SLE is a particularly aggressive disease in children, and represents an unmet medical need. We have found that SLE is characterized by major alterations in the dendritic cell system where uncontrolled IFN alpha release drives unabated activation/maturation of myeloid DCs. We have also found that IFN-alpha is a powerful inducer of plasma cell differentiation and survival possibly contributing to the hypergammaglobulinemia observed in SLE patients. Finally, using global gene expression analyses of SLE PBMCs we have identified clusters of differentially expressed genes i) induced by IFN-alpha. ii) expressed by low density immature and mature neutrophils. We have determined that the expression of neutrophil-specific genes 1) correlates with SLE disease activity, 2) allows to discriminate patients with and without lupus nephritis (LN), and 3) predicts the development of LN. These data support that neutrophils play an important role in the pathogenesis of SLE and in the induction of renal disease. Therefore, the goals of the present application are to i) further define the role of neutrophil-encoded transcripts and proteins as markers of disease activity and predictors of response to therapy, ii) to identify the serum factors responsible for the activation/apoptosis of SLE neutrophils, iii) to determine whether neutrophils represent a source of self-antigens for dendritic cells to be presented to T cells and drive autoimmune responses, and iv) to establish the direct role of neutrophils in kidney pathology. Ultimately these studies will further our understanding of SLE pathogenesis and help us develop better therapies to treat SLE patients.
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