The innate model of lupus pathogenesis: central role of TLR-activated MZ-B cells and pDCs. Presented is a schematic overview of innate activation of MZ-B cells and pDCs with hypomethylated CpG-DNA or microbial DNA. Exposure to self CpG-DNA derived from apoptotic cells initially engages anti-dsDNA reactive low-affinity MZ-B cells. Endosomal delivery of CpG-DNA leads to TLR9-dependent and TLR9-independent activation of MZ-B cells, resulting in enhanced MHC class II, CD40, and CD86 upregulation and more efficient antigen processing/peptide presentation to histone-specific autoreactive T cells. Maturation of MZ-B cells drives secretion of anti-dsDNA antibodies, which then combine with freely circulating dsDNA to promote FcγR-dependent endogenous IFN-α secretion by pDCs (as well as activation of RF-specific B cells). IFN-α produced by pDCs, through a positive feedback loop, further enhances MZ-B cell activation and autoantibody secretion. IFN-α additionally diverts some autoreactive B cell precursors toward the follicular B cell pathway, activates T cells, and promotes development of myeloid dendritic cells (mDCs). Activated T cells direct isotype switching and affinity maturation in autoreactive B cells dependent on CD40/CD40L interaction and IFN-γ secretion. Independently of T cells, pDC-derived IFN-α can additionally help CpG-DNA activated B cells to express T-bet, a key transcription factor that induces isotype switch to complement fixing IgG2a in mice. Myeloid dendritic cell derived BAFF may further promote survival and differentiation of autoreactive B cells. Higher affinity microbial CpG-DNA released during infections directly triggers MZ-B cells and pDC activation, causing flares of lupus. ds, double stranded; IFN, interferon; MHC, major histocompatibility complex; MZ, marginal zone; pDC, plasmacytoid dendritic cell; TCR, T-cell receptor; TLR, Toll-like receptor.