Клинико-патогенетическое значение Foxр3+ регуляторных Т-клеток при ревматоидном артрите

Регуляторные Т-клетки (Трег) играют ключевую роль в иммунной системе благодаря подавлению гипериммунного ответа в отношении аутоантигенов, а также кишечных условно-патогенных микроорганизмов. В последние годы получены данные о способности Трег подавлять различные иммуновоспалительные реакции в ответ на широкий спектр физиологических и патологических стимулов, включая микроорганизмы, опухолевые клетки, аллогенные трансплантаты, клетки плода.

Трег экспрессируют широкий спектр мембранных молекул, которые определяют их функциональную активность и дают возможность идентифицировать эти клетки, однако до сих пор не обнаружен универсальный поверхностный маркер, который позволил бы выделить данную клеточную субпопуляцию из пула Т-лимфоцитов. Наиболее специфическим внутриклеточным маркером Трег является ядерный фактор транскрипции Foxp3, который имеет фундаментальное значение в развитии Трег и их ингибиторной функции.

Результаты подавляющего большинства исследований указывают на увеличение содержания Трег в синовиальной жидкости пациентов с ревматоидным артритом (РА), однако данные об уровне данной клеточной субпопуляции в периферической крови весьма противоречивы. Большинство исследователей наблюдали уменьшение процентного содержания циркулирующих Трег, в то время как в других работах выявлено его увеличение или отсутствие отличий от соответствующего показателя здоровых доноров или пациентов с ос- теоартрозом. Полагают, что количественный дефект CD4+CD25+Foxp3+CD127-регуляторных клеток особенно характерен для раннего РА и ассоциируется с риском развития последнего у бессимптомных пациентов, позитивных по антителам к циклическому цитруллинированному пептиду. Применение базисных и генно-инженерных биологических препаратов сопровождается определенным изменением уровня и функциональной активности Трег, с чем в ряде случаев связывают лечебный эффект препаратов.

Таким образом, Трег в настоящее время отводят важную роль в патогенезе аутоиммунных ревматических заболеваний, в частности, РА. Снижение уровня и функциональной активности Трег, вероятно, лежит в основе развития неконтролируемого хронического воспаления, приводящего к множественным органным повреждениям. 

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. Choy E, Panayi G. Cytokine pathways and joint inflammation in rheumatoid arthritis. N Engl J Med. 2001;344:907-16. doi: 10.1056/NEJM200103223441207

4. Weyand C, Goronzy J. Ectopic germinal center formation in rheumatoid synovitis. Ann NY Acad Sci. 2003;987:140-9. doi: 10.1111/j.1749-6632.2003.tb06042.x

5. Cope A. T cells in rheumatoid arthritis. Arthr Res Ther. 2008;10 Suppl 1:S1. doi: 10.1186/ar2412

6. 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.

7. 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

8. 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

9. 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

10. 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

11. 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

12. 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 2007 Jan 2.

13. 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

14. Wildin RS, Freitas A. IPEX and FOXP3: clinical and research perspectives. J Autoimmun. 2005;25 Suppl:56-62. doi: 10.1016/j.jaut.2005.04.008

15. Rudensky AY. Regulatory T cells and FoxP3. Immunol Rev. 2011;241;260-8. doi: 10.1111/j.1600-065X.2011.01018.x

16. 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

17. 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

18. Sakaguchi S, Miyara M, Costantino CM, Hafler DA. FOXP3+ regulatory T cells in the human immune system. Nat Rev Immunol. 2010;10:490-500. doi: 10.1038/nri2785

19. Tran DQ, Andersson J, Hardwick D, et al. Selective expression of latency-associated peptide (LAP) and IL-1 receptor type I/II (CD121a/CD121b) on activated human FOXP3+ regulatory T cells allows for their purification from expansion cultures. Blood. 2009a;113:5125-33. doi: 10.1182/blood-2009-01-199950

20. 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

21. 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

22. Kmieciak M, Gowda M, Graham L, et al. Human T cells express CD25 and Foxp3 upon activation and exhibit effector/memory phenotypes without any regulatory/suppressor function. J Transl Med. 2009;7:89. doi: 10.1186/1479-5876-7-89

