Preview

Medical Immunology (Russia)

Advanced search

Peripheral blood T helper cell subsets in Löfgren’s and non-Löfgren’s syndrome patients

https://doi.org/10.15789/1563-0625-PBT-2468

Abstract

Sarcoidosis is a multisystemic granulomatous disorder of unknown cause, characterized by formation of immune granulomas in various organs, mainly in lungs. Currently, two main phenotypes of pulmonary sarcoidosis are described, i.e., Lofgren’s syndrome (LS) is an acute form with favorable outcome, and non-Lofgren’s syndrome (nLS) is a chronic type of disease with a high risk of pulmonary fibrosis. Our study was aimed to investigate the balance of main “polarized” CD4+ central and effector memory T cells from treatment-naive patients with pulmonary sarcoidosis (LS (n = 19) and nLS (n = 63)) compared to healthy volunteers (HC, n = 48). This marker might be used as immunological markers for predicting severity of this disorder. Multicolor flow cytometry analysis demonstrated that the patients with nLS showed significantly low levels of relative and absolute numbers of CD3+CD4+ lymphocytes if compared to patients with LS and control group (38.94% (31.33-44.24) versus 48.96% (43.34-53.54) and 47.63% (43.82-52.73), p < 0.001 in both cases). Moreover, patients with nLS had reduced frequencies and absolute numbers of “naive”, CM and EM Th cells if compared with healthy controls. Furthermore, the patients with LS showed increased relative and absolute numbers of peripheral blood EM Th cells, capable for migration to peripheral inflamed tissues, when compared with nLS. Finally, patients with LS had increased frequencies and absolute numbers of effector TEMRA Th cells as compared to HC and nLS. Next, significant differences Th1 and Th2 cells frequencies were shown between the patients with nLS and HC (9.64% (7.06-13.65) versus 13.80% (11.24-18.03) with p < 0.001, and 11.96% (9.86-14.78) versus 10.67% (9.13-12.98) with p = 0.048, respectively). But there were no significant differences in the relative numbers of CXCR5-CCR6+Th17 and CXCR5+ follicular T helper cells (Tfh) between the groups. Finally, both groups of patients with pulmonary sarcoidosis contained low proportions of “non-classical” Th17 and DN Th17 cell, but increased levels of DP Th17 cells within total CXCR5-CCR6+ CM Th if compared with HC. Nevertheless, patients with nLS had increased frequency of “classical” Th17 in comparison with healthy controls. A very similar imbalance between different Th17 cell subsets was observed within total CXCR5CCR6+ effector memory Th, that were able to migrate from the bloodstream to the sites of infection, or tissue injury. Taken together, the data suggest that the proportions of Th17 cell subsets in pulmonary sarcoidosis can be evaluated as a diagnostic and/or prognostic marker in clinical practice and these cells could serve as a new therapeutic target.

About the Authors

I. V. Kudryavtsev
First St. Petersburg State I. Pavlov Medical University; Institute of Experimental Medicine
Russian Federation

Kudryavtsev Igor V. - PhD (Biology), Senior Research Associate, Department of Immunology, IEM; Associate Professor, Department of Immunology, First St. Petersburg State I. Pavlov MU.

197376, St. Petersburg,  Acad. Pavlov str., 12. Phone: 7 (812) 234-16-69

 


Competing Interests:

not



N. M. Lazareva
First St. Petersburg State I. Pavlov Medical University
Russian Federation

Lazareva N.M., PhD (Medicine), Senior Laboratory Assistant, Department of Immunology.

St. Petersburg


Competing Interests:

not



O. P. Baranova
First St. Petersburg State I. Pavlov Medical University
Russian Federation

PhD (Medicine), Senior Research Associate, Research Institute of Interstitial and Orphan Lung Diseases, Associate Professor, Department of Pulmonology.

St. Petersburg


Competing Interests:

not



M. K. Serebriakova
Institute of Experimental Medicine
Russian Federation

Research Associate, Department of Immunology.
St. Petersburg


Competing Interests:

not



T. P. Ses’
First St. Petersburg State I. Pavlov Medical University
Russian Federation

PhD, MD (Biology), Professor, Department of Immunology.

St. Petersburg


Competing Interests:

not



M. M. Ilkovich
First St. Petersburg State I. Pavlov Medical University
Russian Federation

PhD, MD (Medicine), Professor, Director, Research Institute of Interstitial and Orphan Lung Diseases, Head, Department of Pulmonology.

St. Petersburg


Competing Interests:

not



A. A. Totolian
First St. Petersburg State I. Pavlov Medical University; St. Petersburg Pasteur Research Institute of Epidemiology and Microbiology
Russian Federation

PhD, MD (Medicine), Professor, Full Member, Russian Academy of Sceinces, Director, St. Petersburg PRIE M; Head, Department of Immunology, First St. Petersburg State I. Pavlov MU.

