Особенности фенотипа Т-регуляторных клеток при раннем ревматоидном артрите
https://doi.org/10.14412/1995-4484-2016-660-666
Аннотация
Цель – изучить содержание и особенности фенотипа Т-регуляторных клеток (Трег) в периферической крови здоровых доноров и пациентов с ранним ревматоидным артритом (РА) методом многоцветной проточной цитометрии.
Материал и методы. В исследование было включено 39 пациентов с ранним РА. Процентное количество (ПК) и абсолютное содержание Трег (FoxP3+CD25+; CD152+surface; CD152+intracellular; FoxP3+CD127; CD25+CD127-; FoxP3+ICOS+; FoxP3+CD154+; FoxP3+CD274+) определялось методом многоцветной проточной цитофлуориметрии. Контрольную группу составили 20 здоровых доноров, сопоставимых по полу и возрасту с обследованными пациентами.
Результаты и обсуждение. Среди включенных в исследование больных медиана [25-й; 75-й перцентили] DAS28 составили 5,01 [4,2; 5,8], при этом у 22 (48,9%) регистрировалась высокая, у 20 (44,4%) – умеренная и у 3 (6,7%) – низкая активность патологического процесса. У пациентов с ранним РА по сравнению со здоровыми донорами регистрировались более низкое ПК FoxP3+CD25+ клеток, ПК и абсолютное содержание FoxP3+ICOS+, FoxP3+CD154+ и FoxP3+ CD274+ Т-клеток (p<0,05 во всех случаях). Регистрировалась отрицательная корреляционная взаимосвязь: ПК FoxP3+CD25+ с СРБ (r=-0,4); ПК CD152+intracellular с DAS28 (r=-0,35), СОЭ (r=-0,46) и СРБ (r=-0,54); ПК FoxP3+CD127- с СРБ (r=-0,42); ПК CD25+CD127- с DAS28 (r=-0,38), SDAI (r=-0,41), CDAI (r=-0,36), СОЭ (r=-0,39), СРБ (r=-0,47); р<0,05 во всех случаях.
Заключение. Полученные данные свидетельствуют о нарушении функциональной активности Трег при раннем РА, что оказывает влияние на активность воспалительного процесса.
Об авторах
А. С. АвдееваРоссия
115522 Москва, Каширское шоссе, 34А
Ю. П. Рубцов
Россия
кафедра биохимии и молекулярной медицины факультета фундаментальной медицины
119192 Москва, Ломоносовский проспект, 31, корп. 5
Т. В. Попкова
Россия
115522 Москва, Каширское шоссе, 34А
Д. Т. Дыйканов
Россия
кафедра биохимии и молекулярной медицины факультета фундаментальной медицины
119192 Москва, Ломоносовский проспект, 31, корп. 5
Е. Л. Насонов
Россия
115522 Москва, Каширское шоссе, 34А
кафедра ревматологии Института профессионального образования 119991 Москва, ул. Трубецкая, 8, стр. 2
Список литературы
1. Насонов ЕЛ, Каратеев ДЕ, Балабанова РМ. Ревматоидный артрит. В кн.: Насонов ЕЛ, Насонова ВА, редакторы. Ревматология: Национальное руководство. Москва: ГЭОТАР- Медиа; 2008. С. 290-331 [Nasonov EL, Karateev DE, Balabanova RM. Rheumatoid arthritis. In: Nasonov EL, Nasonova VA, editors. Revmatologiya: Natsional’noe rukovodstvo [Rheumatology: National guidelines]. Moscow: GEOTAR-Media; 2008. P. 290-331].
2. Firestein G. Evolving concepts of rheumatoid arthritis. Nature. 2003;423:356-61. doi: 10.1038/nature01661
3. Cope A. T cells in rheumatoid arthritis. Arthritis Res Ther. 2008;10 Suppl 1:S1. doi: 10.1186/ar2412
4. Choy E. Selective modulation of T cell co-stimulation: a novel mode of action for the treatment of rheumatoid arthritis. Clin Exp Rheumatol. 2009;27:510-8.
