Dynamics of T- and B-lymphocytes in patients with rheumatoid arthritis, receiving biological disease-modifying antirheumatic drugs
https://doi.org/10.14412/1996-7012-2022-1-38-45
Abstract
Objective: assessment of the dynamics of T- and B-lymphocytes subpopulations in rheumatoid arthritis (RA) during therapy with synthetic disease-modifying antirheumatic drugs (sDMARDs) and biological disease-modifying antirheumatic drugs (bDMARDs): inhibitors of tumor necrosis factor α (iTNFα) and an inhibitor of interleukin 6 receptors (iIL6R ).
Patients and methods. The study included 77 patients with RA who met the 2010 ACR/EULAR criteria (mean age 56 [44; 62] years). Group 1 included 30 (27 women and 3 men) patients with early RA who had not previously received therapy. Group 2 included 20 (14 women and 6 men) patients on sDMARD therapy who were prescribed iTNFα for the first time. The 3rd group is represented by retrospective data of 27 (23 women and 4 men) patients who previously used sDMARDs (MT – 85%, leflunomide – LEF – 15%), in whom iIL6R therapy was initiated for the first time. All study participants initially and 6 months later underwent immunophenotyping of T- and B-lymphocytes by flow cytofluorometry according to the standard method.
Results and discussion. In all groups, there were no significant changes in the studied T-lymphocyte profile during 6 months of follow-up. When comparing the immunogram data of patients treated with sDMARDs and iTNFα, no significant differences in subpopulations of B-lymphocytes were found. At baseline, the iIL6R group had higher levels of naive B-lymphocytes and plasmablasts and low concentrations of «switched» B-cells. For all methods of treatment, the number of «switched» B-cells decreased, while plasmablasts and plasma cells increased.
Conclusion. From the data obtained, it follows that the simultaneous decrease in the levels of memory B-cells and their «switched» forms, plasmablasts and plasma cells can be used as a marker for the early administration of drugs that disrupt the differentiation of B-lymphocytes, in particular, iIL6R.
Keywords
About the Authors
A. V. MartynovaRussian Federation
Alexandra Vladimirovna Martynova
34A, Kashirskoe shosse, Moscow 115522
T. V. Popkova
Russian Federation
34A, Kashirskoe shosse, Moscow 115522
A. P. Aleksankin
Russian Federation
3, Tsyurupy street, Moscow 117418
G. I. Gridneva
Russian Federation
34A, Kashirskoe shosse, Moscow 115522
E. V. Gerasimova
Russian Federation
34A, Kashirskoe shosse, Moscow 115522
Yu. N. Gorbunova
Russian Federation
34A, Kashirskoe shosse, Moscow 115522
A. M. Lila
Russian Federation
34A, Kashirskoe shosse, Moscow 115522
2/1, Barrikadnaya street, building 1, Moscow 125993
References
1. Nasonov EL. Problems of immunopathology of rheumatoid arthritis: the evolution of the disease. Nauchno-prakticheskaya revmatologiya. 2017;55(3):277-94. (In Russ.).
2. Silverman GJ, Carson DA. Roles of B cells in rheumatoid arthritis. Arthritis Res Ther. 2003;5 Suppl 4(Suppl 4):S1-6. doi: 10.1186/ar1010. Epub 2003 Dec 2.
3. Krishnamurthy A, Joshua V, Haj Hensvold A, et al. Identification of a novel chemokine-dependent molecular mechanism underlying rheumatoid arthritis-associated autoantibodymediated bone loss. Ann Rheum Dis. 2016 Apr;75(4):721-9. doi: 10.1136/annrheumdis-2015-208093.
4. Ford JA, Liu X, Marshall AA, et al. Impact of Cyclic Citrullinated Peptide Antibody Level on Progression to Rheumatoid Arthritis in Clinically Tested Cyclic Citrullinated Peptide Antibody-Positive Patients Without Rheumatoid Arthritis. Arthritis Care Res (Hoboken).2019 Dec;71(12):1583-92.
5. Mellado M, Martinez-Munoz L, Cascio G, et al. T Cell Migration in Rheumatoid Arthritis. Front Immunol. 2015 Jul 27;6:384. doi: 10.3389/fimmu.2015.00384.eCollection 2015.
6. Petrelli A , van Wijk F . CD8(+) T cells in human autoimmune arthritis: the unusual suspects. Nat Rev Rheumatol. 2016 Jul;12(7): 421-8. doi: 10.1038/nrrheum.2016.74. Epub 2016 Jun 3.
7. Kang YM , Zhang X , Wagner UG , et al . CD8 T cells are required for the formation of ectopic germinal centers in rheumatoid synovitis. J Exp Med. 2002 May 20;195(10): 1325-36. doi: 10.1084/jem.20011565.
8. Furst DE, Emery P. Rheumatoid arthritis pathophysiology: update on emerging cytokine and cytokine-associated cell targets. Rheumatology (Oxford). 2014 Sep;53(9): 1560-9. doi: 10.1093/rheumatology/ket414. Epub 2014 Jan 8.
9. Wong P, Quinn J, Sims N, et al. Interleukin-6 modulates production of T lymphocytederived cytokines in antigen-induced arthritis and drives inflammation-induced osteoclastogenesis. Arthritis Rheum. 2006 Jan;54(1): 158-68. doi: 10.1002/art.21537.
10. Yamin R, Berhani O, Peleg H, et al. High percentages and activity of synovial fluid NK cells present in patients with advanced stage active Rheumatoid Arthritis. Sci Rep. 2019 Feb 4;9(1):1351. doi: 10.1038/s41598-018-37448-z.
