In two separate studies, German researchers have discovered a single gene mutation that causes the incurable autoimmune disease lupus. The discovery opens the door to developing new treatments and detecting genetic mutations to 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 relies on detecting the disease early so inflammation can be controlled before it causes permanent damage to organs.
Lupus is hereditary, and several genes are known to contribute to the disease; women are more likely to develop the disease than men. Researchers at the Max Planck Institute for Infection Biology in Germany studied the genetics of lupus erythematosus and discovered a mechanism that can induce the disease.
The innate immune system responds very quickly to invading pathogens, but this rapid response needs to be controlled to prevent it from backing up the body. Researchers have been studying these control mechanisms, focusing on a receptor called Toll-like receptor 7 (TLR7).
TLR7 recognizes the genetic material of viruses and bacteria and triggers an immune response. In order to respond quickly, a certain amount of TLR7 must be present in immune cells, which maintain the balance by constantly producing and degrading receptors.
"We wanted to understand what happens when this balance is tipped," said Olivia Majer, one of the study's corresponding authors.
In their study of TLR7, the researchers found that a protein complex called BORC is required for the degradation of TLR7 within immune cells. In addition, BORC requires another protein, UNC93B1, to properly complete the degradation process. If the degradation process goes wrong, TLR7 is not degraded but accumulates inside the cell.
"We already knew that having too many of these receptors was a problem from early experiments in mice at the University of California, Berkeley, a few years ago," Majer said.
Too many receptors can prompt the immune system to create an autoimmune response, such as lupus erythematosus. Before this study, neither BORC nor UNC93B1 had been associated with lupus.
Fabian Hauck, co-corresponding author of this study and an expert in congenital immune disorders at the Ludwig-Maximilians University Hospital in Munich, confirmed the presence of the UNC93B1 mutation in one of his childhood lupus patients. After examining the patients, they discovered that a single gene mutation leads to weakened BORC interactions and accumulation of TLR7.
In addition to the Max-Planck study published in the journal Science Immunology, researchers at the Technical University of Dresden (TUDresden) in Germany conducted a separate study that also investigated the UNC93B1 gene mutation and its relationship to lupus.
Researchers studied four patients from two families who all developed symptoms of systemic lupus erythematosus (SLE), the most common type of lupus. Because systemic lupus erythematosus is uncommon in very young children, they began looking for a genetic cause and found the UNC93B1 gene mutation in all family members.
Like Majer and Hauck's study, the researchers found that the UNC93B1 mutation leads to selective overactivation of TLR7, leading to autoimmune attack and subsequent inflammation. Additionally, they found that this stimulated the survival of self-reactive B cells, which produce autoantibodies against the body's own cells and fuel autoimmune attacks. From this, they concluded that UNC93B1 can control the activity of TLR7 and other receptors to prevent autoimmunity.
Min Ae Lee-Kirsch, corresponding author of the study, said: "Our study demonstrates a direct causal link between the overactive UNC93B1/TLR7 axis and lupus pathogenesis and suggests that blocking overactive TLR7 may have therapeutic benefits. Therefore, our findings are expected to accelerate the further development of TLR7 inhibitors for patients with systemic lupus erythematosus and related autoimmune diseases."
Taken together, these two studies open the door to new treatments that could potentially prevent the damaging inflammation that characterizes the disease from occurring in the first place. Additionally, testing for mutations in the UNC93B1 gene may become part of lupus treatment, ensuring early diagnosis of the disease.
Both studies were published in the journal Science Immunology.
The research from the Max Planck Institute can be found here:
https://www.science.org/doi/10.1126/sciimmunol.adi9575
The research from TU Dresden can be found here:
https://www.science.org/doi/10.1126/sciimmunol.adi9769