Systemic lupus erythematosus (SLE) is a multiorgan autoimmune disease characterized by the production of autoantibodies to nuclear components. Autoimmunity results from a breakdown in tolerance mechanisms that regulate autoreactive lymphocytes. The etiology of SLE remains unknown; however, investigation into defective mechanisms of tolerance has provided valuable insight into the cause of disease. Currently, the standard of care for SLE is immunosuppression. Understanding the mechanisms that regulate autoreactive B cells would lead to more specific therapies that re-establish tolerance in SLE patients. Recently, we showed that dendritic cells (DCs) and macrophages (MOs) secrete IL-6 and other soluble factors that maintain autoreactive B cells in an unresponsive state during innate immune responses. Therefore, the lack of repressive soluble factors, like IL-6, or the inability to differentially respond to these factors on the part of the autoreactive B cell could lead to a breakdown in tolerance and autoantibody secretion during innate immune responses. We hypothesize that DC and/or MO-mediated tolerance mechanisms are dysfunctional in murine models of lupus disease. We have already demonstrated that DCs and MOs from lupus-prone mice are defective in repressing autoreactive B cells when stimulated through Toll-like Receptors (TLR), coincident with a defect in IL-6 secretion. In this proposal, we plan to determine the cause of defective IL-6 secretion in response to TLR stimulation. Secondly, we will establish whether autoreactive B cells from lupus-prone mice are susceptible to repression by DCs and MOs. Through this proposal, we hope to gain a better understanding of the loss of tolerance in lupus that would translate into more specific therapies in the clinical setting. ? ? ?
| Gilbert, Mileka R; Wagner, Nikki J; Jones, Shannon Z et al. (2012) Autoreactive preplasma cells break tolerance in the absence of regulation by dendritic cells and macrophages. J Immunol 189:711-20 |
| Gilbert, Mileka R; Carnathan, Diane G; Cogswell, Patricia C et al. (2007) Dendritic cells from lupus-prone mice are defective in repressing immunoglobulin secretion. J Immunol 178:4803-10 |