23. Kennedy A, Schmiudt EM, Cribbs AP, et al. A novel upstream enhancer of FOXP3, sensitive to methylation-induced silencing, exhibit dysregulatrd methylation in rheumatoid arthritis Treg cells. Eur J Immunol. 2014;44:2668-78. doi: 10.1002/eji.201444453

24. Seddiki N, Santner-Nanan B, Martinson J, et al. Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells. J Exp Med. 2006;203:1693-700. doi: 10.1084/jem.20060468

25. Hartigan-O’Connor DJ, Poon C, Sinclair E, McCune JM. Human CD4+ regulatory T cells express lower levels of the IL-7 receptor α chain (CD127), allowing consistent identification and sorting of live cells. J Immunol Met. 2007;319:41-52. doi: 10.1016/j.jim.2006.10.008

26. Liu W, Putnam AL, Xu-Yu Z, et al. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ Treg cells. J Exp Med. 2006;203:1701-1. doi: 10.1084/jem.20060772

27. 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

28. 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.

29. 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

30. 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

31. 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

32. 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

33. 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

34. Kroczek RA, Mages HW, Hutloff A. Emerging paradigms of Tcell co-stimulation. Curr Opin Immunol. 2004;16:321-7. doi: 10.1016/j.coi.2004.03.002

35. 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

36. Sperling AI, Bluestone JA. ICOS costimulation: it’s not just for TH2 cells anymore. Nat Immunol. 2001;2:573-4. doi: 10.1038/89709

37. 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

38. 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

39. 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

40. 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

41. 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

42. O’Sullivan B, Thomas R. CD40 and dendritic cell function. Crit Rev Immunol. 2003;23:83-107. doi: 10.1615/CritRevImmunol.v23.i12.50

43. 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

44. Munroe M. Functional roles for T cell CD40 in infection and autoimmune disease: The role of CD40 in lymphocyte homeostasis. Semin Immunol. 2009;21(5):283-8. doi: 10.1016/j.smim.2009.05.008

45. Berner B, Wolf G, Hummel KM, et al. Increased expression of CD154 on CD4+ T cells as a marker of disease activity in RA. Ann Rheum Dis. 2000;59:190-5. doi: 10.1136/ard.59.3.190

46. Hill D, Eastaff-Leung N, Bresatz-Atkins S, et al. Inhibition of activation induced CD154 on CD4+CD25- cells: a valid surro￾gate for human Treg suppressor function. Immunol Cell Biol. 2012;90:812-21. doi: 10.1038/icb.2012.18

47. 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

48. 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

49. Nurieva RI, Liu X, Dong C. Yin-Yang of costimulation: crucial controls of immune tolerance and function. Immunol Rev. 2009;229:88-100. doi: 10.1111/j.1600-065X.2009.00769.x

50. Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008;26:677-704. doi: 10.1146/annurev.immunol.26.021607.090331

51. Freeman GJ, Wherry EJ, Ahmed R, Sharpe AH. Reinvigorating exhausted HIV-specific T cells via PD-1-PD-1 ligand blockade. J Exp Med. 2006;203:2223-7. doi: 10.1084/jem.20061800

52. 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

53. 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

54. Komatsu N, Okamoto K, Sawa S, et al. Pathogenic conversion of Foxp3+ T cells into TH17 cells in autoimmune arthritis. Nat Med. 2014;20:62-70. doi: 10.1038/nm.3432

55. Fossiez F, Djossou O, Chomarat P, et al. T cell interleukin-17 induces stromal cells to produce proinflammatory and hematopoietic cytokines. J Exp Med. 1996;183:2593-603. doi: 10.1084/jem.183.6.2593

56. Moran EM, Mullan R, McCormick J, et al. Human rheumatoid arthritis tissue production of IL-17A drives matrix and cartilage degradation: synergy with tumour necrosis factor-α, Oncostatin M and response to biologic therapies. Arthr Res Ther. 2009;11:R113. doi: 10.1186/ar2772

