Newly identified gene that causes lupus is a potential target for better treatment

(ORDO NEWS) — Gabriela faced painful joint inflammation and debilitating fatigue when her own immune system turned against her at an early age.

A young Spanish patient who suffered from terribly high blood pressure and a leaky heart valve was diagnosed with a severe case of lupus when she was only seven years old.

Now, Gabriela’s genome may have revealed an important clue to this potentially deadly and incurable disease that affects an estimated 5 million people worldwide.

Symptoms vary greatly among and even within patients as the immune system can start attacking any part of the body. This makes lupus difficult to diagnose.

Symptoms may include varying degrees of rash, fever, fatigue, joint pain, anemia, problems with the kidneys and other organs.

“Finding effective treatments for lupus has been a very difficult task; currently, immunosuppressants are predominantly used, which work by lowering the immune system to relieve symptoms,” says ANU immunologist Carola Vinueza.

Suppressing the immune system brings with it all sorts of potentially debilitating side effects.

“Gabriela represents an interesting case because of the early diagnosis of lupus, which means there was probably a large genetic contribution to the development of lupus,” Australian National University (ANU) immunologist Grant Brown told New Scientist.

Brown and colleagues identified the TLR7 gene on Gabriela’s X chromosome, which may explain why the disease affects nine times more women than men.

“This means that women with an overactive TLR7 gene can have two functioning copies, potentially doubling the harm,” Vinuesa explains, “while men can only get one copy of the gene on their single X chromosome.”

When genes don’t work properly, it often means that they, or what they were designed to do, have broken down and can no longer do their job.

However, by wild chance, a genetic mutation can cause a gene or its product to do something too good or something completely new instead. Known as a gain-of-function mutation, such a mutation can wreak havoc on our finely tuned biological circuitry.

The TLR7 gene encodes a protein that is supposed to hunt for viral RNA – detect it by binding to guanosine (in a certain configuration or concentration) and then summon a cavalry of immune cells to fight the invader.

But Gabriela’s mutated version of TLR7 has acquired the ability to be hypersensitive to guanosine, so it binds to much smaller traces of the RNA-related molecule, or to a molecule in a different configuration than usual.

This, through a chain of cell signaling, led to an accumulation of B cells of the immune system; these traitorous cells then attacked Gabriela’s tissues.

To confirm that the TLR7 gene mutation does indeed cause lupus, the team genetically inserted the gene into mice that developed lupus-like symptoms. Gabriela, who is now a teenager, named the new model of the mouse “kika”.

Further testing in kika mice allowed the team to understand the malfunctioning of the immune cell trigger circuit.

“These results suggest that hypersensitive TLR7 signaling mediates the survival of B cells that bind to the self-antigen via their surface B-cell receptor,” Brown and colleagues write in their paper.

Previous studies in mice have shown that duplication of TLR7 enhances autoimmunity and its deletion prevents or reinforces genes in mice with lupus.

However, mutations in this gene have so far been found in only two other lupus patients, suggesting that different parts of the B-cell signaling chain initiated by TLR7 may be causing problems in other people with lupus.

“While perhaps only a small number of people with lupus have variants in TLR7 itself, we know that many patients show signs of overactivity in the TLR7 pathway,” explains Nan Shen, co-director of the China Australian Center for Personalized Immunology.

“By confirming a causal relationship between the gene mutation and the disease, we can start looking for more effective treatments.”

Researchers are working with pharmaceutical companies to explore treatments that target the defective gene and the protein it codes for.

“There are other systemic autoimmune diseases, such as rheumatoid arthritis and dermatomyositis, that belong to the same broad family as lupus,” says Vinuesa. “TLR7 may also play a role in these diseases.”

“I hope this discovery will give hope to people with lupus and help them feel they are not alone in this struggle,” says Gabriela. “Hopefully, research can continue and eventually a specific treatment will be developed that will help many warriors suffering from lupus.”


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