The double face of RNase as a treatment for systemic autoimmune diseases
Researchers from Osaka University show that treating systemic autoimmune diseases with RNases canbe detrimental, depending on the composition of the immune complex
Osaka, Japan – Systemic autoimmune diseases are characterized by inflammation of multiple organs andcan have devastating consequences for patients. There is a dire need for treatments against thesediseases. RNase treatments seem promising in some clinical trials but not all. Researchers from Japan
have uncovered the reasons for this variability.
In a study recently published in the Journal of Clinical Investigation Insight (JCI Insight), researchers from
Osaka University have provided new insights into the opposite effects of RNase treatment—enhancing
and weakening immune activation.
The immune system defends the body. Essentially, it produces antibodies that bind to targets calledantigens. Antibody–antigen complexes, also known as immune complexes, can then be eliminated.
Autoimmune diseases happen when the immune system produces antibodies that recognize its own bodycomponents. Some autoimmune diseases affect one organ, such as pancreatic cells in type I diabetes,but systemic autoimmune diseases involve more. In some systemic autoimmune diseases, antibodies
target nuclear proteins bound to RNA molecules. The resulting immune complexes stimulate theproduction of factors that activate the immune response, such as type I interferons. Because RNases candestroy RNA molecules, these RNA-containing immune complexes can be destabilized by RNases.
Therefore, clinical trials have tested RNase treatment as a potential therapy for systemic autoimmune
diseases. The results are promising, but they also reveal a paradox—RNase treatments can stimulate theautoimmune response. To understand this phenomenon, the researchers investigated the effects ofRNases on the immune response.
“We hypothesized that the efficacy of RNase-based treatments depends on the localization of the RNAbinding site,” says Ryota Naito, lead author of the study. “Indeed, in some antigens, the sites binding toantibodies and those binding to RNA are very close. Removing RNAs might allow more antibodies to bindto the antigens and, consequently, stimulate the immune response.”
The team tested the effects of RNase treatment on the production of type I interferons induced by immune
complexes isolated from patients with systemic autoimmune diseases. “We observed opposite effects ofRNase treatment on the production of type I interferons, and the differences were directly related to thecomposition of the immune complexes,” says Hisashi Arase, senior author.
The researchers also confirmed the increased binding of antibodies to antigens in immune complexes that

stimulated type I interferon production in the presence of RNase. Thus, RNase likely unmasked the bindingsites for the antibodies when removing RNA from antigens. As a result, more immune complexes formed
and stimulated autoimmunity.
This study provides insights into the mechanisms involved in systemic autoimmune diseases. It will most
likely lead to better treatments for patients with these conditions.
###The article, “Positive and negative regulation of the Fcγ receptor-stimulatory activity of RNA-containing
immune complexes by RNase,” was published in the Journal of Clinical Investigation Insight (JCI Insight)
at DOI: org/10.1172/jci.insight.167799
Summary: RNases have been proposed as a treatment against systemic autoimmune diseases.
Researchers from Osaka University showed that RNases have a dual action. In some cases, RNases are
detrimental and stimulate the immune response by promoting the binding of antibodies to their targets.
These findings will improve the understanding and treatment of systemic autoimmune disorders.
Secondary keywords: autoimmune disorders, immune response, drug targets, antigen recognition

Fig. 1The RNA-degrading enzyme enhances the function of immune complexes formed by autoantibodies
against Ro/SSA and La/SSB antigens.
Ryota Naito et al. JCI Insight 2023, conceptual figure (License: CC BY ver 4.0)

Journal: JCI Insight
Title: Positive and negative regulation of the Fcγ receptor-stimulatory activity of RNA-containing immune
complexes by RNase
Authors: Ryota Naito, Koichiro Ohmura, Shuhei Higuchi, Wataru Nakai, Masako Kohyama, Tsuneyo
Mimori, Akio Morinobu, Hisashi Arase
DOI: org/10.1172/jci.insight.167799
Funded by:
Japan Society for the Promotion of Science
Japan Agency for Medical Research and Development