Features of T lymphocyte subpopulation profile in patients with ankylosing spondylitis undergoing genetically engineered biological therapy

The aim of current study was to compare profiles of T cell subsets in the patients with ankylosing spondylitis (AS) who received different modes of genetically engineered biological therapy (GEBT). The research involved 58 patients aged 20 to 58 years diagnosed with AS and treated with anti-TNFα and antiIL-17 drugs, as well as those receiving common anti-inflammatory therapy. The AS diagnostics was based on the modified New York criteria. Disease activity was assessed by means of nomenclature approved by the Assessment of Spondyloarthritis International Society and Outcome Measures in Rheumatology. 45 healthy people aged 18 to 57 were included into the control group. Peripheral blood T cell subsets were analysed by multicolor flow cytometry. It was found that the T lymphocyte subpopulation profiles in AS patients showed significant differences depending on the therapy type. First, T lymphocyte counts were decreased in AS patients receiving traditional anti-inflammatory therapy, whereas relative numbers of T cells with high levels of effector potential and cytokine secretion were increased. Negative correlations between the levels of effector memory and pre-effector cytotoxic T cells and other laboratory and clinical indexes of inflammatory activity in AS may reflect lower efficiency of traditional therapy. Next, the levels of main T cell subsets in AS patients during antiIL-17 therapy fully corresponded to the control values. However, based on numerous correlations between immunological and clinical laboratory parameters, it was concluded that anti-IL-17 therapy had an inhibitory effect on the joint inflammation activity, while the state of T cell subsets was mainly dependent on standard anti-inflammatory therapy. The most pronounced changes in T cell subsets were found in AS patients during anti-TNFα therapy was associated with decreased effector potential of Th cells and cytotoxic T lymphocytes. At the same time, the lowest frequency of extraskeletal manifestations was found in AS patients treated with anti-TNFα drugs. Finally, the higher efficiency of GEBT, compared with conventional methods of therapy, is determined by the effects upon immune targets of AS pathogenesis which manifested, e.g., by changes in the T lymphocyte subpopulation profile. Moreover, usage of anti-TNFα versus anti-IL-17 inhibitors was associated with greater effect upon phenotypic profile of T cells.

1. Akhunova R.R., Akhunova G.R. An integrated approach to the treatment of ankylosing spondylitis from the position of the international classification of functioning. Arkhiv vnutrenney meditsiny = Russian Archives of Internal Medicine, 2020, Vol. 10, no. 1, pp. 5-9. (In Russ.)]

2. Voronina E.V., Lobanova N.V., Yakhin I.R., Romanova N.A., Seregin Yu.A. Role of tumor necrosis factor alpha in immune pathogenesis of different diseases and its significance for evolving anticytokine therapy with monoclonal antibodies. Meditsinskaya immunologiya = Medical Immunology (Russia), 2018, Vol. 20, no. 6, pp. 797-806. (In Russ.) doi: 10.15789/1563-0625-2018-6-797-806.

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

4. Kozlov V.A., Savchenko A.A., Kudryavtsev I.V., Kozlov I.G., Kudlai D.A., Prodeus A.P., Borisov A.G. Clinical immunology: a practical guide for physicians]. Krasnoyarsk: Polikor, 2020. 386 p.

5. Kudryavtsev I.V., Borisov A.G., Vasilyeva E.V., Krobinets I.I., Savchenko A.A., Serebriakova M.K., Totolian Areg A. Phenotypic characterisation of peripheral blood edical Immunology (Russia), 2018, Vol. 20, no. 2, pp. 227-240. (In Russ.) doi: 10.15789/1563-0625-2018-2-227-240.cytotoxic T lymphocytes: regulatory and effector molecules. Meditsinskaya immunologiya = M

6. Kudryavtsev I.V., Borisov A.G., Krobinets I.I., Savchenko A.A., Serebryakova M.K. Multicolor flow cytometric analysis of cytotoxic T cell subsets. Meditsinskaya immunologiya = Medical Immunology (Russia), 2015, Vol. 17, no. 6, pp. 525-538. (In Russ.) doi: 10.15789/1563-0625-2015-6-525-538.

7. Nasonov E.L., Korotaeva T.V., Dubinina T.V., Lila A.M. IL-23/IL-17 Inhibitors in immunoinflammatory rheumatic diseases: new horizons. Nauchno-prakticheskaya revmatologiya = Rheumatology Science and Practice, 2019, Vol. 57, no. 4, pp. 400-406. (In Russ.)

8. Erdes S.F. Interleukin-17A is a new target of anticytokine therapy for ankylosing spondylitis. Nauchno-prakticheskaya revmatologiya = Rheumatology Science and Practice, 2016, Vol. 54, no. 1S, pp. 60-66. (In Russ.)