57. Sato K, Suematsu A, Okamoto K, et al. Th17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction. J Exp Med. 2006;203:2673-82. doi: 10.1084/jem.20061775

58. Abdulahad W, Boots A, Kallenberg C. FoxP3+ CD4+ T cells in systemic autoimmune diseases: the delicate balance between true regulatory T cells and effector Th-17 cells. Rheumatology. 2011;50:646-56. doi: 10.1093/rheumatology/keq328

59. Bettelli E, Carrier Y, Gao W, et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature. 2006;441:235-8. doi: 10.1038/nature04753

60. Du J, Huang C, Zhou B, Ziegler SF. Isoform-specific inhibition of ROR alpha-mediated transcriptional activation by human FOXP3. J Immunol. 2008;180:4785-92. doi: 10.4049/jim￾munol.180.7.4785

61. Koenen HJ, Smeets RL, Vink PM, et al. Human CD25highFoxp3pos regulatory T cells differentiate into IL-17- producing cells. Blood. 2008;112:2340-52. doi: 10.1182/blood- 2008-01-133967

62. Ayyoub M, Deknuydt F, Raimbaud I, et al. Human memory FOXP3+ Tregs secrete IL-17 ex vivo and constitutively express the T(H)17 lineage-specific transcription factor RORgamma t. Proc Natl Acad Sci USA. 2009;106:8635-40. doi: 10.1073/pnas.0900621106

63. Voo KS, Wang YH, Santori FR, et al. Identification of IL-17- producing FOXP3+ regulatory T cells in humans. Proc Natl Acad Sci USA. 2009;106:4793-8. doi: 10.1073/pnas.0900408106

64. Beriou G, Costantino CM, Ashley CW, et al. IL-17-producing human peripheral regulatory T cells retain suppressive function. Blood. 2009;113:4240-9. doi: 10.1182/blood-2008-10-183251

65. Wang T, Sun X, Zhao J. Regulatory T cells in rheumatoid arthritis showed increased plasticity toward Th17 but retained suppressive function in peripheral blood. Ann Rheum Dis. 2014;0:1-9. doi: 10.1136/annrheumdis-2013-204228

66. Harris KM, Fasano A, Mann DL. Monocytes differentiated with IL-15 support Th17 and Th1 responses to wheat gliadin: implications for celiac disease. Clin Immunol 2010;135:430-9. doi: 10.1016/j.clim.2010.01.003

67. Ferretti S, Bonneau O, Dubois GR, et al. IL-17, produced by lymphocytes and neutrophils, is necessary for lipopolysaccharide-induced airway neutrophilia: IL-15 as a possible trigger. J Immunol. 2003;170:2106-12. doi: 10.4049/jimmunol.170.4.2106

68. Cao D, Malmstrom V, Baecher-Allan C, et al. Isolation and functional characterization of regulatory CD25brightCD4+ T cells from the target organ of patients with rheumatoid arthritis. Eur J Immunol. 2003;33:215-23. doi: 10.1002/immu.200390024

69. 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. Arthr Res Ther. 2004;6:R335-46. doi: 10.1186/ar1192

70. Ehrenstein MR, Evans JG, Singt A, et al. Compromised function of regulatory T cells in rheumatoid arthritis and reversal by antiTNFα therapy. J Exp Med. 2004;200(3):277-85. doi: 10.1084/jem.20040165. Epub 2004 Jul 26.

71. Van Amelsfort JMR, Jacobs KMG, Bijlsma JWJ, et al. CD4+CD25+ regulatory T cells in rheumatoid arthritis: differ￾ences in the presence, phenotype, and function between peripheral blood and synovial fluid. Arthritis Rheum. 2004;50:2775-85. doi: 10.1002/art.20499

72. Mottonen M, Heikkinen J, Mustonen L, et al. CD4+ CD25+ T cells with the phenotypic and functional characteristics of regu￾latory 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

73. Liu M-F, Wang C-R, Fung L-L, et al. The presence of cytokinesuppressive 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

74. 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

75. Dombrecht EJ, Aerts NE, Schuerwegh AJ, et al. Influence of anti-tumor necrosis factor therapy (Adalimumab) on regulatory T cells and dendritic cells in rheumatoid arthritis. Clin Exper Rheumatol. 2006;24:31-7.

