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Endosomal TLR signaling is required for anti-nucleic acid and rheumatoid factor autoantibodies in lupus
Proceedings of the National Academy of Sciences of the United States of America, 07/23/09

Kono DH et al. – These findings strongly support the therapeutic targeting of nucleic acid-sensing Toll-like receptor (TLRs) in systemic lupus erythematosus (SLE) and demonstrate the dramatic benefit of simultaneously inhibiting all such TLR family members. These findings also raise the possibility that endosomal TLR (eTLR) signaling may play a critical role in other autoimmune diseases that have anti-nucleic acid Abs.

Methods

Aim was to assess the impact of completely blocking all nucleic acid-sensing TLRs on autoAb production and lupus pathogenesis
Induction and progression of lupus-like disease in mice in which eTLR signaling was abolished by the 3d mutation in Unc93b1 was studied

Results

Unc93b1 3d mutation that selectively abolishes nucleic acid-binding TLR (TLR3, -7, -9) signaling were used to demonstrate that these endosomal TLRs are required for
- Optimal production of IgG autoAbs
- IgM rheumatoid factor, and
- Other clinical parameters of disease
  in 2 lupus strains, B6-Fas^lprand BXSB
Strikingly, treatment with lipid A, an autoAb-inducing TLR4 agonist, could not overcome this requirement
The 3d mutation slightly reduced complete Freund's adjuvant (CFA)-mediated antigen presentation, but did not affect:
- T-independent type 1 or
- Alum-mediated T-dependent humoral responses or
- TLR-independent IFN production induced by cytoplasmic nucleic acids