Dysregulation of Th17 and regulatory T Cells in chronic pulmonary sarcoidosis: a potential biomarker for disease management

Sarcoidosis is a multisystem inflammatory disease of unknown etiology characterized by the formation of non-caseating granulomas, most commonly in the lung tissue. It presents with two main forms: acute and chronic. Patients with chronic sarcoidosis tend to have a less favorable prognosis with a risk of developing lung fibrosis. Sarcoidosis development involves the activation of T cells, which release various chemokines and cytokines that stimulate the inflammatory process. The aim of our study was to investigate the role of the ratio between Th17 and Treg cells in the chronic course of sarcoidosis. We studied peripheral blood plasma samples from patients with chronic sarcoidosis (CS) (n = 101) and healthy individuals (HC) (n = 40). The diagnosis in CS patients was confirmed by histological methods. We determined the levels of Th17 and Treg (% of total lymphocytes) by flow cytometry. The concentration of cytokines (pg/ml) IL-17A and IL-10 was measured by multiplex analysis using Luminex xMap. Correlations between the Th17/Treg ratio and clinical parameters, including serum angiotensin-converting enzyme (sACE) activity level in the peripheral blood, forced expiratory volume in the first second (FEV1, %), fibrosis manifestations, and extrapulmonary manifestations were analyzed in CS patients. Our analysis revealed elevated levels of Th17 cells (p = 0.028) and decreased Treg levels (p = 0.026) in CS patients compared to healthy controls. This resulted in a significantly increased Th17/Treg ratio (p = 0.003) and IL-17A/IL-10 ratio (p < 0.001) in sarcoidosis patients. Furthermore, the Th17/Treg ratio positively correlated with sACE levels (p = 0.018), fibrosis manifestations (p = 0.019), and extrapulmonary manifestations (p = 0.016), and negatively correlated with FEV1% (p = 0.021). Our results indicate an increase in the Th17/Treg ratio, as well as the ratio of their main cytokines in patients with chronic sarcoidosis, which may emphasize their potential role as a diagnostic and prognostic biomarker of disease severity. At the molecular level, the balance between Treg and Th17 cells is maintained by the transcription factors Foxp3 and RORγt, which regulate the differentiation and function of these cells. Disruption of this balance in patients with chronic sarcoidosis may indicate a possible mechanism for disease progression.

1. Zurochka A.V., Khaidukov S.V., Kudryavtsev I.V., Chereshnev V.A. Flow cytometry in biomedical research. Ekaterinburg: Ural Branch of the Russian Academy of Sciences, 2018. 720 p.

2. Kudryavtsev I.V., Lazareva N.M., Baranova O.P., Serebriakova M.K., Ses’ T.P., Ilkovich M.M., Totolian A.A. Peripheral blood T helper cell subsets in Löfgren’s and non-Löfgren’s syndrome patients. Meditsinskaya immunologiya = Medical Immunology (Russia), 2022, Vol. 22, no. 3. pp. 573-586. (In Russ.) doi: 10.15789/1563-0625-PBT-2468.

3. Bettelli E., Carrier Y., Gao W., Korn T., Strom T.B., Oukka M., Weiner H.L., Kuchroo V.K. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature, 2006, Vol. 441, pp. 235-238.

4. Broos C.E., Hendriks R.W., Kool M. T-cell immunology in sarcoidosis: Disruption of a delicate balance between helper and regulatory T-cells. Curr. Opin. Pulm. Med., 2016, Vol. 22, no. 5, pp. 476-483.

5. Capone A., Volpe E. Transcriptional regulators of T helper 17 cell differentiation in health and autoimmune diseases. Front. Immunol., 2020. Vol. 11, 348. doi: 10.3389/fimmu.2020.00348.