76. Van Amelsfort JMR, Van Roon JAG, Noordegraaf M, et al. Proinflammatory mediator-induced reversal of CD4+,CD25+ regulatory T cell-mediated suppression in rheumatoid arthritis. Arthritis Rheum. 2007;56:732-42. doi: 10.1002/art.22414

77. 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

78. 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

79. 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

80. 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

81. Raghavan S, Cao D, Widhe M, et al. FOXP3 expression in blood, synovial fluid and synovial tissue during inflammatory arthritis and intra-articular corticosteroid treatment. Ann Rheum Dis. 2009;68:1908-15. doi: 10.1136/ard.2008.100768

82. Sempere-Ortells JM, Perez-Garcia V, Marin-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

83. 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

84. 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

85. Lina C, Conghua W, Nan L, Ping Z. Combined treatment of etanercept and MTX reverses Th1/Th2, Th17/Treg imbalance in patients with rheumatoid arthritis. J Clin Immunol. 2011;31:596- 605. doi: 10.1007/s10875-011-9542-6

86. Niu Q, Cai B, Huang Z-C, et al. Disturbed Th17/Treg balance in patients with rheumatoid arthritis. Rheumatol Int. 2012;32:2731- 6. doi: 10.1007/s00296-011-1984-x

87. Xq E, Meng HX, Cao Y, et al. Distribution of regulatory T cells and interaction with dendritic cells in the synovium of rheumatoid arthritis. Scand J Rheumatol. 2012;41:413-20. doi: 10.3109/03009742.2012.696135

88. Samson M, Audia S, Janikashvili N, et al. Brief report: inhibition of interleukin-6 function corrects Th17/Treg cell imbalance in patients with rheumatoid arthritis. Arthritis Rheum. 2012;64:2499- 503. doi: 10.1002/art.34477

89. 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

90. 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. Arthr Res Ther. 2014;16:R97. doi: 10.1186/ar4545

91. Guggino G, Giardina A, Ferrante A, et al. The in vitro addition of methotrexate and/or methylprednisolone determines peripher￾al reduction in Th17 and expansion of conventional Treg and of IL-10 producingTh17 lymphocytes in patients with early rheumatoid arthritis. Rheumatol Int. 2015;35:171-5. doi: 10.1007/s00296- 014-3030-2

92. 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

93. 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

94. McGovern JL, Nguyen DX, Notley CA, et al. Th17 cells are restarained by T reg cells via the inhibition of interleukin-6 in patients with rheumatoid arthritis responding to anti-tumor necrosis factor antibody therapy. Arthritis Rheum. 2012;64(10):3129-38. doi: 10.1002/art.34565

95. Wehrens EJ, Mijnheer G, Duurland CL, et al. Functional human regulatory T cells fail to control autoimmune inflammation due to PKB/c-akt hyperactivation in effector cells. Blood. 2011;118:3538-48. doi: 10.1182/blood-2010-12- 328187

96. Raptopoulou AP, Bertsias G, Makrygiannakis D, et al. The programmed death 1/programmed death ligand 1 inhibitory pathway is up-regulated in rheumatoid synovium and regulates peripheral T cell responses in human and murine arthritis. Arthritis Rheum. 2010;62:1870-80. doi: 10.1002/art.27500

97. Yu X, Wang C, Luo J, et al. Combination with methotrexate and cyclophosphamide attenuated maturation of dendritic cells: inducing treg skewing and Th17 suppression in vivo. Clin Devel Immunol. 2013;Article ID 238035, 12 p.

