully understood.

There is a possibility that SLE becomes an overt disease by a two-step mechanism. Classically, accepted stages in SLE development encompass a genetic predisposition in which tolerance breaches under certain environmental factors (smoking, UV exposure, infections) result in a clinically overt disease [1,2]. In addition, external triggers are likely, yet mechanisms inciting aberrant responses are protean. In a second step and likely related to another external trigger, a subsequent (stochastic) immune activation may lead to the development of organ-specific manifestations following the initial breach of tolerance. As such, the pre-existing autoreactive cells and autoantibodies gain functional relevance. The underlying immune abnormalities of steps 1 and 2 have not been fully delineated but there is a possibility that tissue injury including local interferon (IFN) type I induction could drive the second hit, likely entering a chronic autoimmune stage.