Small RNAs and Heterogeneity of Risk for Developing Systemic Lupus Erythematosus
Abstract
Systemic lupus erythematosus (SLE) affects more than 70 per 100,000 people in the U.S., increasing the risk of early death 3-fold. SLE is heterogeneous; this means that the disease can affect nearly every organ in the body and patients can have a variety of symptoms ranging from mild rashes to life-threatening kidney disease. SLE has a strong genetic component and relatives of a patient have a much higher chance of developing SLE. However, because SLE has many nonspecific and heterogeneous symptoms it is difficult to diagnose the disease in its earliest and mildest stages, and even more difficult to predict who will get SLE. If we could better identify those people who will develop SLE, we could treat them with well-tolerated medicines to prevent SLE from occurring. We think we can predict risk of future disease by using small RNAs (sRNA). DNA makes RNA and RNA makes protein, which is a building block of our body. However, investigators discovered short segments of RNA called small RNAs that do not make protein; rather these sRNAs bind to other RNAs to decrease the amount of protein made. In this way they regulate genes. Groups of sRNAs frequently work together to exert a major effect on the function of a cell and have potential for diagnosis, prognosis, and treatment in SLE. There are several Food and Drug Administration-approved sRNA-based tests available for use in other diseases, and there are many sRNA-based drugs in development for diseases such as cancer. None of these are available for SLE. We found that the sRNAs circulating in blood differ in patients with SLE and rheumatoid arthritis (RA) compared to people without autoimmune disease. Also, we found that there are sRNAs in human blood that come from bacteria and viruses – nonhuman sources, and the composition of these also differs in patients with SLE versus controls, with SLE patients having increased circulating viral sRNAs. These nonhuman sRNAs can enter human cells and affect how the cells function. We know that some bacteria and viruses increase the risk of developing SLE, but it is unclear how they do this. We believe circulating bacterial and viral sRNAs may be the mechanism used by bacteria and viruses to affect disease development in humans. Many cells of the human immune system are equipped with defense sensors for single-stranded RNA, including some of the sRNAs in human circulation. These defense sensors help our body detect viral RNA, in particular, but also detect some bacterial and human RNAs. The result of activating these sensors is an increase in type 1 interferon, which is an important signaling molecule to fight infection but that can also worsen SLE. Indeed, anifrolumab, a drug that targets type 1 interferon, was recently approved as a treatment for SLE. Further evidence of the importance of this pathway in SLE is that genetic abnormalities that make the defense sensors more active can cause patients to have SLE. Our preliminary studies show that patients with SLE have more circulating sRNAs predicted to activate these defense sensors. We think that high levels of these sRNAs may trigger SLE and help us predict who is more likely to develop SLE. Our objective is to define the role of human and nonhuman sRNAs in the development of SLE. We hypothesize that human and nonhuman sRNAs can predict development of SLE and that these sRNAs increase type 1 interferon. In our study we will use previously collected blood and clinical information from individuals who are at risk for SLE because they have a direct family member with SLE and are therefore more likely to develop the disease. Among these at-risk individuals, some went on to develop SLE and others did not. To test our hypothesis, we will define (1) human and (2) nonhuman sRNAs that predict those people who will develop SLE. We will test whether these human and nonhuman sRNAs can activate the RNA defense sensors and induce type 1 interferon and thus affect risk
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310342
Entities
People
- Michelle Ormseth
Organizations
- United States Army
- Vanderbilt University