Figure 1. The two-phase paradigm for lupus pathogenesis.

In the initiation phase (i), self–nucleic acids and associated proteins in apoptotic cell debris are taken up by DCs and nontolerant B cells with specific BCRs, leading to endosomal TLR engagement, production of type I IFNs, antigen presentation to helper T cells, and production of autoantibodies. In the amplification phase (ii), autoantibodies complexed with particles containing nucleic acids and proteins are taken up by pDCs, DCs, and B cells, thereby creating an autoamplification loop that sustains the pathogenic response. In some instances, recognition of nucleic acids may be mediated by cytosolic sensors, and microbial nucleic acids may also precipitate these events.