11. Shegarfi H, Naddafi F, Irshafiey A. Natural Killer Cells and Their Role in Rheumatoid Arthritis: Friend or Foe? Scientific World Journal. 2012;2012:491974. doi: 10.1100/2012/491974. Epub 2012 Apr 1.
12. Ahern DJ, Brennan FM. The role of Natural Killer cells in the pathogenesis of rheumatoid arthritis: Major contributors or essential homeostatic modulators? Immunol Lett. 2011 May;136(2):115-21. doi: 10.1016/j.imlet.2010.11.001. Epub 2010 Nov 10.
13. Qu CH, Hou Y, Bi YF, et al. Values of serum IL-10 and IL-17 in rheumatoid arthritis. Eur Rev Med Pharmacol Sci. 2019 Mar; 23(5):1899-1906. doi: 10.26355/eurrev_201903_17227.
14. Jung J, Choe J, Li L, Choi YS. Regulation of CD27 expression in the course of germinal center B cell differentiation: the pivotal role of IL-10. Eur J Immunol. 2000 Aug;30(8):2437-43. doi: 10.1002/1521-4141(2000)30:8< 2437::AID-IMMU2437>3.0.CO;2-M.
15. Li Y, Li Z, Hu F. Double negative (DN) B cells: an under recognized effector memory B cell subset in autoimmunity. Clin Exp Immunol. 2021 Aug;205(2):119-127. doi: 10.1111/cei.13615. Epub 2021 Jun 6.
16. Gerasimova EV, Popkova TV, Aleksankin AP, et al. B-lymphocyte subpopulations in patients with rheumatoid arthritis and the effect of an interleukin-6 receptor inhibitor on them. Nauchno-prakticheskaya revmatologiya. 2018; 56(6):731-8. (In Russ.).
17. Cope AP, Schulze-Koops H, Aringer M. The central role of T cells in rheumatoid arthritis. Clin Exp Rheumatol. Sep-Oct 2007;25(5 Suppl 46):S4-11.
18. Scheeren FA, Nagasawa M, Weijer K, et al. T cell-independent development and induction of somatic hypermutation in human IgM+ IgD+ CD27+ B cells. J Exp Med. 2008 Sep 1;205(9):2033-42. doi: 10.1084/jem.20070447. Epub 2008 Aug 11.
19. Weller S, Faili A, Garcia C, et al. CD40- CD40L independent Ig gene hypermutation suggests a second B cell diversification pathway in humans. Proc Natl Acad Sci U S A. 2001 Jan 30;98(3):1166-70. doi: 10.1073/pnas.98.3.1166.
20. Sanz I, Wei C, Lee FE, Anolik J. Phenotypic and functional heterogeneity of human memory B cells. SeminImmunol. 2008;20(1): 67-82. doi:10.1016/j.smim.2007.12.006
21. Mahmood Z, Muhammad K, Schmalzing M, et al. CD27-IgD- memory B cells are modulated by in vivo interleukin-6 receptor (IL-6R) blockade in rheumatoid arthritis. Arthritis Res Ther. 2015 Mar 14;17(1):61. doi: 10.1186/s13075-015-0580-y.
22. Lemoine S, Morva A, Youinou P, Jamin C. Human T cells induce their own regulation through activation of B cells. J Autoimmun. 2011 May;36(3-4):228-38. doi: 10.1016/j.jaut.2011.01.005. Epub 2011 Feb 12.
23. Blair PA, Noreсa LY, Flores-Borja F, et al. CD19+CD24hi CD38 hi B cells exhibit regulatory capacity in healthy individuals but are functionally impaired in systemic lupus erythematosus patients. Immunity. 2010 Jan 29; 32(1):129-40. doi: 10.1016/j.immuni.2009.11.009. Epub 2010 Jan 14.
24. Flores-Borja F, Bosma А, Ng D, et al. CD19+CD24hiCD38hi B cells maintain regulatory T cells while limiting TH1 and TH17 differentiation. Sci Transl Med. 2013 Feb 20; 5(173):173ra23. doi: 10.1126/scitranslmed.3005407.
25. Palanichamy A, Barnard J, Zheng B, et al. Novel human transitional B cell populations revealed by B cell depletion therapy. J Immunol. 2009 May 15;182(10):5982-93. doi: 10.4049/jimmunol.0801859.
26. Wang Y, Lloyd KA, Melas I, et al. Rheumatoid arthritis patients display B-cell dysregulation already in the naпve repertoire consistent with defects in B-cell tolerance. Sci Rep. 2019 Dec 27;9(1):19995. doi: 10.1038/s41598-019-56279-0.
27. Meffre E, O'Connor KC. Impaired B-cell tolerance checkpoints promote the development of autoimmune diseases and pathogenic autoantibodies. Immunol Rev. 2019 Nov;292(1): 90-101. doi: 10.1111/imr.12821. Epub 2019 Nov 12.
28. Vital EM, Dass S, Rawstron AC, et al. Management of nonresponse to rituximab in rheumatoid arthritis: predictors and outcome of re-treatment. Arthritis Rheum. 2010 May; 62(5):1273-9. doi: 10.1002/art.27359.
29. Hofmann K, Clauder AK, Manz RА. Targeting B Cells and Plasma Cells in Autoimmune Diseases. Front Immunol. 2018 Apr 23;9:835. doi: 10.3389/fimmu.2018.00835.eCollection 2018.
Review
For citations:
Martynova AV, Popkova TV, Aleksankin AP, Gridneva GI, Gerasimova EV, Gorbunova YN, Lila AM. Dynamics of T- and B-lymphocytes in patients with rheumatoid arthritis, receiving biological disease-modifying antirheumatic drugs. Sovremennaya Revmatologiya=Modern Rheumatology Journal. 2022;16(1):38-45. (In Russ.) https://doi.org/10.14412/1996-7012-2022-1-38-45