Discovery in Psoriatic Arthritis May Guide Development of Targeted Treatments

Researchers from the University of Oxford and the Wellcome Sanger Institute identified high levels of a specific receptor in immune cells from patients with psoriatic arthritis (PsA), revealing that PsA may be activated by the same trigger in different patients, according to a study published in Nature Communications.

According to the study authors, this could lead to finding the exact molecular trigger and gives hope for developing a targeted PsA treatment in the future. One-third of patients with the skin condition psoriasis will develop PsA, which typically causes affected joints to become swollen, stiff, and painful. Although some treatments are available, there is currently no cure, and in severe disease, the joints can become permanently damaged with a need for surgery.

Although previous studies have discovered that the disease had a number of genetic predispositions, 1 of which controls how T cells see antigen molecules from disease-causing microorganisms, it is still not understood exactly what triggers the onset of PsA.

Using single cell technology, the researchers analyzed thousands of individual immune cells from fluid drained from the knees of patients with PsA. The team was able to see which genes were switched on in each cell and showed these T cells had an activated inflammatory profile, in addition to amplifying and sequencing the RNA from receptor genes to identify active T-cell receptors in each cell, according to the study authors.

The study found that many T cells in the joint fluid shared an identical T-cell receptor and were clones of each other, likely to have been triggered to reproduce themselves by a particular antigen. By using machine learning to compare these receptors from different patients, the researchers discovered that the expanded clones of T cells were potentially recognizing something in common. These cells share other markers, including a receptor called CXCR3, that directed them to the inflammation site.

“Our data suggest that psoriatic arthritis doesn't just appear out of nowhere. Each receptor is like a unique lock that recognizes a molecular key and we discovered, that across the patients, they are recognizing a common molecule,” said Hussein Al-Mossawi, MD, honorary research associate at the Nuffield Department of Orthopedics, Rheumatology, and Musculoskeletal Sciences, in a press release. “This gives the first evidence that the T cells are seeing and reacting to the same molecule, which acts as a trigger for the disease. We don't know the exact culprit yet, but this a great step forward in understanding the disease."

In addition, the large-scale single cell data from the joints and blood of patients with PsA were then used to investigate how the T cells could transfer from the blood to the joint to cause the damage.

"Our study produced the largest single cell dataset from psoriatic arthritis patients to date,” said Sam Behjati, MD, group leader and Wellcome Trust Intermediate Clinical Fellow at the Wellcome Sanger Institute, in a press release. “It is helping us to understand the intricate mechanisms behind psoriatic arthritis, including starting to unravel the signals that tell the T cells to cross over into the joint fluid. Imagine the cells as train passengers with a ticket that tells them at which station to get off - the single cell data is allowing us to read that destination for each cell and understand the signals."

REFERENCE

Key discovery in psoriatic arthritis points way for developing targeted treatments. EurekAlert! https://www.eurekalert.org/pub_releases/2020-09/uoo-kdi091720.php. Published September 21, 2020. Accessed January 7, 2021.