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TLR-dependent and TLR-independent pathways of type I interferon induction in systemic autoimmunity

Abstract

We formulate a two-phase paradigm of autoimmunity associated with systemic lupus erythematosus, the archetypal autoimmune disease. The initial Toll-like receptor (TLR)-independent phase is mediated by dendritic cell uptake of apoptotic cell debris and associated nucleic acids, whereas the subsequent TLR-dependent phase serves an amplification function and is mediated by uptake of TLR ligands derived from self-antigens (principally nucleic acids) complexed with autoantibodies. Both phases depend on elaboration of type I interferons (IFNs), and therapeutic interruption of induction or activity of these cytokines in predisposed individuals might have a substantial mitigating effect in lupus and other autoimmune diseases.

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Figure 1
Figure 2: TLR-dependent pathways of IFN-α/β induction.
Figure 3: TLR-independent pathways of IFN-α/β induction.
Figure 4: Endogenous stimuli promoting IFN-α/β production by pDCs and conventional DCs, and activation of B cells.
Figure 5: The paradigm of the two-phase IFN-α/β induction in systemic autoimmunity.

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We apologize that space limitations preclude citation of all original articles. We thank K. Occhipinti-Bender for editorial assistance. The work of the authors has been supported by the US National Institutes of Health.

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Baccala, R., Hoebe, K., Kono, D. et al. TLR-dependent and TLR-independent pathways of type I interferon induction in systemic autoimmunity. Nat Med 13, 543–551 (2007). https://doi.org/10.1038/nm1590

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