May 10, 2022

Genetic driver of some cases of lupus identified

At a Glance

  • Researchers found a novel gene mutation in a young girl with lupus that caused the autoimmune attack.
  • Blocking a protein controlled by this gene stopped lupus from developing in mice, suggesting a potential new approach for treating some people with the disease.
Colorized scanning electron micrograph of a B cell Researchers discovered how a mutation in a young girl with lupus caused certain B cells, shown above, to survive for longer than normal. NIAID

In autoimmune diseases, parts of the immune system that normally protect the body from invading microbes instead attack the body’s own tissues. The causes of autoimmune diseases are complex and not well understood. They’re thought to include both genetic risk factors and environmental triggers, such as exposure to certain viruses.

The complexity of autoimmune diseases makes them hard to treat. Most current therapies involve broadly suppressing the immune system. Such approaches can control some symptoms but come with serious side effects. To develop more targeted treatments for autoimmune diseases, scientists need a better understanding of the genes that help drive them.

In a new study, an international research team led by Drs. Carola Vinuesa from the Francis Crick Institute and Vicki Athanasopoulos at Australian National University sequenced the whole genome of a 7-year-old girl with a rare case of severe childhood lupus. Lupus is an autoimmune disease that can damage the skin, joints, heart, lungs, kidneys, and more. It’s about nine times more common in women than men.

The study was funded in part by NIH’s National Human Genome Research Institute (NHGRI), National Heart Lung and Blood Institute (NHBLI), and National Institute of Neurological Disorders and Stroke (NINDS). Results were published on April 27, 2022, in Nature.

The scientists pinpointed a mutation in a gene on the X chromosome, which women have two copies of, called TLR7. The protein encoded by this gene, TLR7, is an immune system protein that helps sense viruses by detecting a compound called guanosine. The mutation made TLR7 more sensitive to guanosine. Whole-genome sequencing of additional people with lupus uncovered two other mutations in TLR7 that seemed to have similar effects.

The team thought that the altered TLR7 might trigger the immune system to attack normal tissues instead of viruses. When they engineered mice to have the abnormal version of TLR7, the mice developed symptoms of lupus and tissue damage similar to those in the girl who carried the gene.

Immune cells isolated from these mice showed a greater response to guanosine compared to immune cells from normal mice. Further work found that extra activity of TLR7 led to certain types of immune system B cells surviving for longer than normal. B cells produce antibodies, including those involved in autoimmune attacks. Those that mistakenly identify normal tissues as a threat usually only live for a few days in the body.

When the researchers engineered mice to have the abnormal TLR7 but lack a protein that TLR7 uses to control B cells, called MyD88, the mice didn’t develop lupus. This suggests that targeting TLR7 or proteins activated by it may help prevent or treat the disease.

“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,” says Dr. Nan Shen from the China Australia Center of Personalized Immunology, a member of the research team. “By confirming a causal link between the gene mutation and the disease, we can start to search for more effective treatments.”

—by Sharon Reynolds

Related Links

References: TLR7 gain-of-function genetic variation causes human lupus. Brown GJ, Cañete PF, Wang H, Medhavy A, Bones J, Roco JA, He Y, Qin Y, Cappello J, Ellyard JI, Bassett K, Shen Q, Burgio G, Zhang Y, Turnbull C, Meng X, Wu P, Cho E, Miosge LA, Andrews TD, Field MA, Tvorogov D, Lopez AF, Babon JJ, López CA, Gónzalez-Murillo Á, Garulo DC, Pascual V, Levy T, Mallack EJ, Calame DG, Lotze T, Lupski JR, Ding H, Ullah TR, Walters GD, Koina ME, Cook MC, Shen N, de Lucas Collantes C, Corry B, Gantier MP, Athanasopoulos V, Vinuesa CG. Nature. 2022 Apr 27. doi: 10.1038/s41586-022-04642-z. Online ahead of print. PMID: 35477763.

Funding: NIH’s National Human Genome Research Institute (NHGRI), National Heart Lung and Blood Institute (NHBLI), and National Institute of Neurological Disorders and Stroke (NINDS); Australian National Health and Medical Research Council; Australian National Collaborative Research Infrastructure Strategy; National Natural Science Foundation of China; Medical Research Future Fund.