The role of apoptotic cells in the breakdown of B cell tolerance

We have recently shown that dendritic cells (DCs) and macrophages (Mphis) are able to produce IL-6, sCD40L, and TNFalpha that regulate autoreactive B cells with an anergic phenotype. In systemic lupus erythematosus (SLE) autoreactive B cells are dysregulated allowing for their activation, production of autoantibodies, and loss of susceptibility to DC/Mphi-mediated regulation. Apoptotic cells have been found to contribute to dysregulation and disease pathogenesis in SLE patients and lupus-prone mice. However, the mechanisms involved have not been defined. MerTKkd or lpr mice have shown a defect in their ability to remove apoptotic cells. For this project we hypothesized that if an apoptotic cell burden is responsible for dysregulation of autoreactive B cells, then removal of the apoptotic cell burden by injected C57BL/6 DCs and Mphis should restore susceptibility of autoreactive B cells to DC/Mphi-mediated regulation. We found that autoreactive B cells from mice with clearance defects, MerTKkd and lpr, were not susceptible to DC/Mphi-mediated regulation. We found that injecting C57BL/6 DCs and Mphis into 2-12H/lpr mice restored autoreactive B cells to be susceptible to CD40L and increased basal pERK levels, while not reducing the apoptotic cell burden in the spleen. We also found that treatment of 2-12H/lpr mice with C57BL/6 DCs and Mphis reduced autoantibody levels. In DC/Mphi treated B6/lpr mice, susceptibility to IL-6 was restored in autoreactive B cells, but there was no change in apoptotic cell burden in the spleen. In addition, autoantibody production by B6/lpr mice was not affected by DC/Mphi treatment. Further optimization of apoptotic cell removal and autoantibody production could make DC/Mphi injection a potential therapeutic for SLE.