SLE is a particularly aggressive disease in children, and represents an unmet medical need. We have foundthat SLE is characterized by major alterations in the dendritic cell (DC) system, where uncontrolled IFN alpharelease drives unabated activation/maturation of myeloid DCs. The ectopic presence of mature DCs in thecirculation represents an attractive explanation for the breaking of tolerance towards self-components, theessence of SLE. We have also found that IFN-alpha is a powerful inducer of plasma cell differentiation andsurvival possibly contributing to the hypergammaglobulinemia observed in SLE patients. Our hypothesis is that SLE results from two combined alterations: one in the antigen presentationpathway, where an excess of IFN induces the unabated activation of DCs, and one in the B cell pathwaywhere B cells generate an excess of autoreactive plasma cells. IFN-activated DCs are key factors in theseprocesses by presenting nucleosomes to autoreactive B cells and allowing their expansion anddifferentiation. Three complementary though independent Aims have been designed to prove our hypothesis:
Aim 1 will determine the capacity of IFN-DCs (DCs made by culturing healthy monocytes with IFNa) and SLEs-DCs(DCs made by culturing healthy monocytes with SLE serum) to induce the differentiation of healthy and SLEB cells into plasma cells or their precursors.
Aim 2 will determine whether IFN-DCs and SLE-DCs loadedwith apoptotic cells, preferentially select nuclear antigen specific B cells.
Aim 3 will analyze the in vivointeractions between IFN-DCs/SLEs-DCs and B cells in humanized mice . Ultimately these studies willfurther our understanding of SLE pathogenesis and help us identify better targets to treat SLE patients.
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