Treatment of autoimmune diseases such as lupus has traditionally relied on the use of steroids to suppress the immune system. However, more precise therapies are currently undergoing clinical trials. Identifying the specific mutations responsible for each patient’s disease is crucial in ensuring that these therapies reach the patients who will benefit from them. Researchers have now identified several dozen mutations associated with hyperactive toll-like receptors, which are a major cause of autoimmune disease, and have linked two mutations to specific patients.
lupus is a lifelong autoimmune disease that can be painful and sometimes fatal. Currently, there are few effective treatments beyond the use of steroids.
Potent steroids are used to suppress the immune system of a patient, which comes with its own set of serious risks.
Fortunately, there are new and promising treatments being tested in clinical trials. However, the term “lupus” does not accurately represent the different causes of the disease. This means that treatments will need to be tailored to ensure that each patient receives the medication that targets the specific genetic mutation responsible for their type of lupus.
Researchers are just starting to connect specific genetic mutations to groups of lupus patients, allowing doctors to customize treatments for those who will benefit most from them.Researchers at the University of California, Berkeley, have made a significant breakthrough in the discovery of genetic mutations linked to autoimmune disease. In a new paper, they have identified two sets of patients with mutations that closely resemble the ones previously found in mice and cell lines. These mutations are associated with lupus and are part of a larger group of mutations in a gene that regulates toll-like receptors (TLR), which are involved in immune system function. This discovery sheds light on the genetic factors contributing to lupus and could lead to new treatments.leader Gregory Barton, a professor of molecular and cell biology at UC Berkeley, is working to identify mutations that could help doctors provide personalized treatment to patients with oversensitive TLRs, specifically oversensitive TLR7 receptors. “We basically have a map now,” said Barton, who is also an investigator at the Howard Hughes Medical Institute. ”It’s not like everyone with lupus has a mutation in the gene that causes overactivation of TLRs and TLR7. But there are drugs being developed that specifically inhibit TLR7. As we sequence more and more people, it will become easier to identify those patients and put them on those drugs.”Autoimmune diseases, such as rheumatoid arthritis and Crohn’s disease, can be devastating for those affected. A new drug has been developed that shows promise in treating lupus, with the potential to be a significant improvement over current treatment options. This oral drug is currently in clinical trials and could provide a much-needed alternative to the harsh therapies currently available. The results of genetic testing and patient mutation details have been published in the Journal of Experimental Medicine, offering hope for those suffering from these conditions.’s disease to scleroderma and various thyroid conditions, stem from the immune system’s attacks on the body’s own cells, leading to the destruction of normal, healthy tissue.
Several studies have connected at least two types of autoimmune disease, lupus and psoriasis, to TLRs. These are a part of the innate immune system that initially detects foreign invaders, such as viruses and bacteria, and stimulates an initial line of defense. Normally, TLRs are finely tuned to only react to foreign DNA and RNA. However, if that tuning is off, they can react to a body’s own nucleic acids and proteins associated with nucleic acids, which bear a strong resemblance to those of pathogens.
This autoimmune reaction becomes extremely dangerous because the TLRs also trigger the body’s more powerful adaptive immune response, which involves T and B cells, macrophages, and other cells. These cells then launch a prolonged attack that results in the destruction of the body’s healthy tissue and leads to persistent inflammation.
For instance, the most prevalent type, systemic lupus erythematosus (SLE), is initially identified by skin rashes, such as a butterfly-shaped rash on the face, but eventually leads to damage to joints, muscles, organs, and skin, causing pain and fatigue. It is most commonly observed in females and often begins during theDuring the teenage years, lupus is generally more common among women from many ethnic and racial minority groups than among white women, with a prevalence of two to three times. “We believe that if nucleic acids come into contact with these receptors, they are likely to be from a virus,” Barton explained. “However, in some individuals, the receptor is more sensitive, so now levels of self-nucleic acids that wouldn’t normally activate the receptor in a healthy person do so. We believe that one of the ways these mutations work is by increasing levels of self-nucleic acids that wouldn’t normally stimulate the receptor in a normal person.”The role of misregulated TLRs in lupus is being investigated by Barton and his lab colleagues, with a focus on the protein UNC93B1, also known as UNC. They conducted a screening of over 100 genetic mutations in the UNC gene to identify which ones overstimulated TLRs in cell culture. Some details were published in earlier papers, but the complete list was not published due to limited available data on the genome sequence.
