Multiple organ inflammation is a hallmark of systemic autoimmune disorders, which can have disastrous effects on patients. Treatments for these disorders are desperately needed. In some clinical trials, RNase therapies appear promising, but not in all. The causes of this variability have been discovered by Japanese researchers.
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 body is protected by the immune system. In essence, it creates antibodies that bind to substances known as antigens. Immune complexes, also known as antibody-antigen complexes, can then be removed. When the immune system creates antibodies that identify the body's own components, autoimmune disorders are the result. Systemic autoimmune disorders affect more than one organ; certain autoimmune diseases only affect one organ, such as pancreatic cells 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 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. (ANI)
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