5. Steward-Tharp S, Song Y, Siegel R, O’Shea J. New insights into T cells biology and T cells directed therapy for autoimmunity inflammation and immunosuppression. Ann NY Acad Sci. 2010;1183:123-48. doi: 10.1111/j.1749-6632.2009.05124.x
6. Быковская СН, Насонов ЕЛ. Роль дефектов иммуносупрессии в развитии аутоиммунных заболеваний. Научно-практическая ревматология. 2005;(4):81-4 [Bykovskaya SN, Nasonov EL. Role of immunosupression defects in the development of autoimmune diseases. Nauchno- Prakticheskaya Revmatologiya = Rheumatology Science and Practiсе. 2005;43(4):81-4 (In Russ.)]. doi: 10.14412/1995-4484-2005-623
7. Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and immune tolerance. Cell. 2008;133(5):775-87. doi: 10.1016/j.cell.2008.05.009
8. Zeng H, Chi H. The interplay between regulatory T cells and metabolism in immune regulation. OncoImmunology. 2013;2(11):e26586. Epub 2013 Oct 21. doi: 10.4161/onci.26586
9. Buckner JH. Mechanisms of impaired regulation by CD4+CD25+FOXP3+ regulatory T cells in human autoimmune diseases. Nat Rev Immunol. 2010;10:849-59. doi: 10.1038/nri2889
10. Rudensky AY. Regulatory T cells and FoxP3. Immunol Rev. 2011;241;260-8. doi: 10.1111/j.1600-065X.2011.01018.x
11. Abbas AK, Benoist C, Bluestone JA, et al. Regulatory T cells: recommendations to simplify the nomenclature. Nat Immunol. 2013;14:300-8. doi: 10.1038/ni.2554
12. Miyara M, Yoshioka Y, Kitoh A, et al. Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity. 2009b;30:899- 911. doi: 10.1016/j.immuni.2009.03.019
13. Miyara M, Ito Y, Sakaguchi S. T reg-cell therapies for autoimmune rheumatic duseases. Nat Rev Rheumatol. 2014 Sep;10(9):543-51. doi: 10.1038/nrhheum.2014.105
14. Prakken B, Wehrens E, van Wijl F. Quality or Quantity? Unraveling the role of T reg cells in rheumatoid arthritis. Arthritis Rheum. 2013;65:552-4. doi: 10.1002/art.37831
15. Klimiuk PA, Yang H, Goronzy JJ, Weyand CM. Production of cytokines and metalloproteinases in rheumatoid synovitis is T cell dependent. Clin Immunol. 1999;90:65- 78. doi: 10.1006/clim.1998.4618
16. Lahl K, Loddenkemper C, Drouin C, et al. Selective depletion of Foxp3+ regulatory T cells induces a scurfy-like disease. J Exp Med. 2007;204(1):57-63. doi: 10.1084/jem.20061852. Epub 2007Jan 2.
17. Cao D, Malmstrom V, Baecher-Allan C, et al. Isolation and functional characterization of regulatory CD25brightCD4+ T cells fromthe target organ of patients with rheumatoid arthritis. Eur J Immunol. 2003;33:215-23. doi: 10.1002/immu.200390024
18. Cao D, van Vollenhoven R, Klareskog L, et al. CD25+CD4+ regulatory T cells are enriched in inflamed joints of patients with chronic rheumatic disease. Arthritis Res Ther. 2004;6:R335-46. doi: 10.1186/ar1192
19. Van Amelsfort JMR, Jacobs KMG, Bijlsma JWJ, et al. CD4+CD25+ regulatory T cells in rheumatoid arthritis: differences in the presence, phenotype, and function between peripheral blood and synovial fluid. Arthritis Rheum. 2004;50:2775-85. doi: 10.1002/art.20499
20. Mottonen M, Heikkinen J, Mustonen L, et al. CD4+ CD25+T cells with the phenotypic and functional characteristics of regulatory T cells are enriched in the synovial fluid of patients with rheumatoid arthritis. Clin Exper Immunol. 2005;140:360-7. doi: 10.1111/j.1365-2249.2005.02754.x
