[Dec. 14, 2023: JJ Shavit, The Brighter Side of News]
Age spots of redness on the face from systemic lupus erythematosus. (CREDIT: Creative Commons)
Lupus is a long-term autoimmune disorder leading to inflammation in organs and joints, influencing mobility and skin health, and inducing fatigue. In its most severe form, the symptoms can be incapacitating, and some complications can be life-threatening. Despite its prevalence in approximately 50,000 individuals in the UK, lupus remains without a cure. Present treatments mainly involve immune suppressors, which modulate the immune response to reduce symptoms.
However, a recent article in Nature has pinpointed DNA mutations in a gene responsible for detecting viral RNA as a root cause of lupus. This marks the inaugural discovery of a TLR7 mutation linked to the onset of lupus, offering definitive insight into one of the potential origins of the condition.
In their study, the international team of researchers carried out whole-genome sequencing on the DNA of a Spanish child named Gabriela, who was diagnosed with severe lupus when she was 7 years old. Such a severe case with early onset of symptoms is rare and indicates a single genetic cause.
The researchers found a single point mutation in the TLR7 gene, which causes the TLR7 protein to bind more easily to a nucleic acid component called guanosine and become more active. This increases the sensitivity of the immune cell, making it more likely to incorrectly identify healthy tissue as foreign or damaged and mount an attack against it.
Via referrals from the US and the China Australia Centre of Personalised Immunology (CACPI) at Shanghai Renji Hospital, they identified other cases of severe lupus where this gene was also mutated. To confirm that the mutation causes lupus, the team used CRISPR gene-editing to introduce it into mice.
These mice went on to develop the disease and showed similar symptoms, providing evidence that the TLR7 mutation was the cause. The mouse model and the mutation were both named ‘kika’ by Gabriela, the young girl central to this discovery.
Carola Vinuesa, senior author and principal investigator at the Centre for Personalised Immunology in Australia, co-director of CACPI, and now group leader at the Crick says: “It has been a huge challenge to find effective treatments for lupus, and the immune-suppressors currently being used can have serious side effects and leave patients more susceptible to infection. There has only been a single new treatment approved by the FDA in about the last 60 years."
Professor Nan Shen, co-director of CACPI adds: “While it may only be a small number of people with lupus who have variants in TLR7 itself, we do know that many patients have signs of overactivity in the TLR7 pathway. By confirming a causal link between the gene mutation and the disease, we can start to search for more effective treatments.”
Interestingly, other studies have shown mutations that cause TLR7 to become less active are associated with some cases of severe COVID-19 infection, highlighting the delicate balance of a healthy immune system.
The work may also help explain why lupus is about 10 times more frequent in females than in males. As TLR7 sits on the X chromosome, females have two copies of the gene while males have one. Usually, in females, one of the X chromosomes is inactive, but in this section of the chromosome, silencing of the second copy is often incomplete. This means females with a mutation in this gene can have two functioning copies.
TLR7 structure 6IF5. Regions in red were restrained through all simulations with a harmonic restraint of force constant 5 kcal/mol/Å2. Guanosine and R848 illustrated with binding geometries from crystal structures 5GMF and 5GMH14. L1-L3 indicate ligand atoms used for Boresch restraints, which were restrained relative to the three depicted protein alpha carbons of residues F408, G379 and F325 (not to scale). Distances and angles in gold, and dihedrals in pink show the values for the 6DoF Boresch restraints. Additional geometric relationships between the restrained atoms, as measured from the starting structure, are shown in grey smaller print. Boresch dihedral restraints are relative to the two atoms connecting either side of the location of print. White hydrogen spheres and red oxygen spheres show the atoms used in the calculation for determining the number of waters within 3.5 Å of the tail region that each ligand interacted with. (CREDIT: Nature)
Dr Carmen de Lucas Collantes, a co-author of this study says: “Identification of TLR7 as the cause of lupus in this unusually severe case ended a diagnostic odyssey and brings hope for more targeted therapies for Gabriela and other lupus patients likely to benefit from this discovery”.
Gabriela's story has provided a breakthrough in understanding the genetic basis of lupus, which has long been a mystery to researchers. While previous studies had hinted at the role of the TLR7 gene in the development of lupus, this is the first time that a clear causal link has been established.
The findings have been hailed as a significant step forward in the search for more effective treatments for lupus, which currently relies on immune-suppressing drugs that can have serious side effects and leave patients vulnerable to infections.
Peddy diagrams used to establish relatedness. Each red dot represents a child/parent pair (child mother and child father). The grey dot is a no-relatedness control. Coefficient of relatedness should be 0.5 for a parent-child pair. ibs0: the number of sites at which the 2 samples shared no alleles (should approach 0 for parent-child pairs). ibs2: the number of sites in which the child vs parent samples where both hom-ref, both het, or both hom-alt. Shared_hets: the number of sites at which both child and parent samples were hets. (b) Ancestry check using Peddy (proband and parents are purple dots). (CREDIT: Nature)
The team of researchers involved in the study hope that their findings will lead to the development of new therapies that can specifically target the TLR7 gene, potentially offering a more targeted and effective approach to treating the disease.
In addition to providing new insights into the genetic basis of lupus, the study may also have implications for other autoimmune diseases, such as rheumatoid arthritis and dermatomyositis, which are part of the same broad family of conditions.
Carola Vinuesa, who has started a new laboratory at the Francis Crick Institute to further investigate the mechanisms underlying autoimmune diseases, said: "This study has opened up a whole new field of research into the role of the TLR7 gene in the development of autoimmune diseases. We hope that our findings will pave the way for new treatments that can target this gene, and potentially benefit patients with lupus and other related conditions."
Gabriela, who remains in touch with the research team and is now a teenager, is proud to have played a role in advancing our understanding of lupus. She hopes that her story will inspire others with the condition to remain hopeful and continue fighting for a cure.
"I hope that my experience will give hope to other people with lupus and make them feel that they are not alone in this fight," she said. "I am so grateful to the researchers who worked on this study and I hope that their findings will lead to new treatments that can help so many people who suffer from this disease."
The research was funded by the National Health and Medical Research Council of Australia, the Australian Research Council, and the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences. The researchers involved in the study hailed from institutions in Australia, China, the United States, and Spain.
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