A team of investigators from The Australian National University (ANU) reporting today in Nature Communications say they have discovered a gene mutation that is responsible for causing psoriasis, the chronic inflammatory disease that results in red, scaly, itchy patches on the skin. The researchers showed that if two copies of a mutated gene (IKBKB) are present, then people may also progress to psoriatic arthritis which results in joint pain, stiffness, and swelling.
“Using a mouse model, we identified that this mutation led to an abnormal function in a group of immune cells known as regulatory T cells,” said Chelisa Cardinez, PhD, an immunologist and researcher from the ANU John Curtin School of Medical Research. “These cells are normally considered gatekeepers of the immune system. However, we found that this mutation alters the function of these cells, causing them to contribute to inflammation and promote the onset of disease.”
The team’s principal finding identified that pathway that drives the formation of Foxp3+ CD4+ tissue resident regulatory T cells to become pro-inflammatory and pathological.
“This modified Treg population arises spontaneously in vivo as a result of increased activity of the canonical NF-κB pathway, conferred by a GoF missense mutation in Ikbkb (p.V203I),” the investigators noted. “The size of this modified Treg subset varies with the magnitude of IKK2 activity, as both abundance and end-organ consequences of their pro-inflammatory actions are gene-dose dependent.”
Rebecca Davey, the CEO of Arthritis ACT, an Australian based non-profit that seeks to improve the quality of life of people suffering from arthritis or other chronic pain, suffers from psoriatic arthritis. She notes that people without the condition don’t realize how debilitating it is, with symptoms ranging from constant pain and stiffness, poor sleep, and the resulting fatigue.
The hope is that the new research from ANU shows the causes of progression from a skin-only disease to a skin and joint disease will aid in both the prevention of disease progression via new therapeutic approaches.
In their mouse study, the ANU team found that the models detailed disease susceptibility based on whether they were heterozygous or homozygous for the IKBKB genetic mutation.
“The threshold for skin diseases appears to be lower than that for joint and systemic diseases since the former is observed in heterozygous mice, while the latter is only observed in homozygotes,” the researchers wrote. “Interestingly, the resultant skin pathology resembles psoriasis, and the systemic disease accurately models psoriatic arthritis, with axial and digital arthritis, characteristic nail changes, and marked inflammatory infiltrates in the bone marrow adjacent to affected joints, mimicking bone marrow edema.”
As with many autoimmune diseases, the diagnosis of psoriasis and psoriatic arthritis and not always easy to make. Cardinez hopes that these new findings can lead to earlier diagnoses.
“Studies have shown that delays in psoriatic arthritis diagnosis is linked to worse clinical outcomes for patients. Therefore, earlier detection and treatment of these immune diseases is key to improving health outcomes,” she said. “By developing a better understanding of the IKBKB gene and the role it plays in promoting the onset of these diseases, it could bring us a step closer to one day finding a cure.”
