Positive and negative regulation of the Fcγ receptor–stimulating activity of RNA-containing immune complexes by RNase
Ryota Naito, … , Akio Morinobu, Hisashi Arase
Ryota Naito, … , Akio Morinobu, Hisashi Arase
Published July 11, 2023
Citation Information: JCI Insight. 2023;8(16):e167799. https://doi.org/10.1172/jci.insight.167799.
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Research Article

Positive and negative regulation of the Fcγ receptor–stimulating activity of RNA-containing immune complexes by RNase

Abstract

The U1RNP complex, Ro/SSA, and La/SSB are major RNA-containing autoantigens. Immune complexes (ICs) composed of RNA-containing autoantigens and autoantibodies are suspected to be involved in the pathogenesis of some systemic autoimmune diseases. Therefore, RNase treatment, which degrades RNA in ICs, has been tested in clinical trials as a potential therapeutic agent. However, no studies to our knowledge have specifically evaluated the effect of RNase treatment on the Fcγ receptor–stimulating (FcγR-stimulating) activity of RNA-containing ICs. In this study, using a reporter system that specifically detects FcγR-stimulating capacity, we investigated the effect of RNase treatment on the FcγR-stimulating activity of RNA-containing ICs composed of autoantigens and autoantibodies from patients with systemic autoimmune diseases such as systemic lupus erythematosus. We found that RNase enhanced the FcγR-stimulating activity of Ro/SSA- and La/SSB-containing ICs, but attenuated that of the U1RNP complex–containing ICs. RNase decreased autoantibody binding to the U1RNP complex, but increased autoantibody binding to Ro/SSA and La/SSB. Our results suggest that RNase enhances FcγR activation by promoting the formation of ICs containing Ro/SSA or La/SSB. Our study provides insights into the pathophysiology of autoimmune diseases involving anti-Ro/SSA and anti-La/SSB autoantibodies, and into the therapeutic application of RNase treatment for systemic autoimmune diseases.

Authors

Ryota Naito, Koichiro Ohmura, Shuhei Higuchi, Wataru Nakai, Masako Kohyama, Tsuneyo Mimori, Akio Morinobu, Hisashi Arase

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Figure 7

Enhancement of the FcγRIIIA-stimulating activity of Ro60 and La by RNase requires anti-Ro60 and anti-La antibodies, respectively.

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Enhancement of the FcγRIIIA-stimulating activity of Ro60 and La by RNase...
The effect of RNase on the FcγRIIIA-stimulating activity of Ro60 or La mixed with the serum or plasma from patients with systemic autoimmune diseases and healthy donors was examined. (A) For Ro60, 174 samples were examined and are shown separately as the anti-Ro60 antibody–positive group (n = 42) and –negative group (n = 132). (B) For La, 15 patients with SS were examined and are shown separately as the anti-La antibody–positive SS group (n = 3) and –negative SS group (n = 12). (C) The effect of RNase on the FcγRIIIA-stimulating activity of Ro60 mixed with anti-Ro60 antibody–containing plasma from a patient with rheumatoid arthritis (RA) or MCTD. In A, the median, 25th percentile, 75th percentile (box), and range (whiskers) are shown. In B, each dot represents 1 patient. In C, the results of 3 independent experiments with plasma from 1 patient are plotted. In A–C, the vertical axis represents the change in GFP expression (%) of reporter cells relative to the Ro60- or La-free control for each condition. The significance of differences was determined by paired, 2-tailed t test in A and B, and by 2-tailed Student’s t test in C. *P < 0.05, **P < 0.01, ***P < 0.001.