Systemic Lupus Erythematosus (SLE) is a prototype systemic autoimmune disease characterized by flares of high morbidity for which we have no predictors. Current treatment is symptomatic and based on non-specific immune suppression by glucocorticoids and chemotherapy. Three recent progresses from our group may lead to novel therapeutic modalities in SLE. First, we have shown that monocytes from SLE blood act as dendritic cells (DCs) in an IFN-alpha dependent fashion. Thus, unabated DC induction may drive the autoimmune response in SLE. Second, we found that IFN-alpha is a powerful inducer of plasma cell differentiation and survival, possibly explaining the hypergammaglobulinemia observed in SLE patients. Third, we have confirmed, by oligonucleotide microarrays of patients' white blood cells, the role of IFN and shown that SLE can be distinguished by overexpression of granulopoiesis-related and interferon-induced genes. Repeated IV infusion of glucocorticoids at high dose, the standard treatment of disease flares, shuts down the interferon signature. Thus, SLE may be controlled by targeting IFN-alpha, and targeting IFN-alpha may benefit all SLE patients. These results lead to two fundamental questions: 1) Can we generate IFN antagonists to use as therapeutic agents for the management of SLE? (beside the scope of the present proposal), 2) Why is there so much interferon in SLE patients? To address the second question (the focus of the current proposal) several mechanisms can be considered, including i) the presence of multiple IFN-alpha species, ii) the presence of multiple cells able to produce it, and iii) alterations in IFN transcription/half life. With this in mind we propose the following aims:
Aim 1 will determine whether the interferon subspecies produced by SLE PBMCs are different from those produced by healthy PBMCs;
Aim 2 will determine whether the different IFN subspecies identified in SLE PBMCs are the product of different IFN-producing cells;
Aim 3 will determine the molecular mechanisms leading to excessive IFN production in SLE PBMCs. Thus, the studies proposed here will provide insights into mechanisms of IFN action in SLE as well as invaluable information necessary for developing tools to block the excess of type 1 IFN as novel therapy in SLE. ? ?
