Systemic lupus erythematosus (SLE) is characterized by abnormal activation of B cells. Circulating plasmablasts produce autoantibodies that contribute to disease manifestations. The abnormal activation of B cells in SLE could result from inherent hyperactivity of the mechanisms that control B cell activation, as suggested by genetic analyses, and/or from stimulation of these pathways by exposure to abnormal antigens, such as immune complexes containing nucleosomal material from improperly cleared apoptotic cells. Published and preliminary observations suggest a mechanistic link between increased IFN1, increased BLyS and the induction of plasmablasts. An inherent hyperactivity, perhaps induced by IFN1, of the BLyS/BAFF-R system in SLE could drive B cell activation in SLE. The investigators on this proposal have unique assays for analysis of the BLyS and IFN1 responses in humans, as documented in the preliminary data. To induce a BLyS- or IFN1-dependent immune response, we will challenge SLE subjects (not in active flare or undergoing cytotoxic therapy) and healthy controls with either pneumococcal capsule antigens or with influenza viral antigens. Pneumbvax is known to induce a robust plasmablast response and the flu vaccine has been shown to activate IFN-inducible genes. We will determine whether the production of BLyS, the induction of IFN1 pathways or the generation of plasmablasts differs between the SLE and healthy subjects during an immune response to either type of antigen. Our long-term goal is to determine whether or not there is an inherent hyperactivity of the mechanisms that induce B cell activation in human SLE. In this R21, we propose an initial, limited study designed to measure the variability in these responses between SLE and healthy subjects because we need to develop the data required to perform a proper power calculation. Given the expected variability in responses, our aims are:
Aim 1. Measure the variability in plasmablasts responses to pneumovax and flu vaccine in SLE and healthy subjects, Aim 2. Determine whether an increase in BLyS or BAFF-R occupancy occur in a normal immune response to either pneumococcal polysaccharides or viral antigens and, if so, the variability in this response in SLE and healthy subjects, Aim 3. Determine whether an increase in serum IFN1 or in IFNl-induced genes in PBMC occurs in a normal immune response to either pneumococcal polysaccharides or viral antigens and, if so, the variability in this response between SLE and healthy subjects. ? ? ? ?
