RNase Treatment of Autoimmune Disorders Save

U1RNP complex, Ro/SSA and La/SSB are major RNA-containing autoantigens associated with autoimmune disorders. Immune complexes (ICs) composed of RNA-containing autoantigens and autoantibodies are suspected to be involved in the pathogenesis of some systemic autoimmune diseases. Treatment with RNase treatment to degrade RNA in ICs may be a potential therapeutic agent.  Researchers from Osaka University have provided new insights into the opposite effects of RNase treatment—enhancing and weakening immune activation.

The immune system produces antibodies to specific antigens. 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 body components.

In some systemic autoimmune diseases, antibodies target nuclear proteins bound to RNA molecules. The resulting immune complexes stimulate the production of factors that activate the immune response, such as type I interferons. Because RNases can destroy 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 the autoimmune response. To understand this phenomenon, the researchers investigated the effects of RNases on the immune response.

“We hypothesized that the efficacy of RNase-based treatments depends on the localization of the RNA-binding site,” says Ryota Naito, lead author of the study. “Indeed, in some antigens, the sites binding to antibodies and those binding to RNA are very close. Removing RNAs might allow more antibodies to bind to 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 of RNase treatment on the production of type I interferons, and the differences were directly related to the composition 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 binding sites for the antibodies when removing RNA from antigens. As a result, more immune complexes formed and stimulated autoimmunity.

They found RNase enhances Fcγ receptor activation by promoting the formation of ICs containing Ro/SSA or La/SSB, supporting the role of these autoantibodies in the pathogenesis of autoimmune disease.

This study provides insights into the mechanisms involved in systemic autoimmune diseases and may lead to novel treatments for patients with these conditions.