St. Petersburg


Competing Interests:

not



References

1. Vizel A.A., Vizel I.Yu., Amirov N.B. Epidemiology of sarcoidosis in the Russian Federation. Vestnik sovremennoy klinicheskoy meditsiny = Bulletin of Contemporary Clinical Medicine, 2017, Vol. 10, no. 5, pp. 66-73. (In Russ.)

2. 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.

3. Kudryavtsev I.V., Borisov A.G., Krobinets I.I., Savchenko A.A., Serebriakova M.K., Totolian A.A. Chemokine receptors at distinct differentiation stages of T-helpers from peripheral blood. Meditsinskaya immunologiya = Medical Immunology (Russia), 2016, Vol. 18, no. 3, pp. 239-250. (In Russ.) doi: 10.15789/1563-0625-2016-3-239-250.

4. Lazareva N.M., Kudryavtsev I.V., Baranova O.P., Serebriakova M.K., Bazhanov A.A., Ses’ T.P., Ilkovich M.M., Totolian A.A. Peripheral blood B cell subsets from patients with various activity of chronic sarcoidosis. Meditsinskaya immunologiya = Medical Immunology (Russia), 2019, Vol. 21, no. 6, pp. 1081-1098. (In Russ.) doi: 10.15789/15630625-2019-6-1081-1098.

5. Agostini C., Cassatella M., Zambello R., Trentin L., Gasperini S., Perin A., Piazza F., Siviero M., Facco M., Dziejman M., Chilosi M., Qin S., Luster A.D., Semenzato G. Involvement of the IP-10 chemokine in sarcoid granulomatous reactions. J. Immunol., 1998, Vol. 161, no. 11, pp. 6413-6420.

6. Belperio J.A., Dy M., Murray L., Burdick M.D., Xue Y.Y., Strieter R.M., Keane M.P. The role of the Th2 CC chemokine ligand CCL17 in pulmonary fibrosis. J. Immunol., 2004, Vol. 173, no. 7, pp. 4692-4698.

7. Bennett D., Bargagli E., Refini R.M., Rottoli P. New concepts in the pathogenesis of sarcoidosis. Expert Rev. Respir. Med., 2019, Vol. 13, no. 10, pp. 981-991.

8. 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.

9. Broos C.E., Koth L.L., van Nimwegen M., In ‘tVeen J.C.C.M., Paulissen S.M.J., van Hamburg J.P., Annema J.T., Heller-Baan R., Kleinjan A., Hoogsteden H.C., Wijsenbeek M.S., Hendriks R.W., van den Blink B., Kool M. Increased T-helper 17.1 cells in sarcoidosis mediastinal lymph nodes. Eur Respir J., 2018, Vol. 51, no. 3, 1701124. doi: 10.1183/13993003.01124-2017.

10. Broquet A., Jacqueline C., Davieau M., Besbes A., Roquilly A., Martin J., Caillon J., Dumoutier L., Renauld J.C., Heslan M., Josien R., Asehnoune K. Interleukin-22 level is negatively correlated with neutrophil recruitment in the lungs in a Pseudomonas aeruginosa pneumonia model. Sci. Rep., 2017, Vol. 7, no. 1, 11010. doi: 10.1038/s41598-017-11518-0.

11. Ding J., Dai J., Cai H., Gao Q., Wen Y. Extensively disturbance of regulatory T cells – Th17 cells balance in stage II pulmonary sarcoidosis. Int. J. Med. Sci., 2017, Vol. 14, no. 11, pp. 1136-1142.

12. Duhen T., Geiger R., Jarrossay D., Lanzavecchia A., Sallusto F. Production of interleukin 22 but not interleukin 17 by a subset of human skin-homing memory T cells. Nat. Immunol., 2009, Vol. 10, no. 8, pp. 857-863.

13. Facco M., Baesso I., Miorin M., Bortoli M., Cabrelle A., Boscaro E., Gurrieri C., Trentin L., Zambello R., Calabrese F., Cassatella M.A., Semenzato G., Agostini C. Expression and role of CCR6/CCL20 chemokine axis in pulmonary sarcoidosis. J. Leukoc. Biol., 2007, Vol. 82, no. 4, pp. 946-955.

14. Facco M., Cabrelle A., Teramo A., Olivieri V., Gnoato M., Teolato S., Ave E., Gattazzo C., Fadini G.P., Calabrese F., Semenzato G., Agostini C. Sarcoidosis is a Th1/Th17 multisystem disorder. Thorax, 2011, Vol. 66, no. 2, pp. 144-150.

15. Georas S.N., Chapman T.J., Crouser E.D. Sarcoidosis and T-helper cells. Th1, Th17, or Th17.1? Am. J. Respir. Crit. Care Med., 2016, Vol. 193, no 11, pp. 1198-1200.

