Increased plasma microbial tDR-1 in at-risk individuals is associated with decreased conversion to clinical rheumatoid arthritis and reduces an in vitro macrophage type 1 interferon response.

Abstract

Microbial small RNAs (sRNAs) can regulate human genes. Higher plasma concentrations of microbial tRNA-derived RNA-1 (tDR-1) were previously associated with lower rheumatoid arthritis (RA) disease activity. This study examined whether tDR-1 concentrations differ in anti-cyclic citrullinated peptide-3 positive (CCP3+) at-risk individuals (ARI) based on who later develops clinical RA and discriminate later conversion status beyond established risk factors, and whether tDR-1 has in vitro effects. Plasma tDR-1 concentrations were measured in CCP3+ ARI. Group differences in log-transformed tDR-1 were assessed by lognormal Welch's t-test and logistic regression. Area under the receiver operating characteristic curve (AUROC) was used to evaluate discriminatory ability. Human THP-1 monocyte-derived macrophages were treated with tDR-1 versus scramble control and gene expression was assessed by NanoString Immunology panel. Among 60 CCP3+ ARI, 25 later developed clinical RA ("converters") over a mean of 2.2 years, while 35 did not ("non-converters") over a mean of 5.3 years. Baseline plasma tDR-1 concentrations were significantly higher (5.4-fold) in non-converters versus converters, even after adjustment for additional RA risk factors (shared epitope, smoking, rheumatoid factor) (P=5.1x10^-4). The AUROC improved from 0.722 for these risk factors alone to 0.902 with the addition of tDR-1 (P=0.003). In vitro, tDR-1 significantly downregulated many type 1 interferon response genes in THP-1 cells. Higher plasma tDR-1 concentrations were associated with non-conversion to clinical RA in CCP3+ ARI. tDR-1's reducing type 1 interferon response gene expression suggests a potential mechanism by which microbes, and tDR-1, could affect RA development.