The double face of RNase as a treatment for systemic autoimmune diseases

Newswise — Osaka, Japan – Systemic autoimmune disorders manifest as inflammatory responses affecting numerous organs, posing severe consequences for patients. The demand for effective therapies targeting these conditions is urgent. Although RNase treatments have shown promise in certain clinical trials, their efficacy is not consistent across all cases. A team of Japanese researchers has made significant strides in understanding the reasons behind this variability.

In a recent publication in the Journal of Clinical Investigation Insight (JCI Insight), scientists from Osaka University have shed light on the dual effects of RNase treatment—both enhancing and weakening immune activation.

The immune system is responsible for safeguarding the body by generating antibodies that target specific substances called antigens. These immune complexes, formed by the interaction of antibodies and antigens, are subsequently eliminated. However, autoimmune diseases arise when the immune system produces antibodies that mistakenly recognize the body's own components. While some autoimmune disorders affect only one organ, like pancreatic cells in type I diabetes, systemic autoimmune diseases involve multiple organs.

In certain systemic autoimmune diseases, antibodies target nuclear proteins bound to RNA molecules, leading to the formation of immune complexes that trigger the production of immune response-activating factors, such as type I interferons. Researchers have explored the potential of RNases, which can degrade RNA molecules, as a therapy for these conditions. Initial results from clinical trials have shown promise, but paradoxically, RNase treatments can also stimulate the autoimmune response.

To comprehend this phenomenon, the researchers investigated the effects of RNases on the immune response. They put forth the hypothesis that the effectiveness of RNase-based treatments depends on the location of the RNA-binding site. According to Ryota Naito, the lead author of the study, some antigens have RNA-binding sites situated very close to the sites that bind to antibodies. Consequently, removing RNAs might increase the binding of antibodies to antigens, thereby triggering an immune response.

The team conducted experiments to assess the impact of RNase treatment on type I interferon production, induced by immune complexes obtained from patients with systemic autoimmune diseases. Senior author Hisashi Arase reported observing contrasting effects of RNase treatment on type I interferon production, with the differences directly linked to the composition of the immune complexes.

Furthermore, the researchers validated that the presence of RNase led to an increased binding of antibodies to antigens within the immune complexes, consequently enhancing type I interferon production. It appears that RNase removal of RNA from antigens uncovered additional binding sites for antibodies, leading to the formation of more immune complexes and subsequent stimulation of autoimmunity.

This study has provided valuable insights into the underlying mechanisms of systemic autoimmune diseases, offering the potential for improved treatments for affected patients.

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The article, “Positive and negative regulation of the Fcg receptor-stimulatory activity of RNA-containing immune complexes by RNase,” was published in the Journal of Clinical Investigation Insight (JCI Insight) at DOI: https://doi.org/10.1172/jci.insight.167799