16. Golovkin A., Kalinina O., Bezrukikh V., Aquino A., Zaikova E., Karonova T., Melnik O., Vasilieva E., Kudryavtsev I. Imbalanced immune response of T-Cell and B-Cell subsets in patients with moderate and severe COVID-19. Viruses, 2021, Vol. 13, no. 10, 1966. doi: 10.3390/v13101966.

17. Greaves S.A., Atif S.M., Fontenot A.P. Adaptive immunity in pulmonary sarcoidosis and chronic beryllium disease. Front. Immunol., 2020, Vol. 11, 474. doi: 10.3389/fimmu.2020.00474.

18. Hauber H.P., Gholami D., Meyer A., Pforte A. Increased interleukin-13 expression in patients with sarcoidosis. Thorax, 2003, Vol. 58, no. 6, pp. 519-524.

19. Huang H., Lu Z., Jiang C., Liu J., Wang Y., Xu Z. Imbalance between Th17 and regulatory T-Cells in sarcoidosis. Int. J. Mol. Sci., 2013, Vol. 14, no. 11, pp. 21463-21473.

20. Kudryavtsev I., Serebriakova M., Starshinova A., Zinchenko Y., Basantsova N., Malkova A., Soprun L., Churilov L.P., Toubi E., Yablonskiy P., Shoenfeld Y. Imbalance in B cell and T follicular helper cell subsets in pulmonary sarcoidosis. Sci Rep., 2020, Vol. 10, no. 1, 1059. doi: 10.1038/s41598-020-57741-0.

21. Kudryavtsev I.V., Lazareva N.M., Baranova O.P., Golovkin A.S., Isakov D.V., Serebriakova M.K., Ses’ T.P., Ilkovich M.M., Totolian A.A. CD39+ expression by regulatory T cells in pulmonary sarcoidosis and Lofgren’s syndrome. Medical Immunology (Russia), 2019, Vol. 21, no. 3. pp. 467-478. doi: 10.15789/1563-0625-2019-3-467478.

22. Kumar P., Rajasekaran K., Palmer J.M., Thakar M.S., Malarkannan S. IL-22: An evolutionary missing-link authenticating the role of the immune system in tissue regeneration. J. Cancer., 2013, Vol. 4, no. 1, pp. 57-65.

23. Lazareva N.M., Baranova O.P., Kudryavtsev I.V., Isakov D.V., Arsentieva N.A., Liubimova N.E., Ses’ T.P., Ilkovich M.M., Totolian A.A. chemokines CCL17 and CCL22 in sarcoidosis. Medical Immunology (Russia), 2021, Vol. 23, no. 4, pp. 791-798. doi: 10.15789/1563-0625-CCA-2340.

24. Locke L.W., Crouser E.D., White P., Julian M.W., Caceres E.G., Papp A.C., Le V.T., Sadee W., Schlesinger L.S. IL-13-regulated macrophage polarization during granuloma formation in an in vitro human sarcoidosis model. Am. J. Respir. Cell Mol. Biol., 2019, Vol. 60, no. 1, pp. 84-95.

25. Loke W.S., Herbert C., Thomas P.S. Sarcoidosis: immunopathogenesis and immunological markers. Int. J. Chronic Dis., 2013, Vol. 2013, 928601. doi: 10.1155/2013/928601.

26. Ly N.T.M., Ueda-Hayakawa I., Nguyen C.T.H., Okamoto H. Exploring the imbalance of circulating follicular helper CD4+ T cells in sarcoidosis patients. J. Dermatol. Sci., 2020, Vol. 97, no. 3, pp. 216-224.

27. Malkova A., Starshinova A., Zinchenko Y., Gavrilova N., Kudryavtsev I., Lapin S., Mazing A., Surkova E., Pavlova M., Belaeva E., Stepanenko Т., Yablonskiy P., Shoenfeld Y. New laboratory criteria of the autoimmune inflammation in pulmonary sarcoidosis and tuberculosis. Clin. Immunol., 2021, Vol. 227, 108724. doi: 10.1016/j.clim.2021.108724.

28. Miedema J.R., Kaiser Y., Broos C.E., Wijsenbeek M.S., Grunewald J., Kool M. Th17-lineage cells in pulmonary sarcoidosis and Löfgren’s syndrome: Friend or foe? J. Autoimmun., 2018, Vol. 87, pp. 82-96.

29. Moller D.R. Cells and cytokines involved in the pathogenesis of sarcoidosis. Sarcoidosis Vasc. Diffuse Lung Dis., 1999, Vol. 16, no. 1, pp. 24-31.

30. Mortaz E., Rezayat F., Amani D., Kiani A., Garssen J., Adcock I.M., Velayati A. The Roles of T Helper 1, T Helper 17 and кegulatory T Cells in the pathogenesis of sarcoidosis. Iran J. Allergy Asthma Immunol., 2016, Vol. 15, no. 4, pp. 334-339.

