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 (DC) system, where uncontrolled IFN alpha release drives unabated activation/maturation of myeloid DCs. The ectopic presence of mature DCs in the circulation represents an attractive explanation for the breaking of tolerance towards self-components, the essence of SLE. 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. Our hypothesis is that SLE results from two combined alterations: one in the antigen presentation pathway, where an excess of IFN induces the unabated activation of DCs, and one in the B cell pathway where B cells generate an excess of autoreactive plasma cells. IFN-activated DCs are key factors in these processes by presenting nucleosomes to autoreactive B cells and allowing their expansion and differentiation. 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 SLE B cells into plasma cells or their precursors.
Aim 2 will determine whether IFN-DCs and SLE-DCs loaded with apoptotic cells, preferentially select nuclear antigen specific B cells.
Aim 3 will analyze the in vivo interactions between IFN-DCs/SLEs-DCs and B cells in humanized mice . Ultimately these studies will further our understanding of SLE pathogenesis and help us identify better targets to treat SLE patients.
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