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

Po-Ku Chen; Tsai-Ling Liao; Shih-Hsin Chang; Kai-Jieh Yeo; Chia-Hui Chou; Der-Yuan Chen

doi:10.3389/fmed.2022.1097514

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

Front Med (Lausanne). 2023 Jan 9:9:1097514. doi: 10.3389/fmed.2022.1097514. eCollection 2022.

Authors

Po-Ku Chen^{1

2

3}, Tsai-Ling Liao^{4

5}, Shih-Hsin Chang^{1

2

4}, Kai-Jieh Yeo^{1

2}, Chia-Hui Chou^{2

6}, Der-Yuan Chen^{1

2

3

4}

Affiliations

¹ Rheumatology and Immunology Center, China Medical University Hospital, Taichung, Taiwan.
² College of Medicine, China Medical University, Taichung, Taiwan.
³ Translational Medicine Laboratory, Rheumatology and Immunology Center, Taichung, Taiwan.
⁴ Ph.D. Program in Translational Medicine and Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung, Taiwan.
⁵ Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan.
⁶ Division of Infection, China Medical University Hospital, Taichung, Taiwan.

Abstract

Objective: Neutralizing anti-interferon (IFN)-γ autoantibodies are linked to opportunistic infections (OIs). To explore the association between anti-IFN-γ 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-γ 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-γ-signaling was evaluated with flow-cytometry analysis and immunoblotting. IFN-γ-mediated production of supernatant chemokines, including monocyte chemoattractant protein-1 (MCP-1) and IFN-γ inducible protein-10 (IP-10), were measured by ELISA.

Results: Among 29 AOSD patients, high titers of anti-IFN-γ 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-γ autoAbs-positive AOSD patients with OIs restored phosphorylated STAT-1 upon IFN-γ treatment. Sera from autoantibody-positive AOSD patients more effectively inhibited IFN-γ-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-γ-signaling were from two patients with high-titer autoantibodies and OIs.

Conclusion: AOSD patients have a high positive rate and titers of anti-IFN-γ autoantibodies. The remarkable blockade effect of high-titer autoantibodies on IFN-γ-mediated STAT1-phosphorylation and chemokines could make these patients susceptible to OIs.

Keywords: IFN-γ inducible protein-10 (IP-10); MCP-1; adult onset Still's disease (AOSD); anti-interferon-γ autoantibodies; opportunistic infections.

Grants and funding

This work was supported by a grant from China Medical University Hospital (DMR-111-200) and by a grant (MOST 110-2314-B-039-051) from the Ministry of Science and Technology, Taiwan.