Researchers have found that unconventional immune cells trigger disturbed cytokine production in the chronic joint inflammation, spondyloarthritis.
Cytokine blockade of Tumor Necrosis Factor (TNF) and more recently Interleukin-17 (IL-17) has revolutionised the perspectives of patients suffering from chronic joint inflammation by achieving high levels of therapeutic efficacy.
Spondyloarthritis differs substantially from rheumatoid arthritis, another form of chronic joint inflammation, not only in the clinical presentation but also in the response to therapy: unlike the benefits of IL-17 inhibition in spondyloarthritis, this therapy failed in rheumatoid arthritis. Reported in Nature Communication, Koen Venken and Dirk Elewaut from the VIB-UGent Inflammation Research Centerx, Belgium, now address that rare populations of unconventional T cells may account for this intriguing clinical observation.
What do you now about spondyloarthritis?
This chronic joint inflammation refers to a cluster of inflammatory rheumatic diseases with a significant social-economic burden, affecting almost 1–2% of the Western population.
With a diverse range of disease manifestations including spinal and peripheral joint inflammation, this complex disease also tissues outside the musculoskeletal system which may affect the skin, eye and gut.
Venken explains: “When we started this project, most data on IL-17 production by unconventional T cells was derived from mouse models, and only limited information was available from humans. We could delineate rare subsets of RORγt+ unconventional T cells in the blood of healthy individuals showing a specific phenotype, enabling them to rapidly induce Th17-like immune responses.
“Interestingly, we observed a skewing towards RORγt+ cell subsets in blood samples taken from SpA patients, and remarkably this trend was even more pronounced within inflamed joints from these patients.”
When the researchers depleted these unconventional T cells from SpA joint samples, there was a drastic reduction in IL17 production, which indicates that they act as principal sources of pro-inflammatory cytokines in this disease.
Elewaut adds: “This is a fascinating result as it indicates that rare cell types can play significant roles in inflammatory diseases; something which is often overlooked at in the research community.”
Comparing other forms of chronic joint inflammation
The new observations of unconventional T cells in SpA appear to be a discriminative feature compared to other common forms of chronic arthritis such as Rheumatoid Arthritis (RA).
Dirk Elewaut: “RA is a chronic autoimmune joint disease which has also been linked to IL-17 mediated pathology. Unexpectedly, treatment of these patients with anti-IL-17 failed to demonstrate major clinical benefits. By comparing gene expression profiles in unconventional T cells from SpA and RA patients – we discovered clear differences, showing an enrichment of IL-17 related genes in SpA as compared to RA derived cells.”
Venken concludes: “When we tested the RORγt inhibitor, we observed a striking difference between Th17 and unconventional T cells. While in Th17 cells both IL-17 and IL-22 were inhibited, only IL-17 was inhibited in unconventional T cells. This may have therapeutic implications since IL-22 plays a protective role at gut barrier surfaces.”
These new findings essentially highlight a unique diversity of human RORγt+ T cells and underscore the potential of RORγt in the treatment of IL-17 driven diseases.