9. Abdal S.J., Yesmin S., Shazzad M.N., Azad M.A.K., Shahin M.A., Choudhury M.R., Islam M.N., Haq S.A. Development of a Bangla version of the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and the Bath Ankylosing Spondylitis Functional Index (BASFI). Int. J. Rheum. Dis., 2021, Vol. 24, no. 1, pp. 74-80.

10. Ahmadi M., Hajialilo M., Dolati S., Eghbal-Fard S., Heydarlou H., Ghaebi M., Ghassembaglou A., AghebatiMaleki L., Samadi Kafil H., Kamrani A., Rahnama B., Rikhtegar R., Yousefi M. The effects of nanocurcumin on Treg cell responses and treatment of ankylosing spondylitis patients: A randomized, double-blind, placebo-controlled clinical trial. J. Cell. Biochem., 2020, Vol. 121, no. 1, pp. 103-110.

11. Al-Mossawi M.H., Chen L., Fang H., Ridley A., de Wit J., Yager N., Hammitzsch A., Pulyakhina I., Fairfax B.P., Simone D., Yi Y., Bandyopadhyay S., Doig K., Gundle R., Kendrick B., Powrie F., Knight J.C., Bowness P. Unique transcriptome signatures and GM-CSF expression in lymphocytes from patients with spondyloarthritis. Nat. Commun., 2017, Vol. 8, no. 1, 1510. doi: 10.1038/s41467-017-01771-2.

12. Chen B., Li J., He C., Li D., Tong W., Zou Y., Xu W. Role of HLA-B27 in the pathogenesis of ankylosing spondylitis (Review). Mol. Med. Rep., 2017, Vol. 15, no. 4, pp. 1943-1951.

13. Chen L., Liu L., Xie Z.Y., Wang F., Sinkemani A., Zhang C., Wang X.H., Wang K., Hong X., Wu X.T. Endoplasmic reticulum stress facilitates the survival and proliferation of nucleus pulposus cells in TNF-α Stimulus by activating unfolded protein response. DNA Cell Biol., 2018, Vol. 37, no. 4, pp. 347-358.

14. Faist B., Schlott F., Stemberger C., Dennehy K.M., Krackhardt A., Verbeek M., Grigoleit G.U., Schiemann M., Hoffmann D., Dick A., Martin K., Hildebrandt M., Busch D.H., Neuenhahn M. Targeted in-vitro-stimulation reveals highly proliferative multi-virus-specific human central memory T cells as candidates for prophylactic T cell therapy. PLoS One, 2019, Vol. 14, no. 9, e0223258. doi: 10.1371/journal.pone.0223258.

15. Feng X., Yang Q., Wang C., Tong W., Xu W. Punicalagin exerts protective effects against ankylosing spondylitis by regulating NF-κB-TH17/JAK2/STAT3 signaling and oxidative stress. Biomed. Res. Int., 2020, Vol. 2020, 4918239. doi: 10.1155/2020/4918239.

16. Gupta S., Su H., Narsai T., Agrawal S. SARS-CoV-2-Associated T-Cell responses in the presence of humoral immunodeficiency. Int. Arch. Allergy Immunol., 2021, Vol. 182, no. 3, pp. 195-209.

17. Koch S., Larbi A., Derhovanessian E., Ozcelik D., Naumova E., Pawelec G. Multiparameter flow cytometric analysis of CD4 and CD8 T cell subsets in young and old people. Immun. Ageing, 2008, Vol. 5, 6. doi: 10.1186/1742-4933-5-6.

18. Lee S., Eun Y., Kim H., Cha H.S., Koh E.M., Lee J. Machine learning to predict early TNF inhibitor users in patients with ankylosing spondylitis. Sci. Rep., 2020, Vol. 10, no. 1, 20299. doi: 10.1038/s41598-020-75352-7.

19. Libri V., Azevedo R.I., Jackson S.E., Di Mitri D., Lachmann R., Fuhrmann S., Vukmanovic-Stejic M., Yong K., Battistini L., Kern F., Soares M.V., Akbar A.N. Cytomegalovirus infection induces the accumulation of short-lived, multifunctional CD4+CD45RA+CD27+ T cells: the potential involvement of interleukin-7 in this process. Immunology, 2011, Vol. 132, no. 3, pp. 326-339.

20. Lovšin N., Marc J. Glucocorticoid receptor regulates TNFSF11 transcription by binding to glucocorticoid responsive element in TNFSF11 proximal promoter region. Int. J. Mol. Sci., 2021, Vol. 22, no. 3, 1054. doi: 10.3390/ijms22031054.

21. Ma S.Y., Wang Y., Xu J.Q., Zheng L. Cupping therapy for treating ankylosing spondylitis: The evidence from systematic review and meta-analysis. Complement Ther. Clin. Pract., 2018, Vol. 32, pp. 187-194.

