The identification of a variant of the TLR7 gene as a cause of lupus erythematosus opens the door to the search for more effective treatments for the disease.
Lupus is an autoimmune disease caused by the activation of the immune system against the body's own tissues, leading to inflammation and damage to joints and certain organs. Its causes include both environmental and genetic factors, which have not yet been characterized in detail.
Currently, lupus is an incurable disease. Although there are treatments aimed at alleviating its symptoms, some of them, which focus on reducing the action of the immune system, have the side effect of increasing patients' susceptibility to infections.
This is one of the main reasons why it is necessary to complete the puzzle of genetic factors that influence its development to a greater or lesser extent. Deciphering the genetic causes of the disease will allow us to better understand the biological mechanisms involved in it and identify points where therapeutic action could be taken.
A recent study led by researchers at the Australian National University, with Spanish direction and participation, has just taken a very important step towards better understanding lupus.
The researchers have identified a genetic cause of the disease that offers a new path for the development of treatments: the presence of gain-of-function variants in TLR7, a gene involved in protecting the immune system against viral infections. The results are published in Nature.
Identifying the connection between TLR7 and lupus
The TLR7 gene encodes a receptor, also called TLR7, that recognizes single-stranded RNA molecules derived from viruses and bacteria and activates the immune system in response. In addition, it can also be activated by the nucleoside guanosine and its endogenous derivatives, although this does not normally represent a threat to health because it occurs to a lesser extent.
Previous studies had already suggested that TLR7 function played a role in systemic lupus. Increased activity had been found in some B lymphocytes from patients and some common polymorphisms were associated with the disease. However, until now no genetic change had been identified in the TLR7 gene that had a determining effect on the onset of lupus.
The first direct link between the TLR7 gene and lupus was found when sequencing the genome of Gabriela, a young Spanish girl who had been diagnosed with a severe case of the disease at the age of 7. The severity and early onset of lupus led researchers to believe that it must be a case caused by a single genetic mutation.
By analysing Gabriela's entire genome, the researchers found a variant in the TLR7 gene that was likely to cause lupus: p.Tyr264His. Various elements pointed to the variant as being responsible for the young woman's disease: the variant caused an amino acid change, it was located in a region of the protein conserved between species, and the computer programs used to predict its effects indicated that it was a harmful variant.
As further evidence, the researchers found two more variants in TLR7 when analyzing the whole exome of other patients with systemic lupus, without detecting changes in any other known lupus-related genes in the implicated families.
Mutation causes lupus when introduced into mice
Based on functional studies in cells, the researchers found that the presence of the p.Tyr264His variant produces a TLR7 protein with greater affinity towards certain endogenous ligands with guanosine that, normally, would not activate the protein, which could explain the development of the autoimmune reaction characteristic of lupus.
To confirm the mutation's role in the development of lupus, the researchers introduced the mutation into mice, creating a strain they named kika, in reference to the name Gabriela had given to a stuffed animal she had been given during one of her hospital visits.
The team observed that the mutation (also called kika) was enough to cause lupus in the animals, which developed different autoimmune symptoms and experienced various organ damage.
The results explain why lupus is more common in women
The study also offers an explanation for why 9 out of 10 people with lupus are women. The TLR7 gene is located on the X chromosome, so that people with a male chromosomal sex have one copy, while those with a female sex have two.
As a biological mechanism of dosage compensation, in women one of the two X chromosomes is inactivated in their cells. However, TLR7 escapes inactivation in immune cells, which leads to the fact that in women there may be two active copies compared to the single copy present in male cells.
Thus, if there is an autoimmune response influenced by TLR7, the effect may be greater in women. And if, in addition, they are carriers of a variant that increases the affinity towards endogenous ligands such as the p.Tyr264His variant, its impact would be even greater.
The opposite example has been observed in the case of the response to SARS-CoV-2 infection, where the presence of genetic variants that produce a deficiency in TLR7 has been linked to a higher risk of developing COVID-19 in men.
Relevance for the development of therapies for lupus and other autoimmune diseases
The study shows that the identified TLR7 gain-of-function variant is sufficient to induce lupus, at least in mice. This result, together with previous data, offers an important step forward for the development of therapies for the disease.
“Even though there are only a small number of people with lupus who have variants in the TLR7 gene, we know that many patients have signs of overactivity in the TLR7 pathway,” said Nan Shen, co-director of the China-Australia Centre for Personalised Immunology, who was involved in the study. “By confirming a causal connection between the gene mutation and the disease, we can begin to look for more effective treatments.”
The team is currently working with pharmaceutical companies to develop or adapt treatments targeting the TLR7 gene that could be beneficial for lupus patients.
These treatments could also be relevant for other autoimmune diseases. “There are other systemic autoimmune diseases such as rheumatoid arthritis and dermatomyositis that fit into the same family as lupus,” says Carola Vinuesa, a researcher at the Australian Centre for Personalised Immunology, co-director of the China-Australia Centre for Personalised Immunology and director of the work.
“TLR7 could also play a role in these conditions,” says the researcher, who has formed a new research team at the Francis Crick Institute focused on identifying the mechanisms that contribute to the development of autoimmunity.
Another question that researchers point out as pending resolution is whether certain environmental stimuli such as the presence of viruses that can activate TLR7 (as is the case with SARS-CoV-2, responsible for COVID-19) can exacerbate the effect of the variant.
Reference: Brown, GJ, Cañete, PF, Wang, H. et al. TLR7 gain-of-function genetic variation causes human lupus. Nature. 2022. DOI: https://doi.org/10.1038/s41586-022-04642-z
0 komentar:
Post a Comment