Study provided new insight into opposite effects of RNase treatment

TOKYO. Inflammation of multiple organs is a hallmark of systemic autoimmune disorders, which can have devastating effects on patients. There is a dire need for treatment of these disorders. In some clinical trials, RNase treatments appear to be promising, but not in all. The reasons for this variability have been discovered by Japanese researchers. In a study recently published in the Journal of Clinical Investigation Insight (JCI Insight), researchers at Osaka University have provided new insight into the opposite effects of RNAse treatment – enhancing and weakening immune activation. The body is protected by the immune system. In short, it makes antibodies that bind to substances called antigens. Then the immune complexes, also called antibody-antigen complexes, can be removed. When the immune system makes antibodies that recognize the body’s own components, autoimmune disorders result. Systemic autoimmune disorders affect more than one organ; Some autoimmune diseases affect only one organ, such as the cells of the pancreas in type I diabetes. RNA-bound nuclear proteins are the target of antibodies in various systemic autoimmune disorders. 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 an autoimmune response. To understand this phenomenon, the researchers examined the effects of RNases on the immune response. “We hypothesized that the efficacy of an RNAse-based treatment depends on the localization of the RNA-binding site,” says Ryota Naito, lead author of the study. “Indeed, in some antigens, the antibody binding sites are very close to the RNA binding sites. The removal of RNA may allow more antibodies to bind to the antigen and, as a result, stimulate an immune response. The team tested the effects of RNase treatment on the production of type I interferon induced by immune complexes isolated from patients with systemic autoimmune diseases. “We observed opposite effects of RNase treatment on the production of type I interferon, and the differences were directly related to the composition of the immune complexes,” says senior author Hisashi Arase. The researchers also confirmed increased binding of antibodies to antigens in immune complexes, which stimulated type I interferon production in the presence of RNAse. Thus, RNase probably exposed binding sites for antibodies while removing the RNA from the antigen. As a result, more immune complexes are formed and autoimmunity is stimulated.