22. Machado P.M., Landewé R., Heijde D.V.; Assessment of SpondyloArthritis international Society (ASAS). Ankylosing Spondylitis Disease Activity Score (ASDAS): 2018 update of the nomenclature for disease activity states. Ann. Rheum. Dis., 2018, Vol. 77, no. 10, pp. 1539-1540.

23. Maneiro J.R., Souto A., Salgado E., Mera A., Gomez-Reino J.J. Predictors of response to TNF antagonists in patients with ankylosing spondylitis and psoriatic arthritis: systematic review and meta-analysis. RMD Open, 2015, Vol. 1, no. 1, e000017. doi: 10.1136/rmdopen-2014-000017.

24. Miao J., Zhu P. Functional defects of treg cells: new targets in rheumatic diseases, including ankylosing spondylitis. Curr. Rheumatol. Rep., 2018, Vol. 20, no. 5, 30. doi: 10.1007/s11926-018-0729-1.

25. Miossec P. Local and systemic effects of IL-17 in joint inflammation: a historical perspective from discovery to targeting. Cell Mol. Immunol., 2021, Vol. 18, no. 4, pp. 860-865.

26. Nagai S., Azuma M. The CD28-B7 family of co-signaling molecules. Adv. Exp. Med. Biol., 2019, Vol. 1189, pp. 25-51.

27. Nam E.J., Lee W.K. Early achievement of ASDAS clinical response is associated with long-term improvements in metrological outcomes in patients with ankylosing spondylitis treated with TNF-α blockers. Medicine (Baltimore), 2020, Vol. 99, no. 41, e22668. doi: 10.1097/MD.0000000000022668.

28. Ortolan A., Ramiro S., van Gaalen F., Kvien T.K., Landewe R.B.M., Machado P.M., Ruyssen-Witrand A., van Tubergen A., Bastiaenen C., van der Heijde D. Development and validation of an alternative ankylosing spondylitis disease activity score when patient global assessment is unavailable. Rheumatology (Oxford), 2021, Vol. 60, no. 2, pp. 638-648.

29. Pedersen S.J., Maksymowych W.P. The Pathogenesis of ankylosing spondylitis: an update. Curr. Rheumatol. Rep., 2019, Vol. 21, no. 10, 58. doi: 10.1007/s11926-019-0856-3.

30. Qiu J., Zhou F., Li X., Zhang S., Chen Z., Xu Z., Lu G., Zhu Z., Ding N., Lou J., Ye Z., Qian Q. Changes and clinical significance of detailed peripheral lymphocyte subsets in evaluating the immunity for cancer patients. Cancer Manag. Res., 2020, Vol. 12, pp. 209-219.

31. Russell T., Bridgewood C., Rowe H., Altaie A., Jones E., McGonagle D. Cytokine “fine tuning” of enthesis tissue homeostasis as a pointer to spondyloarthritis pathogenesis with a focus on relevant TNF and IL-17 targeted therapies. Semin. Immunopathol., 2021, Vol. 43, no. 2, pp. 193-206.

32. Shimizu Y., Tsukada T., Sakata-Haga H., Sakai D., Shoji H., Saikawa Y., Hatta T. Exposure to maternal immune activation causes congenital unfolded protein response defects and increases the susceptibility to postnatal inflammatory stimulation in offspring. J. Inflamm. Res., 2021, Vol. 14, pp. 355-365.

33. Tahir H., Moorthy A., Chan A. Impact of secukinumab on patient-reported outcomes in the treatment of ankylosing spondylitis: current perspectives. Open Access Rheumatol., 2020, Vol. 12, pp. 277-292.

34. van der Linden S., Valkenburg H.A., Cats A. Evaluation of diagnostic criteria for ankylosing spondylitis. A proposal for modification of the New York criteria. Arthritis Rheum., 1984, Vol. 27, no. 4, pp. 361-368.

35. Vargas-Franco J.W., Castaneda B., Gama A., Mueller C.G., Heymann D., Rédini F., Lézot F. Geneticallyachieved disturbances to the expression levels of TNFSF11 receptors modulate the effects of zoledronic acid on growing mouse skeletons. Biochem. Pharmacol., 2019, Vol. 168, pp. 133-148.

36. Walsh M.C., Choi Y. Regulation of T cell-associated tissues and T cell activation by RANKL-RANK-OPG. J. Bone Miner. Metab., 2021, Vol. 39, no. 1, pp. 54-63.

37. Watad A., Bridgewood C., Russell T., Marzo-Ortega H., Cuthbert R., McGonagle D. The early phases of ankylosing spondylitis: emerging insights from clinical and basic science. Front. Immunol., 2018, Vol. 9, 2668. doi: 10.3389/fimmu.2018.02668.

38. Xu F., Guanghao C., Liang Y., Jun W., Wei W., Baorong H. Treg-promoted new bone formation through suppressing TH17 by secreting Interleukin-10 in ankylosing spondylitis. Spine (Phila Pa 1976), 2019, Vol. 44, no. 23, pp. E1349-E1355.