Why Lupus can be Unresponsive to Glucocorticoid Therapy

Glucocoriticoids, including the natural hormone cortisol, are powerful immune suppressants. Synthetic glucocorticoids, such as dexamethasone and prednisone, are often taken by mouth to control autoimmune diseases. However, controlling the autoimmune disease systemic lupus erythematosus (SLE, lupus) often requires more aggressive treatments with high doses of more potent glucocorticoids, such as methylpredisolone, given intravenously.

Lupus is characterized by serum antibodies to nucleic acids (anti-nuclear antibodies, ANA), by a pattern of interferon-alpha-induced genes transcribed ("IFN signature”), and by an increase in plasmacytoid dendritic cells (PDC). PDC help produce antibodies and IFN. The IFN signature and PDC levels in patients are reduced to normal levels by high doses of intravenous glucocorticoids (see Figure 1c).

The authors noted that serum nucleic acids, which trigger the production of ANA, also stimulate PDC though specific receptors called toll-like receptors-7 and -9 (TLR-7 & -9) expressed on many cells of the immune system. Further, they hypothesized that TLR stimulation renders the PDC resistant to the suppressive effects of glucocorticoids.

Indeed, purified PDC treated with glucocorticoids (1-10 uM) do not survive overnight in a flask unless they are also treated with a nucleic acid (CpG) that stimulates TLRs (Figure 2a, first panel shown here). Nucleic acid-mediated protection is partially reversed by IRS, a synthetic oligonucleotide inhibitor of TLRs (IRS 954). Nucleic acid-containing immune complexes, isolated from the sera of lupus patients, also protected PDC by triggering TLRs.

Similar results were obtained with PDC from healthy people, suggesting that the PDC of lupus patients are not different but instead PDC are made glucocorticoid resistant by chronic stimulation of TLRs by nucleic acids. The authors conclude that “inhibitors of TLR7 and 9 signaling could prove to be effective corticosteroid-sparing drugs.”

Guiducci C, Gong M, Xu Z, Gill M, Chaussabel D, Meeker T, Chan JH, Wright T, Punaro M, Bolland S, Soumelis V, Banchereau J, Coffman RL, Pascual V, Barrat FJ. “TLR recognition of self nucleic acids hampers glucocorticoid activity in lupus.” Nature. 2010 Jun 17;465(7300):937-41.

Note: Similar results were reported by Lepelletier and colleagues at the Hopital Necker.