Twin Study Identifies NFIL3 Gene Mutation as Potential Driver of Juvenile Arthritis

Twin Study Identifies NFIL3 Gene Mutation as Potential Driver of Juvenile Arthritis

By studying identical twin girls with juvenile arthritis, researchers have found that a single mutation in the NFIL3 gene may cause the disease.

The study, “NFIL3 mutations alter immune homeostasis and sensitise for arthritis pathology,” was published in the Annals of the Rheumatic Diseases.

Juvenile arthritis — the most common childhood rheumatic disease — has symptoms that are not unique and multiple subtypes that can progress in different ways. Therefore, the disease could be the consequence of several genetic and environmental factors as well as molecular drivers.

In the study, the researchers examined two identical twin girls who were diagnosed with oligoarticular juvenile idiopathic arthritis (JIA) — the most common form of the disease, affecting between one and four joints — at the ages of 4 (patient 1) and 6 (patient 2). By age 9 (patient 1) and 11 (patient 2), they developed inflammation of the thyroid gland triggered by autoimmunity (autoimmune thyroiditis).

At disease onset, one of the twins (patient 1) had about 3 times the normal level of C-reactive protein (CRP), indicating that she had active inflammation. Also, both sisters had increased levels of IgG antibodies and were positive for antinuclear antibodies, which indicated an autoimmune disease.

One of the sisters (patient 1) was treated with intra-articular steroids and methotrexate (brand name Otrexup, among others), and later, adalimumab (brand name Humira, among others) was added after a relapse. Prolonged treatment led to liver problems that were only managed when she discontinued methotrexate and adalimumab treatments. After two years, her liver condition improved significantly but she suffered another relapse of knee arthritis.

The other twin (patient 2) remained in clinical remission after a course of non-steroidal anti-inflammatory drugs, and an intra-articular steroid infiltration.

Evaluation of the twin’s family clinical history revealed that the maternal grandmother had psoriatic arthritis. Therefore, researchers suspected there was a genetic driver to JIA in the girls, given their family history and particular clinical manifestations.

Genetic analysis revealed the twins had a mutation in the NFIL3 gene, which reduced the levels of its coded protein by 50% — the pro-inflammatory IL-3 signaling protein.

NFIL3 is an important player within the immune system. Expression of NFIL3 is reduced in patients with Crohn’s disease and ulcerative colitis, and silencing this gene in the T and B cells promotes autoimmunity. (Gene expression is the process by which information in a gene is synthesized to create a working product, such as a protein).

“Independent of the role of NFIL3 mutations in disease, the identification of an NFIL3-deficient family allows the first analysis of the in vivo functions of NFIL3 in humans,” the researchers wrote.

To further explore the effects of the NFIL3 genetic variant, the researchers genetically engineered mice to lack the NFIL3 gene. These animals developed inflammatory arthritis earlier and had more severe joint inflammation than mice carrying a normal NFIL3 gene. In addition, deletion of NFIL3 was found to promote the production of pro-inflammatory molecules, namely IL-1beta and TNF, by infiltrating immune cells (neutrophils and monocytes/macrophages).

Taken together, these findings suggest that NFIL3 may be a genetic contributor to inflammatory arthritis by supporting the production of innate inflammatory signaling molecules.

“The identification of a single gene that can cause juvenile idiopathic arthritis is an important milestone,” Carine Wouters, MD, PhD, UZ Leuven researcher who coordinated the clinical aspect of the study, said in a news release.

“A parallel mouse model with the same genetic mutation is a great tool to dissect the disease mechanism in more detail and to develop more effective targeted therapies for this condition,” she said.

How useful was this post?

Click on a star to rate it!

Average rating 0 / 5. Vote count: 0

No votes so far! Be the first to rate this post.

As you found this post useful...

Follow us on social media!

We are sorry that this post was not useful for you!

Let us improve this post!

Tell us how we can improve this post?