21. Liu M-F, Wang C-R, Fung L-L, et al. The presence of cytokine-suppressive CD4+CD25+ T cells in the peripheral blood and synovial fluid of patients with rheumatoid arthritis. Scand J Immunol. 2005;62:312-7. doi: 10.1111/j.1365-3083.2005.01656.x
22. Cao D, Borjesson O, Larsson P, et al. FOXP3 identifies regulatory CD25brightCD4+ T cells in rheumatic joints. Scand J Immunol. 2006;63:444-52. doi: 10.1111/j.1365-3083.2006.001755.x
23. Jiao Z, Wang W, Jia R, et al. Accumulation of FoxP3-expressing CD4+CD25+ T cells with distinct chemokine receptors in synovial fluid of patients with active rheumatoid arthritis. Scand J Rheumatol. 2007;36:428-33. doi: 10.1080/03009740701482800
24. Moradi B, Schnatzer P, Hagmann S, et al. CD4+CD25+/highCD127low/- regulatory T cells are enriched in rheumatoid arthritis and osteoarthritis joints – analysis of frequency and phenotype in synovial membrane, synovial fluid and peripheral blood. Arthritis Res Ther. 2014;16: R97. doi: 10.1186/ar4545
25. Dejaco C, Duftner C, Klauser A, Schirmer M. Altered T-cell subtypes in spondyloarthritis, rheumatoid arthritis and polymyalgia rheumatic. Rheumatol Int. 2010;30:297-303. doi: 10.1007/s00296-009-0949-9
26. Sempere-Ortells JM, Perez-Garcia V, Martin-Alberca G, et al. Quantification and phenotype of regulatory T cells in rheumatoid arthritis according to disease activity Score- 28. Autoimmunity. 2009;42:636-45. doi: 10.3109/08916930903061491
27. Kawashiri S-Y, Kawakami A, Okada A, et al. CD4+CD25(high)CD127(low/-) Treg cell frequency from peripheral blood correlates with disease activity in patients with rheumatoid arthritis. J Rheumatol. 2011;38:2517-21. doi: 10.3899/jrheum.110283
28. Han GM, O’Neil-Andersen NJ, Zurier RB, Lawrence DA. CD4+CD25high T cell numbers are enriched in the peripheral blood of patients with rheumatoid arthritis. Cell Immunol. 2008;253:92-101. doi: 10.1016/j.cellimm.2008.05.007
29. Lin SC, Chen K-H, Lin C-H, et al. The quantitative analysis of peripheral blood FOXP3- expressing T cells in systemic lupus erythematosus and rheumatoid arthritis patients. Eur J Clin Invest. 2007;37:987-96. doi: 10.1111/j.1365-2362.2007.01882.x
30. Ji L, Geng Y, Zhou W, Zhang Z. A study on relationship among apoptosis rates, number of peripheral T cell subtypes and disease activity in rheumatoid arthritis. Int J Rheum Dis. 2016;19:167-71. doi: 10.1111/1756-185X.12211
31. Dombrecht EJ, Aerts NE, Schuerwegh AJ, et al. Influence of antitumor necrosis factor therapy (Adalimumab) on regulatory T cells and dendritic cells in rheumatoid arthritis. Clin Exper Rheumatol. 2006;24:31-7.
32. Lawson CA, Brown AK, Bejarano V, et al. Early rheumatoid arthritis is associated with a deficit in the CD4+CD25high regulatory T cell population in peripheral blood. Rheumatology (Oxford). 2006;45(10):1210-7. doi: 10.1093/rheumatology/kel089
33. Hensor RMA, Hunt L, Patmar R, et al. Predicting the evaluation of inflammatory arthritis in ACPA-positive individuals: can T-cell subset help? Ann Rheum Dis. 2014;73 Suppl 1:A14. doi: 10.1136/annrheumdis-2013-205124.32
34. Linsley PS, Greene JL, Tan P, et al. Coexpression and functional cooperation of CTLA-4 and CD28 on activated T lymphocytes. J Exp Med. 1992;176:1595-604. doi: 10.1084/jem.176.6.1595
35. Harper K, Balzano C, Rouvier E, et al. CTLA-4 and CD28 activated lymphocyte molecules are closely related in both mouse and human as to sequence, message expression, gene structure, and chromosomal location. J Immunol. 1991;147:1037-44.