98. Li Y, Jiang L, Zhang S, et al. Methotrexate attenuates the Th17/IL-17 levels in peripheral blood mononuclear cells from healthy individuals and RA patients. Rheumatol Internat. 2012;32:2415-22. doi: 10.1007/s00296-011-1867-1

99. Pericolini E, Gabrielli E, Alunno A, et al. Functional improvement of regulatory T cells from rheumatoid arthritis subjects induced by capsular polysaccharide glucuronoxylomannogalac￾tan. PLoS One. 2014;9:Article ID e111163. doi: 10.1371/journal.pone.0111163

100. Peres R, Liew F, Talbot J, et al. Low expression of CD39 on regulatory T cells as a biomarker for resistance to methotrexate therapy in rheumatoid arthritis. PNAS. 2015;122:2509-14. doi: 10.1073/pnas.1424792112

101. Cribbs AP, Kennedy A, Penn H, et al. Methotrexate restores regulatory T cell function through demethelation of the FoxP3 upstream enhancer in patients with rheumatoid arthritis. Arthritis Rheum. 2015;67:1182-92. doi: 10.1002/art.39031

102. Da Silva JC, Mariz HA, da Rocha LF Jr, et al. Hydroxychloroquine decreases Th17-related cytokines in systemic lupus erythematosus and rheumatoid arthritis patients. Clinics. 2013;68:766-71. doi: 10.6061/clinics/2013(06)07

103. De Paz B, Alperi-Lopez M, Ballina-Garcia FJ, et al. Cytokines and regulatory T cells in rheumatoid arthritis and their relationship with response to corticosteroids. J Rheumatol. 2010;37:2502- 10. doi: 10.3899/jrheum.100324

104. De Paz B, Prado C, Alperi-Lopez M, et al. Effects of glucocorticoid treatment on CD25-FOXP3+ population and cytokine producing cells in rheumatoid arthritis. Rheumatology. 2012;51:1198- 207. doi: 10.1093/rheumatology/kes039

105. Valencia X, Stephens G, Goldbach-Mansky R, et al. TNF down modulate the function of human CD4+CG25hiT-regulatory cells. Blood. 2006;108(1):253-61. doi: 10.1182/blood- 2005-11- 4567

106. Huang Z, Yang B, Shi Y, et al. Anti-TNF-α therapy improves Тreg and suppresses Тeff in patients with rheumatoid arthritis. Cell Immunol. 2012;279:25-9. doi: 10.1016/j.cellimm.2012.09.001

107. Fujimoto M, Serada S, Mihara M, et al. Interleukin-6 blockade suppresses autoimmune arthritis in mice by the inhibition of inflammatory Th17 responses. Arthritis Rheum. 2008;58:3710-9. doi: 10.1002/art.24126

108. Pesce B, Soto L, Sabugo F, et al. Effect of interleukin-6 receptor blockade on the balance between regulatory T cells and T helper type 17 cells in rheumatoid arthritis patients. Clin Exper Immunol. 2012;171:237-42. doi: 10.1111/cei.12017

109. Kikuchi J, Hashizume M, Kaneko Y, et al. Peripheral blood CD4+CD25+CD127low regulatory T cells are significantly increased by tocilizumab treatment in patients with rheumatoid arthritis: increase in regulatory T cells correlates with clinical response. Arthr Res Ther. 2015;17:10. doi: 10.1186/s13075-015- 0526-4

110. Hamel KM, Cao Y, Ashaye A, et al. B cell depletion enhance T regulatory cell activity essential in the supression of arthritis. J Immunol. 2011;187(9):4900-6. doi: 10.4049/jimmunol. 1101844

111. Alvarez-Quiroga C, Abud-Mendoza C, Doniz-Padilla L, et al. CTLA-4-Ig therapy diminishes the frequency but enhances the function of treg cells in patients with rheumatoid arthritis. J Clin Immunol. 2011;31:588-95. doi: 10.1007/s10875-011- 9527-5

112. Pieper J, Herrath J, Raghavan S, et al. CTLA4-Ig (abatacept) therapy modulates T cell effector functions in autoantibody-positive rheumatoid arthritis patients. BMC Immunol. 2013;14:34. doi: 10.1186/1471-2172-14-34

113. Picchianti Diamanti A, Rosado MM, Scarsella M, et al. Abatacept (cytotoxic T lymphocyte antigen 4-immunoglobulin) improves B cell function and regulatory T cell inhibitory capacity in rheumatoid arthritis patients non-responding to anti-tumour necrosis factor-α agents. Clin Exper Immunol. 2014;177:630-40. doi: 10.1111/cei.12367

114. Scarsi M, Zanotti C, Chiarini M, et al. Reduction of peripheral blood T cells producing IFN-γ and IL-17 after therapy with abatacept for rheumatoid arthritis. Clin Exper Rheumatol. 2014;32:204-10.

