Numerous abnormalities in T cells have been described in patients with systemic lupus erythematosus (SLE), including lymphopenia, DNA demethylation, expression of endogenous retroviruses, increased cell death, enlarged mitochondria, production of reactive oxygen species (ROS), and the appearance of CD4-CD8- T cells. We propose a model in which accelerated homeostatic proliferation of T cells promotes an epigenetic and metabolic program leading to this cluster of abnormalities. Recent Advances: Growing knowledge of the innate immune disorders in SLE has included increased mitochondrial size and ROS production that induces oligomerization of mitochondrial antiviral-signaling (MAVS) protein and type I Interferon production, as well as DNA demethylation, upregulation of inflammatory genes, and expression of certain endogenous retroviruses in SLE peripheral blood mononuclear cells (PBMC). All of these events are part of the cellular program that occurs during homeostatic proliferation of T cells.
Despite extensive knowledge of the myriad autoantibodies in SLE and other immune abnormalities, a cogent model has been lacking to link the numerous and seemingly disparate immune aberrations. This may partly explain the general lack of new drugs specifically for SLE in over 50 years. A more coherent model of SLE would not only unify the variety of immune abnormalities is SLE, it would also suggest new therapies.
The model of augmented homeostatic proliferation leading to increased mitochondrial mass, ROS, DNA demethylation, and upregulation of inflammatory genes suggests strategic new targets for SLE, including antioxidants and certain inhibitors of metabolism.