Studies discover single-gene mutation that can cause lupus
In two separate studies, German researchers have identified the single-gene mutation that can lead to the incurable autoimmune disease lupus. The discovery opens the door to developing new therapeutic approaches and testing for the mutation, which would ensure early diagnosis of the disease.
Lupus causes the immune system to attack the body’s tissues and organs, causing inflammation of the kidneys, brain and central nervous system, blood vessels, lungs, and heart. Effective treatment depends on recognizing the disease as early as possible so the inflammation can be controlled before it does permanent organ damage.
Lupus is hereditary, with several genes known to promote the disease; women are much more likely than men to be affected. Researchers at the Max Planck Institute for Infection Biology in Germany looked into the genetics underlying lupus and discovered a mechanism that can trigger the disease.
The innate immune system is very quick to respond to invading pathogens, but that speedy response needs to be kept in check to prevent it from turning against the body. The researchers had been looking into these control mechanisms, focusing on a receptor called Toll-like receptor 7 (TLR7), which, when hyperactive, has been known to drive autoimmune disease in mice.
TLR7 recognizes the genetic material of viruses and bacteria and triggers an immune response. To provide a quick response, a certain number of TLR7 must be present in immune cells, which maintain balance by constantly producing and then degrading the receptors.
“We wanted to understand what happens when this balance is disturbed,” said Olivia Majer, one of the study's corresponding authors.
In their work on TLR7, the researchers showed that a protein complex called BORC is required to degrade TLR7 within immune cells. In addition, BORC requires another protein, UNC93B1, to carry out the degradation process correctly. If there’s an error in the process, TLR7 is not degraded and accumulates in the cells.
“From earlier experiments in mice carried out a few years ago at the University of Berkeley in California, we already knew that too many of these receptors are a problem,” said Majer.
Too many receptors push the immune system towards an autoimmune response such as that seen in lupus. Before the current study, neither BORC nor UNC93B1 had been associated with the disease.
Things came together when the study’s co-corresponding author, Fabian Hauck, a specialist in congenital immune disorders at the Ludwig Maximilian University Hospital in Munich, confirmed the existence of the UNC93B1 mutation in a patient of his with childhood-onset lupus. After examining the patient, they found that the single-gene mutation caused reduced BORC interaction and the accumulation of TLR7.
Along with the Max Planck study published in the journal Science Immunology was a separate study by researchers from the Technical University of Dresden (TU Dresden), also in Germany, that also investigated mutations of the UNC93B1 gene and their relationship to lupus.
The researchers studied four patients from two families who developed symptoms of systemic lupus erythematosus (SLE), the most common type of lupus. Because SLE is uncommon in very young children, they went searching for a genetic cause and found the UNC93B1 mutation in all family members.
As in Majer and Hauck’s study, the researchers found that UNC93B1 mutations led to selective overactivation of TLR7, resulting in an autoimmune attack and subsequent inflammation. Further, they found that this stimulated the survival of self-reactive B cells, which produced autoantibodies directed against the body’s own cells and fueled the autoimmune attack. From this, they concluded that UNC93B1 controls the activity of receptors like TLR7 to prevent autoimmunity.
“Our study demonstrates a direct causal link between an overactive UNC93B1/TLR7 axis and lupus pathogenesis and indicates that blocking overactive TLR7 might be therapeutically effective,” said Min Ae Lee-Kirsch, corresponding author of the study. “As such, our findings are expected to accelerate further development of TLR7 inhibitors for patients with SLE and related autoimmune diseases.”
Taken together, both studies open the door to new therapeutic approaches that could potentially prevent the damaging inflammation that characterizes the disease from developing in the first place. Additionally, testing for UNC93B1 mutations may become part of lupus treatment, ensuring early disease diagnosis.