115. Oh JS, Kim Y-G, Lee SG, et al. The effect of various disease modifying anti-rheumatic drugs on the suppressive function of CD4+CD25+ regulatory T cells. Rheumatol Int. 2013;33:381-8. doi: 10.1007/s00296-012-2365-9

116. Van Nies JA, Gaujoux-Viala C, Tsonaka R, et al. When does the therapeutic window of opportunity in rheumatoid arthritis close? A study in two early RA cohorts. Ann Rheum Dis. 2014;73 Suppl. 2:73. doi: 10.1136/annrheumdis-2014-eular.5266

117. Cronstein BN. Low-dose methotrexate: A mainstay in the treatment of rheumatoid arthritis. Pharmacol Rev. 2005;57(2):163-72. doi: 10.1124/pr.57.2.3

118. Cronstein BN, Eberle MA, Gruber HE, Levin RI. Methotrexate inhibits neutrophil function by stimulating adenosine release from connective tissue cells. Proc Natl Acad Sci USA. 1991;88(6):2441- 5. doi: 10.1073/pnas.88.6.2441

119. Deaglio S, Dwyer KM, Gao W, et al. Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J Exp Med. 2007;204(6):1257-65. doi: 10.1084/jem.20062512

120. Montesinos MC, Yap JS, Desai A, et al. Reversal of the antiinflammatory effects of methotrexate by the nonselective adenosine receptor antagonists theophylline and caffeine: Evidence that the antiinflammatory effects of methotrexate are mediated via multiple adenosine receptors in rat adjuvant arthritis. Arthritis Rheum. 2000;43(3):656-63. doi: 10.1002/1529- 0131(200003)43:33.0.CO;2-H

121. Nesher G, Mates M, Zevin S. Effect of caffeine consumption on efficacy of methotrexate in rheumatoid arthritis. Arthritis Rheum. 2003;48(2):571-2. doi: 10.1002/art.10766

122. Montesinos MC, Takedachi M, Thompson LF, et al. The antiinflammatory mechanism of methotrexate depends on extracellular conversion of adenine nucleotides to adenosine by ecto-5’- nucleotidase: findings in a study of ecto-5’-nucleotidase genedeficient mice. Arthritis Rheum. 2007;56(5):1440-5. doi: 10.1002/art.22643

123. Sitkovsky MV, Ohta A. The ‘danger’ sensors that STOP the immune response: The A2 adenosine receptors? Trends Immunol. 2005;26(6):299-304. doi: 10.1016/j.it.2005.04.004

124. Hasko G, Linden J, Cronstein B, Pacher P. Adenosine receptors: therapeutic aspects for inflammatory and immune diseases. Nat Rev Drug Discov. 2008;7(9):759-70. doi: 10.1038/nrd2638

125. Hasko G, Cronstein BN. Adenosine: An endogenous regulator of innate immunity. Trends Immunol. 2004;25(1):33-9. doi: 10.1016/j.it.2003.11.003

126. Carregaro V, Sa-Nunes A, Cunha TM, et al. Nucleosides from Phlebotomus papatasi salivary gland ameliorate murine collagen-induced arthritis by impairing dendritic cell functions. J Immunol. 2011;187(8):4347-59. doi: 10.4049/jimmunol.1003404

127. Li L, Huang L, Ye H, et al. Dendritic cells tolerized with adenosine A2AR agonist attenuate acute kidney injury. J Clin Invest. 2012;122(11):3931-42. doi: 10.1172/JCI63170

128. Blache C, Lequerre T, Roucheux A, et al. Number and phenotype of rheumatoid arthritis patients’ CD4+CD25hi regulatory T cells are not affected by adalimumab or etanercept. Rheumatology. 2011;50:1814-22. doi: 10.1093/rheumatology/ker183

