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Aurélie Hautefort, MSc; Barbara Girerd, PhD; David Montani, MD, PhD; Sylvia Cohen-Kaminsky, PhD; Laura Price, MD, PhD; Bart N. Lambrecht, MD, PhD; Marc Humbert, MD, PhD; Frédéric Perros, PhD
Author and Funding Information

From the Faculté de médecine (Ms Hautefort and Drs Girerd, Montani, Cohen-Kaminsky, Humbert, and Perros), Université Paris-Sud; AP-HP (Drs Girerd, Montani, and Humbert), DHU TORINO, Centre de Référence de l’Hypertension Pulmonaire Sévère, Service de Pneumologie et Réanimation Respiratoire, Hôpital Bicêtre; INSERM UMR-S 999 (Ms Hautefort and Drs Girerd, Montani, Cohen-Kaminsky, Humbert, and Perros), Labex LERMIT, Hypertension Artérielle Pulmonaire: Physiopathologie et Innovation Thérapeutique, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France; Pulmonary Hypertension Service (Dr Price), Royal Brompton Hospital; and VIB Inflammation Research Center (Dr Lambrecht), University of Ghent.

CORRESPONDENCE TO: Frédéric Perros, PhD, INSERM U999, Centre Chirurgical Marie Lannelongue, 133, Ave de la Résistance, F-92350 Le Plessis-Robinson, France; e-mail: frederic.perros@inserm.fr


CONFLICT OF INTEREST: D. M. has received speaker fees or honoraria for consultations from Actelion Pharmaceuticals Ltd, Bayer, GlaxoSmithKline, Eli Lilly and Company, Novartis, Pfizer Inc, and United Therapeutics Corporation. M. H. has received speaker fees or honoraria for consultations from Actelion Pharmaceuticals Ltd, Bayer, Bristol-Myers Squibb, GlaxoSmithKline, Eli Lilly and Company, Novartis, Pfizer Inc, and United Therapeutics Corporation. None declared (A. H., B. G., S. C.-K., L. P., B. N. L., F. P.).

FUNDING/SUPPORT: Ms Hautefort is supported by a PhD grant from Région Ile de France (CORDDIM). This study was supported by grants from the National Funding Agency for Research (ANR) [Grant ANR-13-JSV1-001] and from the Fondation pour la Recherche Médicale (FRM) [EQ20100318257].

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2015;148(4):e132-e133. doi:10.1378/chest.15-1573
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To the Editor:

We thank Dr Harbaum and colleagues for their comments on our study in CHEST.1 Although we compared the frequency of IL17A-producing CD4+ T-helper (Th) 17 cells in patients affected with pulmonary arterial hypertension (PAH) and healthy control (HC) subjects and investigated the mechanisms of their polarization though dendritic- and T-cell interaction, they measured the serum concentration of IL17A in HC subjects and patients with idiopathic PAH. The relatively low number of samples that displayed a detectable level of IL17A led them to question the relevance of the Th17 response in PAH. However, we would suggest that it is important to realize that cytokines in the serum result from the “overflow” of tissue cytokines into the circulation as tissue damage increases. Hence, it does not directly mirror the circulating cell and local pulmonary responses.

We should also highlight potential technical issues in their study. Gaowa et al2 recently analyzed the Th17 and regulatory T-cell subsets (a T-cell lineage that counteracts proinflammatory cascades activated by Th17 cells) in patients with connective tissue diseases (CTDs) and CTD-associated PAH (CTD-aPAH) as compared with HC subjects. They found that patients with CTD-aPAH had significantly higher serum IL17A than did those with CTDs or HC subjects. IL17A was detectable in all groups, with values almost 10 times higher than those from Dr Harbaum and colleagues.

Moreover, circulating Th cells do not produce cytokines “at rest” but need to be activated to start producing cytokines. Gaowa et al2 also analyzed the IL17A-producing T cells, as we did, after in vitro stimulation of isolated circulating T cells, to have a direct quantification of Th17 cells. They found an increase in peripheral Th17 cells and in RORγt messenger RNA levels (a transcription factor that drives the Th17 lineage commitment). Importantly, the Th17/regulatory T-cell subsets ratio was significantly related to the severity and prognosis of CTD-aPAH. Moreover, microarray data confirmed that gene functional groups shared by systemic sclerosis associated-PAH and idiopathic PAH lungs include IL17A signaling.3 Importantly, IL21, which is mainly derived from Th17 cells, plays a critical role in the pathogenesis of experimental PAH in mice,4 and one can expect similar mechanisms in patients with PAH.

Finally, it has been shown that prostaglandin (PG) I2 (prostacyclin) signaling drives Th17 differentiation by inhibiting the production of cytokines known to negatively regulate Th17 production.5 However, we had too few patients with PAH treated with PGI2 to make a correlation between PGI2 exposure and Th17 polarization. This deserves further investigation, because a potential PGI2-driven Th17 response may aggravate a potential autoimmune background in these patients.

Acknowledgments

Role of sponsors: The sponsors had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript.

Hautefort A, Girerd B, Montani D, et al. T-helper 17 cell polarization in pulmonary arterial hypertension. Chest. 2015;147(6):1610-1620. [CrossRef] [PubMed]
 
Gaowa S, Zhou W, Yu L, et al. Effect of Th17 and Treg axis disorder on outcomes of pulmonary arterial hypertension in connective tissue diseases. Mediators Inflamm. 2014;2014:247372. [CrossRef] [PubMed]
 
Hsu E, Shi H, Jordan RM, Lyons-Weiler J, Pilewski JM, Feghali-Bostwick CA. Lung tissues in patients with systemic sclerosis have gene expression patterns unique to pulmonary fibrosis and pulmonary hypertension. Arthritis Rheum. 2011;63(3):783-794. [CrossRef] [PubMed]
 
Hashimoto-Kataoka T, Hosen N, Sonobe T, et al. Interleukin-6/interleukin-21 signaling axis is critical in the pathogenesis of pulmonary arterial hypertension. Proc Natl Acad Sci U S A. 2015;112(20):E2677-E2686. [CrossRef] [PubMed]
 
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. [CrossRef] [PubMed]
 

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References

Hautefort A, Girerd B, Montani D, et al. T-helper 17 cell polarization in pulmonary arterial hypertension. Chest. 2015;147(6):1610-1620. [CrossRef] [PubMed]
 
Gaowa S, Zhou W, Yu L, et al. Effect of Th17 and Treg axis disorder on outcomes of pulmonary arterial hypertension in connective tissue diseases. Mediators Inflamm. 2014;2014:247372. [CrossRef] [PubMed]
 
Hsu E, Shi H, Jordan RM, Lyons-Weiler J, Pilewski JM, Feghali-Bostwick CA. Lung tissues in patients with systemic sclerosis have gene expression patterns unique to pulmonary fibrosis and pulmonary hypertension. Arthritis Rheum. 2011;63(3):783-794. [CrossRef] [PubMed]
 
Hashimoto-Kataoka T, Hosen N, Sonobe T, et al. Interleukin-6/interleukin-21 signaling axis is critical in the pathogenesis of pulmonary arterial hypertension. Proc Natl Acad Sci U S A. 2015;112(20):E2677-E2686. [CrossRef] [PubMed]
 
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. [CrossRef] [PubMed]
 
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