Mechanisms of interferon-alpha inhibition by intravenous immunoglobulin

Several lines of evidence implicate type I interferons (IFN-I, including IFN-alpha and IFN-beta) in the pathogenesis of systemic lupus erythematosus (SLE). Plasmacytoid dendritic cells (pDCs) are specialized in the production of IFN-alpha and produce high concentrations of this cytokine following exposure to immune complexes (ICs) containing nucleic acids such as those that are found in the serum and tissues of patients with SLE. We previously reported that normal human serum inhibits IFN-alpha production by pDCs in response to SLE ICs and that inhibition is mediated, in part, by immunoglobulin G (IgG). IgG is the major component ofintravenous Ig (IVIg), a therapeutic that is well known to exert anti-inflammatory properties and is used to treat several diseases associated with increased IFN-I expression. Although the sialylated subfraction of IVIg has been implicated as the key anti-inflammatory component in murine models of arthritis and thrombocytopenia, the mechanism of inhibition of IFN-alpha by IgG and the importance of sialylation have not been studied.;To address these questions we stimulated human primary cells with immune complexes or Toll-like receptor (TLR) agonists and then evaluated their IFN-alpha production after addition of total IgG, its proteolytic fragments or differentially glycosylated subfractions. We discovered two very different mechanisms of inhibition by IgG. In the first, IgG potently inhibited IC-induced IFN-alpha by blocking binding of ICs to FcgammaRIIa on pDCs, which required the Fc portion of IgG but not sialylation. We also elucidated a novel second mechanism by which IgG inhibited TLR agonist-induced IFN-alpha that was independent of FcgammaR interaction. F(ab')2 fragments from the sialylated subfraction of IgG induced monocytes to produce prostaglandin E2 (PGE2) which potently inhibited pDC production of IFN-alpha. We found that PGE2 could inhibit IFN-alpha by direct activity on pDCs, but the signaling pathways involved in the inhibition of IFN-alpha by PGE2 are not well understood. We demonstrated that an activator of PKA (dibutyryl-cAMP) or a suppressor of mTOR (rapamycin) also inhibited IFN-alpha production, implicating the PKA and mTOR pathways as key regulators. Future studies will address the identification of the target molecule(s) on monocytes that are important for PGE2 production and the signal transduction pathways responsible for PGE2 suppression of IFN-alpha production by pDCs. These findings could lead to more efficient therapies for immune modulation in SLE and other diseases in which IFN-I is thought to play an important role.