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We read with interest the study conducted by Truchetet and colleagues on the regulation of PGI2 in Th17 cells differentiation in systemic sclerosis (SSc). Actually, previous in vitro studies have found that synthetic PGI2 enhanced Th17 cells differentiation1. Zhou et al2 has also demonstrated that PGI2 induced Th17 cells differentiation through modulating the ratio of IL-23/IL-12 in a mouse model of experim...
We read with interest the study conducted by Truchetet and colleagues on the regulation of PGI2 in Th17 cells differentiation in systemic sclerosis (SSc). Actually, previous in vitro studies have found that synthetic PGI2 enhanced Th17 cells differentiation1. Zhou et al2 has also demonstrated that PGI2 induced Th17 cells differentiation through modulating the ratio of IL-23/IL-12 in a mouse model of experimental autoimmune encephalitis. However, in this study, Truchetet et al3 treated SSc-related digital ulcers with iloprost, providing evidence for the first time that iloprost increases the frequency of Th17 cells in human study. The results have important clinical implications as PGI2 and its analogs are commonly used to treat human diseases, such as digital ulcers, raynaud phenomenon and pulmonary artery hypertension in connective tissue disease.
Although the definite role of Th17 cells in SSc is still controversial4, preclinical and clinical data have convinced that Th17 cells are associated with the pathogenesis of several other autoimmune diseases such as arthritis, multiple sclerosis, psoriasis, and lupus; and targeting the interleukin-17 (IL-17) pathway has attenuated disease severity in preclinical models of autoimmune diseases5. This raises a clinical concern that when PGI2 is used to treat these diseases, whether it would exacerbate autoimmune conditions presumed to be driven by Th17-associated inflammation? Taking lupus for example, in china, lupus is a common cause of connective tissue disease-associated pulmonary artery hypertension (CTD-PAH), many of these patients with NYHA class III and IV are treated with PGI2 analogs. Although previous clinical trails have confirmed the hemodynamic and clinical improvement of PGI2 analogs, they don’t evaluate the immune effect of PGI2 in the treatment of lupus associated PAH.
I also have two concerns about the experiment design. First, Truchetet et al evaluated the regulation of PGI2 in Th17 cells differentiation without immunosuppressive agents. However, in most cases, PGI2 is used clinically combined with immunosuppressive agents to treat CTD-associated complications. Several studies has evaluated the suppression of immunosuppressive drugs in Th17 cells. In giant cell arteritis patients, glucocorticoid treatment was shown to effectively suppress Th17 responses, including the suppression of Th17-promoting cytokines (IL-1beta, IL-6, and IL-23)6. In rheumatoid arthritis patients, MTX dose dependently suppressed the production of IL-17 at the mRNA level by PBMCs from healthy donors and RA patients7. Therefore, immunosuppressive agents may affect PGI2-induced Th17 cells differentiation, and it needs further study.
Second, I wonder whether SSc patients were in a stable phase, when they received illoprost treatment. This is an important issue, because the differentiation of Th17 cells depends on the local cytokine environment. Obviously, in the active inflammatory phase of SSc, the cytokines in the serum are elevated8, and conventional T cells are inclined to differentiate into Th17 cells in an inflammatory environment.
Therefore, this study raises many questions needing answers. Further studies are needed to evaluate the immune effect of PGI2 in the treatment of human disease.
1. Li H, Bradbury JA, Dackor RT, et al. Cyclooxygenase-2 regulates Th17 cell differentiation during allergic lung inflammation. Am J Respir Crit Care Med 2011; 184(1):37-49.
2. Zhou W, Dowell DR, Huckabee MM, et al. Prostaglandin I2 signaling drives Th17 differentiation and exacerbates experimental autoimmune encephalomyelitis. PloS one 2012;7(5):e33518.
3. Truchetet ME, Allanore Y, Montanari E, et al. Prostaglandin I(2) analogues enhance already exuberant Th17 cell responses in systemic sclerosis. Ann Rheum Dis 2012;71(12):2044-50.
4. Brembilla NC, Chizzolini C. T cell abnormalities in systemic sclerosis with a focus on Th17 cells. Eur Cytokine Netw 2012; 23(4):128-39.
5. Waite JC, Skokos D. Th17 response and inflammatory autoimmune diseases. Int J Inflam 2012;2012:819467.
6. Deng J, Younge BR, Olshen RA, et al. Th17 and Th1 T-cell responses in giant cell arteritis. Circulation 2010;121(7):906-15.
7. Li Y, Jiang L, Zhang S, et al. Methotrexate attenuates the Th17/IL-17 levels in peripheral blood mononuclear cells from healthy individuals and RA patients. Rheumatol Int 2012;32(8):2415-22.
8. Stuart RA, Littlewood AJ, Maddison PJ, et al. Elevated serum interleukin-6 levels associated with active disease in systemic connective tissue disorders. Clin Exp rheumatol 1995;13(1):17-22.