36. Yokosuka T, Kobayashi W, Takamatsu M, et al. Spatiotemporal basis of CTLA-4 costimulatory molecule-mediated negative regulation of T cell activation. Immunity. 2010;33:326-39. doi: 10.1016/j.immuni.2010.09.006
37. Cribbs AP, Kennedy A, Penn H, et al. Regulatory T cell function in rheumatoid arthritis is compromised by CTLA-4 promoter methylation resulting in a failure to activate the IDO pathway. Arthritis Rheum. 2014 Sep;66(9):2344-54. doi: 10.1002/art.38715
38. Schneider H, Downey J, Smith A, et al. Reversal of the TCR stop signal by CTLA-4. Science. 2006;313:1972-5. doi: 10.1126/science. 1131078
39. Hutloff A, Dittrich AM, Beier KC, et al. ICOS is an inducible Tcell co-stimulator structurally and functionally related to CD28. Nature. 1999;397:263-6. doi: 10.1038/16717
40. Yoshinaga SK, Whoriskey JS, Khare SD, et al. T-cell co-stimulation through B7RP-1 and ICOS. Nature. 1999;402:827-32. doi: 10.1038/45582
41. Kroczek RA, Mages HW, Hutloff A. Emerging paradigms of T-cell co-stimulation. Curr Opin Immunol. 2004;16:321-7. doi: 10.1016/j.coi.2004.03.002
42. Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Ann Rev Immunol. 2005;23:515-48. doi: 10.1146/annurev.immunol.23.021704.115611
43. Sperling AI, Bluestone JA. ICOS costimulation: it’s not just for TH2 cells anymore. Nat Immunol. 2001;2:573-4. doi: 10.1038/89709
44. Bonhagen K, Liesenfeld O, Stadecker MJ, et al. ICOS Th cells produce distinct cytokines in different mucosal immune responses. Eur J Immunol. 2003;33:392-401. doi: 10.1002/immu.200310013
45. Burmeister Y, Lischke T, Dahler A, et al. ICOS controls the pool size of effector-memory and regulatory T cells. J Immunol. 2008;180:774-82. doi: 10.4049/jimmunol.180.2.774
46. Hasegawa M, Fujimoto M, Matsushita T, et al. Augmented ICOS expression in patients with early diffuse cutaneous systemic sclerosis. Rheumatology. 2013;52:242-51. doi: 10.1093/rheumatology/kes258
47. Grimbacher B, Hutloff A, Schlesier M, et al. Homozygous loss of ICOS is associated with adult-onset common variable immunodeficiency. Nat Immunol. 2003;4:261-8. doi: 10.1038/ni902
48. Bishop GA, Hostager BS. The CD40–CD154 interaction in B cell-T cell liaisons. Cytokine Growth Factor Rev. 2003;14:297-309. doi: 10.1016/S1359-6101(03)00024-8
49. O’Sullivan B, Thomas R. CD40 and dendritic cell function. Crit Rev Immunol. 2003;23:83-107. doi: 10.1615/CritRevImmunol.v23.i12.50
50. Peters A, Stunz L, Bishop G. CD40 and autoimmunity: the dark side of a great activator. Semin Immunol. 2009 Oct;21(5):293-300. doi: 10.1016/j.smim.2009.05.012
51. Hill D, Eastaff-Leung N, Bresatz-Atkins S, et al. Inhibition of activation induced CD154 on CD4+CD25- cells: a valid surrogate for human Treg suppressor function. Immunol Cell Biol. 2012;90: 812-21. doi: 10.1038/icb.2012.18
52. Sharpe AH, Wherry EJ, Ahmed R, Freeman GJ. The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection. Nat Immunol. 2007;8:239-45. doi: 10.1038/ni1443
53. Okazaki T, Honjo T. PD-1 and PD-1 ligands: from discovery to clinical application. Int Immunol. 2007;19:813-24. doi: 10.1093/intimm/dxm057
54. Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Ann Rev Immunol. 2008;26:677-704. doi: 10.1146/annurev.immunol.26.021607.090331
55. Francisco L, Sage P, Sharpe A. The PD-1 pathway in tolerance and autoimmunity. Immunol Rev. 2010;236:219-42. doi: 10.1111/j.1600-065X.2010.00923.x
56. Fife B, Pauken K. The role of the PD-1 pathway in autoimmunity and peripheral tolerance. Ann NY Acad Sci. 2011;1217:45-59. doi: 10.1111/j.1749-6632.2010.05919.x
57. Behrens F, Himsel A, Rehart S, et al. Imbalance in distribution of functional autologous regulatory T cells in rheumatoid arthritis. Ann Rheum Dis. 2007;66:1151-6. doi: 10.1136/ard.2006.068320
Рецензия
Для цитирования:
Авдеева А.С., Рубцов Ю.П., Попкова Т.В., Дыйканов Д.Т., Насонов Е.Л. Особенности фенотипа Т-регуляторных клеток при раннем ревматоидном артрите. Научно-практическая ревматология. 2016;54(6):660-666. https://doi.org/10.14412/1995-4484-2016-660-666
For citation:
Avdeeva A.S., Rubtsov Yu.P., Popkova T.V., Dyikanov D.T., Nasonov E.L. PHENOTYPIC FEATURES OF T REGULATORY CELLS IN EARLY RHEUMATOID ARTHRITIS. Rheumatology Science and Practice. 2016;54(6):660-666. (In Russ.) https://doi.org/10.14412/1995-4484-2016-660-666