Interleukin-9 Overexpression and Th9 Polarization Characterize the Inflamed Gut, the Synovial Tissue, and the Peripheral Blood of Patients With Psoriatic Arthritis

Objective: This study was undertaken to investigate the expression and tissue distribution of Th9 related cytokines in patients with psoriatic arthritis (PsA).
 Methods: Quantitative gene expression analysis of Th1, Th17, and Th9 cytokines was performed in intestinal biopsy samples obtained from patients with PsA, with HLA-27 positive-ankylosing spondylitis (AS), Crohn's disease (CD) and healthy controls. IL-23, IL-17, IL-22, IL-9 and IL-9R expression and tissue distribution were evaluated by immunohistochemistry and confocal microscopy. Flow cytometry was used to study the frequency of Th9 cells among peripheral blood (PBMC), lamina propria (LPMC) and synovial (SMC) mononuclear cells. The functional relevance of IL-9R expression on epithelial cells was assessed in functional in vitro studies. Th9 cells were also studied in synovial samples of PsA patients. Results: subclinical gut inflammation of PsA patients was characterized by a clear Th17 and Th22, but not Th1, polarized immune responses. Unlike AS and CD, a strong and significant upregulation of IL-9 immunologically was observed in PsA gut, especially among infiltrating mononuclear cells, high endothelial venules and Paneth cells (PC). IL-9 mononuclear cells were demonstrated to be in large part Th9 cells. IL-9 over-expression was accompanied by significant PC hyperplasia. PC strongly over-expressed IL-9R and stimulation of epithelial cells, isolated from PsA patients, with IL-9 resulted in over-expression of α-defensin5 and IL-23p19. Peripheral and synovial expansion of α4β7 + Th9 cells was also observed in patients with PsA. Increased expression of IL-9 and IL-9R was also found in synovial tissues. Conclusions: A strong IL-9/Th9 polarization seems to be the predominant immunological signature of patients with PsA.