31. Nguyen C.T.H., Kambe N., Ueda-Hayakawa I., Kishimoto I., Ly N.T.M., Mizuno K., Okamoto H. TARC expression in the circulation and cutaneous granulomas correlates with disease severity and indicates Th2-mediated progression in patients with sarcoidosis. Allergol. Int., 2018, Vol. 67, no. 4, pp. 487-495.

32. Nguyen Q.P., Deng T.Z., Witherden D.A., Goldrath A.W. Origins of CD4+ circulating and tissue-resident memory T-cells. Immunology, 2019, Vol. 157, no. 1, pp. 3-12.

33. Palchevskiy V., Hashemi N., Weigt S.S., Xue Y.Y., Derhovanessian A., Keane M.P., Strieter R.M., Fishbein M.C., Deng J.C., Lynch J.P., Elashoff R., Belperio J.A. Immune response CC chemokines CCL2 and CCL5 are associated with pulmonary sarcoidosis. Fibrogenesis Tissue Repair, 2011, Vol. 4, 10. doi: 10.1186/1755-1536-4-10.

34. Paulissen S.M., van Hamburg J.P., Dankers W., Lubberts E. The role and modulation of CCR6+ Th17 cell populations in rheumatoid arthritis. Cytokine, 2015, Vol. 74, no. 1, pp. 43-53.

35. Ramstein J., Broos C.E., Simpson L.J., Ansel K.M., Sun S.A., Ho M.E., Woodruff P.G., Bhakta N.R., Christian L., Nguyen C.P., Antalek B.J., Benn B.S., Hendriks R.W., van den Blink B., Kool M., Koth L.L. IFN-γproducing T-Helper 17.1 Cells are increased in sarcoidosis and are more prevalent than T-Helper type 1 Cells. Am. J. Respir. Crit. Care Med., 2016, Vol. 193, no. 11, pp. 1281-1291.

36. Sakthivel P., Bruder D. Mechanism of granuloma formation in sarcoidosis. Curr. Opin. Hematol., 2017, Vol. 24, no. 1, pp. 59-65.

37. Sallusto F., Zielinski C.E., Lanzavecchia A. Human Th17 subsets. Eur. J. Immunol., 2012, Vol. 42, no. 9, pp. 2215-2220.

38. Shamaei M., Mortaz E., Pourabdollah M., Garssen J., Tabarsi P., Velayati A., Adcock I.M. Evidence for M2 macrophages in granulomas from pulmonary sarcoidosis: A new aspect of macrophage heterogeneity. Hum. Immunol., 2018, Vol. 79, no. 1, pp. 63-69.

39. 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.

40. Simonian P.L., Wehrmann F., Roark C.L., Born W.K., O’Brien R.L., Fontenot A.P. γδ T cells protect against lung fibrosis via IL-22. J. Exp. Med., 2010, Vol. 207, no. 10, pp. 2239-2253.

41. Starshinova A.A., Malkova A.M., Basantsova N.Y., Zinchenko Y.S., Kudryavtsev I.V., Ershov G.A., Soprun L.A., Mayevskaya V.A., Churilov L.P., Yablonskiy P.K. Sarcoidosis as an Autoimmune Disease. Front. Immunol., 2020, Vol. 10, 2933. doi: 10.3389/fimmu.2019.02933.

42. Tarasidis A., Arce S. Immune response biomarkers as indicators of sarcoidosis presence, prognosis, and possible treatment: An immunopathogenic perspective. Autoimmun Rev., 2020, Vol. 19, no. 3, 102462. doi: 10.1016/j.autrev.2020.102462.

43. Ten Berge B., Paats M.S., Bergen I.M., van den Blink B., Hoogsteden H.C., Lambrecht B.N., Hendriks R.W., Kleinjan A. Increased IL-17A expression in granulomas and in circulating memory T cells in sarcoidosis. Rheumatology (Oxford), 2012, Vol. 51, no. 1, pp. 37-46.

44. Wacleche V.S., Goulet J.P., Gosselin A., Monteiro P., Soudeyns H., Fromentin R., Jenabian M.A., Vartanian S., Deeks S.G., Chomont N., Routy J.P., Ancuta P. New insights into the heterogeneity of Th17 subsets contributing to HIV-1 persistence during antiretroviral therapy. Retrovirology, 2016, Vol. 13, no. 1, 59. doi: 10.1186/s12977-0160293-6.

45. 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.


Supplementary files

Review

For citations:


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. Medical Immunology (Russia). 2022;24(3):573-586. (In Russ.) https://doi.org/10.15789/1563-0625-PBT-2468

Views: 598


Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.


ISSN 1563-0625 (Print)
ISSN 2313-741X (Online)