129. Aravena O, Pesce B, Soto L, et al. Anti-TNF therapy in patients with rheumatoid arthritis decreases Th1 and Th17 cell populations and expands IFN-γ-producing NK cell and regulatory T cell subsets. Immunobiology. 2011;216:1256-63. doi: 10.1016/j.imbio.2011.07.006

130. Vigna-Perez M, Abud-Mendoza C, Portillo-Salazar H, et al. Immune effects of therapy with Adalimumab in patients with rheumatoid arthritis. Clin Exper Immunol. 2005;141:372-80. doi: 10.1111/j.1365-2249.2005.02859.x

131. Nie H, Zheng Y, Li R, et al. Phosphorylation of FOXP3 controls regulatory T cell function and is inhibited by TNF-α in rheumatoid arthritis. Nat Med. 2013;19:322-8. doi: 10.1038/nm.3085

132. Vandenabeele P, Declercq W, Beyaert R, Fiers W. Two tumor necrosis factor receptors: structure and function. Trends Cell Biol. 1995;5:392-9. doi: 10.1016/S0962-8924(00)89088-1

133. Pinckard JK, Sheehan KC, Arthur CD, Schreiber RD. Constitutive shedding of both p55 and p75 murine TNF receptors in vivo. J Immunol. 1997;158:3869-73.

134. Xanthoulea S, Pasparakis M, Kousteni S, et al. Tumor necrosis factor (TNF) receptor shedding controls thresholds of innate immune activation that balance opposing TNF functions in infectious and inflammatory diseases. J Exp Med. 2004;200:367-76. doi: 10.1084/jem.20040435

135. Chen G, Goeddel DV. TNF-R1 signaling: a beautiful pathway. Science. 2002;296:1634-5. doi: 10.1126/science.1071924

136. Wajant H, Pfizenmaier K, Scheurich P. Tumor necrosis factor signaling. Cell Death Differ. 2003;10:45-65. doi: 10.1038/sj.cdd.4401189

137. Grell M, Becke FM, Wajant H, et al. TNF receptor type 2 mediates thymocyte proliferation independently of TNF receptor type 1. Eur J Immunol. 1998;28:257-63. doi: 10.1002/(SICI)1521- 4141(199801)28:013.0.CO;2-G

138. Arnett HA, Mason J, Marino M, et al. TNF alpha promotes proliferation of oligodendrocyte progenitors and remyelination. Nat Neurosci. 2001;4:1116-22. doi: 10.1038/nn738

139. Cope AP. Regulation of autoimmunity by proinflammatory cytokines. Curr Opin Immunol. 1998;10:669-76. doi: 10.1016/S0952-7915(98)80087-3

140. Clark J, Vagenas P, Panesar M, Cope AP. What does tumour necrosis factor excess do to the immune system long term? Ann Rheum Dis. 2005;64 Suppl 4:70-6. doi: 10.1136/ard.2005.042523

141. Kollias G, Kontoyiannis D. Role of TNF/TNFR in autoimmunity: specific TNF receptor blockade may be advantageous to antiTNF treatments. Cytokine Growth Factor Rev. 2002;13:315-21. doi: 10.1016/S1359-6101(02)00019-9

142. Grewal IS, Grewal KD, Wong FS, et al. Local expression of transgene encoded TNF alpha in islets prevents autoimmune diabetes in nonobese diabetic (NOD) mice by preventing the development of auto-reactive islet-specific T cells. J Exp Med. 1996;184:1963-74. doi: 10.1084/jem.184.5.1963

143. Jacob CO, Aiso S, Michie SA, et al. Prevention of diabetes in nonobese diabetic mice by tumor necrosis factor (TNF): similarities between TNF-alpha and interleukin 1. Proc Natl Acad Sci USA. 1990;87:968-72. doi: 10.1073/pnas.87.3.968

