High-titer anti-interferon-gamma neutralizing autoantibodies linked to opportunistic infections in patients with adult-onset still's disease

Objective Neutralizing anti-interferon (IFN)-gamma autoantibodies are linked to opportunistic infections (OIs). To explore the association between anti-IFN-gamma autoantibodies and OIs in patients with adult-onset Still's disease (AOSD), we aimed to examine the ability of these autoantibodies to blockade signal transducer and activator of transcription (STAT1)-phosphorylation and chemokines production.Methods Serum titers of anti-IFN-gamma autoantibodies were quantified using ELISA in 29 AOSD and 22 healthy controls (HC). The detectable autoantibodies were verified with immunoblotting assay, and their neutralizing capacity against IFN-gamma-signaling was evaluated with flow-cytometry analysis and immunoblotting. IFN-gamma-mediated production of supernatant chemokines, including monocyte chemoattractant protein-1 (MCP-1) and IFN-gamma inducible protein-10 (IP-10), were measured by ELISA.Results Among 29 AOSD patients, high titers of anti-IFN-gamma neutralizing autoantibodies were detectable in two patients with OIs. Immunoblotting assay revealed more effective inhibition of STAT1-phosphorylation in THP-1 cells treated with sera from autoantibody-positive AOSD patients (56.7 +/- 34.79%) compared with those from HC (104.3 +/- 29.51%), which was also demonstrated in flow-cytometry analysis (47.13 +/- 40.99 vs. 97.92 +/- 9.48%, p < 0.05). Depleted serum IgG from anti-IFN-gamma autoAbs-positive AOSD patients with OIs restored phosphorylated STAT-1 upon IFN-gamma treatment. Sera from autoantibody-positive AOSD patients more effectively inhibited IFN-gamma-mediated production of MCP-1 (45.65 pg/ml) and IP-10 (22.44 pg/ml) than sera from HC (263.1 pg/ml and 104.0 pg/ml, both p < 0.05). Serum samples showing the strongest inhibition of IFN-gamma-signaling were from two patients with high-titer autoantibodies and OIs.Conclusion AOSD patients have a high positive rate and titers of anti-IFN-gamma autoantibodies. The remarkable blockade effect of high-titer autoantibodies on IFN-gamma-mediated STAT1-phosphorylation and chemokines could make these patients susceptible to OIs.