Mutation-causing lupus identified in humans

Research published in Nature April 27, 2022 shows that systemic lupus erythematosus (SLE), an now incurable chronic autoimmune disease, is caused by a gain-of-function mutation in a gene called TLR7 that enhances affinity for nucleoside guanosine and cyclic nucleotides. Provide proof. It results in cGMP, abnormal TLR7 activation and childhood-onset SLE.

“Finding an effective treatment for lupus is a major challenge, and the immunosuppressive drugs currently in use can cause serious side effects and make patients more susceptible to infections over the last 60 years. There is only one new treatment approved by, “said Dr. Carola Vinuesa, Principal Investigator and Co-Director of CACPI (China) at the Center for Personal Immunology in Australia. Australian Center for Individual Immunology), and Group Leader of the Francis Crick Institute. “This is the first time that the TLR7 mutation has been shown to cause lupus and provides clear evidence of one possible way for the disease to occur.”

This study was published in an article titled “”.Gain-of-function research genetic variation of TLR7 causes human lupus erythematosus.. This discovery paves the way for the development of new treatments for SLE that cause inflammation of organs and joints, affect exercise and skin health, and cause chronic fatigue. In severe cases, symptoms can be debilitating with fatal complications.

Lupus affects 1.5 million Americans and at least 5 million people worldwide. Current treatment options are primarily drugs that dial down the immune system to relieve symptoms and cause additional complications.

Co-author, Professor and Co-Director of CACPI, Nan Shen, PhD, said: TLR7 As such, we know that many patients show signs of overactivity in the TLR7 pathway. By identifying the causal relationship between genetic mutations and disease, you can start looking for more effective treatments. “

An international team of scientists who conducted the study performed a whole-genome sequence of DNA in a Spanish child diagnosed with severe cyst at age 7. By genetic analysis conducted at the Australian National University TLR7 gene.

Carmende Lucas Collantes, PhD, co-author of this study, said: TLR7 The cause of lupus in this unusually severe case ends the diagnostic odyssey and provides hope for a more targeted treatment. The team then identified other SLE cases with the same mutation.

To confirm that the mutation causes lupus, the team used CRISPR gene editing to introduce the mutation into mice. Mutant mice exhibited SLE-like symptoms, confirming that the TLR7 point mutation is the genetic cause of SLE.

When mating TLR7 mutant mice with mice lacking the adapter protein MyD88 downstream of TLR7, researchers rescued autoimmunity, abnormal B cell survival, and all cell and serological phenotypes. We further identified the causative role of TLR7 mutations in the development of SLE.

Through cell studies, the team showed that the mutant TLR7 protein sensitizes immune cells, misidentifying healthy tissue as foreign or damaged and increasing the likelihood of launching an attack on it. .. The authors show that increased TLR7 signaling abnormally increases the survival of B cell receptor-expressing B lymphocytes in addition to CD11c-expressing B cells located in the germinal center of lymphoid organs.

SLE is about 10 times more frequent in women.Since then The TLR7 gene X-Chromosomal genes, current studies may explain why gain-of-function mutations in genes are more harmful in women who may have two copies of the aberrant gene.

The team is currently working with a pharmaceutical company to reuse drugs targeting TLR7 for the treatment of SLE. Corantes, who is starting a new laboratory at the Crick Institute, will investigate the causative mechanisms of diseases that occur downstream of the TLR7 mutation. Collantes believes that TLR7 may also be involved in other autoimmune diseases such as rheumatoid arthritis and dermatomyositis.

Gabriella, now a teenage 7-year-old patient, said: Hopefully, research will continue and can end up with specific treatments that can benefit so many lupus warriors suffering from this disease. “