Researchers used to struggle to find enough genetic influences of lupus patients to compare with the mutations that overstimulated TLRs.
However, in recent years, the cost of genome sequencing has dropped significantly. This led to a breakthrough when the mother of a young girl with a severe autoimmune disease found Barton. The young girl’s DNA had been sequenced, revealing a mutation in a region of UNC that Barton’s team had previously identified in a research paper.
Lupus in the family
Rael and undergraduate Madeleine Weiss utilized the same cell culture screening technique to study the new mutation from the young girl. They discovered that it had an overstimulating effect, similar to the effect of o
Other mutations were found in the UNC gene area. Interestingly, the patient only had the genetic mutation on one of the two UNC alleles, which means she had one normal UNC gene, but still experienced severe autoimmune symptoms.
Barton and his team also discovered a family of five individuals affected by lupus. All of them had mutations on one UNC allele in a different area of the UNC protein that Barton’s team had previously identified. This mutation, when tested in cell lines, also resulted in overactive TLRs.
“We were doubtful that just one copy of a gene could cause a disease,” Rael said. “It wasn’t until we analyzed the patients’ mutations that we became convinced.”The researchers conducted experiments to turn gene mutations into cell lines and found that they caused a significant increase in TLR hyper-responsiveness. This led them to realize that the mutations had the potential to cause disease. Rael and Yano then replicated the screening process in the laboratory and discovered that 32 different mutations in the UNC gene, approximately one-third of those tested, increased the sensitivity of TLR7 to nucleic acids by at least two times. An additional five mutants also increased TLR7 sensitivity, but to a lesser extent. Prior to these experiments, only two mutations in the UNC protein had been linked to increased TLR7 sensitivity in mice, although three more had also been identified.It has been reported that several human mutations were recently discovered. Barton believes that by making a complete list of TLR hypersensitivity mutations available, doctors can better identify lupus patients who may benefit from the anti-TLR drugs currently being tested. One of these drugs, M5049, or Enpatoran, works by attaching to the human receptors TLR7 and TLR8, preventing them from binding to nucleic acids.
Rael, Yano, and other members of Barton’s lab are studying how these unique UNC mutations impact the way the disease presents in a patient. They have replicated these mutations in mice in order to model how they affect the disease.
Human lupus.
“Using mouse models, researchers can begin to consider how mutations in the same protein can lead to breakdowns in the different mechanisms of TLR regulation, activation of immune cells, and variations in the symptoms experienced by patients,” Rael explained.
The research team is also investigating how UNC regulates TLRs, possibly by controlling the quantity and arrangement of TLRs on immune cells. A higher number of TLRs may increase an individual’s sensitivity to the small amount of self-nucleic acids present in the body.
“UNC93B1 plays a crucial role in transporting the receptors to the proper location for functioning,””The function of TLR9 is not only to recognize nucleic acids, but also to regulate them once they are detected,” stated Barton. ”This protein plays a complex role in determining whether the nucleic acid it has bound to is of viral origin or from the body’s own cells.”
Barton expressed hope that doctors would include this gene in the list of genes associated with lupus, so that any mutations, even those that are heterozygous, would be further investigated.
The other senior authors of the study include Bo Liu from the Chinese Academy of Sciences in Shanghai and Olivia Majer from the Max Planck Institute for Infection Biology in Berlin, Germany. Additionally, there are co-authors involved in the research.The research involved doctors from UC San Francisco, Stanford University, and hospitals in Missouri, North Carolina, and Washington. The study was partially funded by the Lupus Research Institute, the Lupus Research Alliance, and the National Institutes of Health (R01AI072429).