144. Kontoyiannis D, Kollias G. Accelerated autoimmunity and lupus nephritis in NZB mice with an engineered heterozygous deficiency in tumor necrosis factor. Eur J Immunol. 2000;30:2038-47. doi: 10.1002/1521-4141(200007)30:73.0.CO;2-K

145. Kollias G, Kontoyiannis D, Douni E, Kassiotis G. The role of TNF/TNFR in organ-specific and systemic autoimmunity: implications for the design of optimized ‘anti-TNF’ therapies. Curr Dir Autoimmun. 2002;5:30-50. doi: 10.1159/000060546

146. Chen X, Subleski JJ, Kopf H, et al. Cutting edge: expression of TNFR2 defines a maximally suppressive subset of mouse CD4+CD25+FoxP3+ T regulatory cells: applicability to tumorinfiltrating T regulatory cells. J Immunol. 2008;180:6467-71. doi: 10.4049/jimmunol.180.10.6467

147. Kleijwegt FS, Laban S, Duinkerken G, et al. Critical role for TNF in the induction of human antigen-specific regulatory T cells by tolerogenic dendritic cells. J Immunol. 2010;185:1412- 8. doi: 10.4049/jimmunol.1000560

148. Ablamunits V, Bisikirska B, Herold KC. Acquisition of regulatory function by human CD8(+) T cells treated with anti-CD3 antibody requires TNF. Eur J Immunol. 2010;40:2891-901. doi: 10.1002/eji.201040485

149. Mougiakakos D, Johansson CC, Jitschin R, et al. Increased thioredoxin-1 production in human naturally occurring regulatory T cells confers enhanced tolerance to oxidative stress. Blood. 2011;117:857-61. doi: 10.1182/blood-2010-09-307041

150. Chen X, Hamano R, Subleski JJ, et al. Expression of costimulatory TNFR2 induces resistance of CD4+FoxP3- conventional T cells to suppression by CD4+FoxP3+ regulatory T cells. J Immunol. 2010;185:174-82. doi: 10.4049/jimmunol.0903548

151. Van Mierlo GJ, Scherer HU, Hameetman M, et al. Cutting edge: TNFR-shedding by CD4+CD25+ regulatory T cells inhibits the induction of inflammatory mediators. J Immunol. 2008;180:2747- 51. doi: 10.4049/jimmunol.180.5.2747

152. Chen X, Baumel M, Mannel DN, et al. Interaction of TNF with TNF receptor type 2 promotes expansion and function of mouse CD4+CD25+ T regulatory cells. J Immunol. 2007;179:154-61. doi: 10.4049/jimmunol.179.1.154

153. Calzascia T, Pellegrini M, Hall H, et al. TNF-alpha is critical for antitumor but not antiviral T cell immunity in mice. J Clin Invest. 2007;117:3833-45.

154. Chen X, Oppenheim J. Contrasting effects of TNF and anti-TNF on the activation of effector T cells and regulatory T cells in autoimmunity. FEBS Letters. 2011;585:3611-8. doi: 10.1016/j.febslet.2011.04.025

155. Sarantopoulos A, Tselios K, Gkougkourelas I, et al. Tocilizumab treatment leads to a rapid and sustained increase in Treg cell levels in rheumatoid arthritis patients: comment on the article by Thiolat et al. Arthritis Rheum. 2014;66:2638. doi: 10.1002/art.38714

156. Thiolat A, Semerano L, Pers YM, et al. Interleukin-6 receptor blockade enhances CD39 regulatory T cell development in rheumatoid arthritis and in experimental arthritis. Arthritis Rheum. 2014;66:273-83. doi: 10.1002/art.38246

157. Feuchtenberger M, Muller S, Roll P, et al. Frequency of regulatory T cells is not affected by transient B cell depletion using antiCD20 antibodies in rheumatoid arthritis. Open Rheumatol J. 2008;2:81-8. doi: 10.2174/1874312900802010081

158. Lee S, Moon J, Lee C, et al. Abatacept alleviates severe autoimmune symptoms in a patient carrying a de novo variant in CTLA-4. J Allerg Clin Immunol. 2015;137:327-30. doi: 10.1016/j.jaci.2015.08.036