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.

OBJECTIVE

Microbial small RNAs can regulate human genes. Higher plasma concentrations of microbial transfer RNA (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 anticyclic citrullinated peptide-3 positive (CCP3+) at-risk individuals (ARI), based on who later develops clinical RA, or discriminate later conversion status beyond established risk factors and if tDR-1 has in vitro effects.

METHODS

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.

RESULTS

Among 60 CCP3+ ARI, 25 later developed clinical RA ("converters") over a mean of 2.2 years, whereas 35 did not ("nonconverters") over a mean of 5.3 years. Baseline plasma tDR-1 concentrations were significantly higher (5.4-fold) in nonconverters versus converters, even after adjustment for additional RA risk factors (shared epitope, smoking, rheumatoid factor) (P = 5.1 × 10-4). 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 down-regulated many type 1 interferon (IFN) response genes in THP-1 cells.

CONCLUSION

Higher plasma tDR-1 concentrations were associated with nonconversion to clinical RA in CCP3+ ARI. tDR-1's reducing type 1 IFN response gene expression suggests a potential mechanism by which microbes and tDR-1 could affect RA development.