6. Hunninghake G.W., Costabel U., Ando M., Baughman R., Cordier J.F., du Bois R., Eklund A., Kitaichi M., Lynch J., Rizzato G., Rose C., Selroos O., Semenzato G., Sharma O.P. ATS/ERS/WASOG statement on sarcoidosis. American thoracic society/European respiratory society/world association of sarcoidosis and other granulomatous disorders. Sarcoidosis Vasc. Diffuse. Lung. Dis., 1999, Vol. 16, no. 2, pp. 149-173.

7. Kudryavtsev I., Zinchenko Y., Starshinova A., Serebriakova M., Malkova A., Akisheva T., Kudlay D., Glushkova A., Yablonskiy P., Shoenfeld Y. Circulating regulatory T cell subsets in patients with sarcoidosis. Diagnostics, 2023. Vol. 13, no. 8, 1378. doi: 10.3390/diagnostics13081378.

8. Lazareva N.M., Kudryavtsev I.V., Baranova O.P., Isakov D.V., Serebriakova M.K., Bazhanov A.A., Arsentieva N.A., Liubimova N.E., Ses’ T.P., Ilkovich M.M., Totolian A.A. Sarcoidosis clinical picture governs alterations in type 17 T helper cell subset composition and cytokine profile. Medical Immunology (Russia), 2023, Vol. 25, no. 5, pp. 1049-1058. doi: 10.15789/1563-0625-SCP-2694.

9. Polverino F., Balestro E., Spagnolo P. Clinical presentations, pathogenesis, and therapy of sarcoidosis: state of the art. J. Clin. Med., 2020, Vol. 9, no. 8, 2363. doi: 10.3390/jcm9082363.

10. Schnell A., Littman D.R., Kuchroo V.K. TH17 cell heterogeneity and its role in tissue inflammation. Nat. Immunol., 2023. Vol. 24, no. 1, pp. 19-29.

11. Shigehara K., Shijubo N., Ohmichi M., Takahashi R., Kon S., Okamura H., Kurimoto M., Hiraga Y., Tatsuno T., Abe S., Sato N. IL-12 and IL-18 are increased and stimulate IFN-gamma production in sarcoid lungs. J. Immunol., 2001, Vol. 166, no. 1, pp. 642-649.

12. Tartar D.M., VanMorlan A.M., Wan X., Guloglu F.B., Jain R., Haymaker C.L., Ellis J.S., Hoeman C.M., Cascio J.A., Dhakal M., Oukka M., Zaghouani H. FoxP3+RORgammat+ T helper intermediates display suppressive function against autoimmune diabetes. J. Immunol. (Baltimore, Md. : 1950), 2010, Vol. 184, no. 7, pp. 3377-3385.

13. Valencia X., Stephens G., Goldbach-Mansky R., Wilson M., Shevach E.M., Lipsky P.E. TNF downmodulates the function of human CD4+CD25hi T-regulatory cells. Blood, 2006, Vol. 108, no. 1, pp. 253-261.

14. Valeyre D., Brauner M., Bernaudin J.F., Carbonnelle E., Duchemann B., Rotenberg C., Berger I., Martin A., Nunes H., Naccache J.M., Jeny F. Differential diagnosis of pulmonary sarcoidosis: a review. Front. Med. (Lausanne), 2023, Vol. 10, 1150751. doi: 10.3389/fmed.2023.1150751.

15. Wang J., Zhao X., Wan Y.Y. Intricacies of TGF-β signaling in Treg and Th17 cell biology. Cell. Mol. Immunol., 2023. Vol. 20, no. 9, pp. 1002-1022.

16. Weeratunga P., Moller D.R., Ho L.P. Immune mechanisms in fibrotic pulmonary sarcoidosis. Eur. Respir. Rev., 2022, Vol. 31, no. 166, 220178. doi: 10.1183/16000617.0178-2022.

17. Zhang H., Costabel U., Dai H. The role of diverse immune cells in sarcoidosis. Front. Immunol., 2021, Vol. 12, 788502. doi: 10.3389/fimmu.2021.788502.