Preview

Rheumatology Science and Practice

Advanced search

THE RELATIONSHIP OF FoxP3+ T REGULATORY CELLS TO DISEASE ACTIVITY AND ANTIBODY LEVELS IN EARLY RHEUMATOID ARTHRITIS

https://doi.org/10.14412/1995-4484-2017-245-251

Abstract

Objective: to analyze the relationship of the count of FoxP3+ T regulatory cells (Tregs) to the clinical and laboratory parameters of disease activity and the levels of antibodies in a group of patients with early rheumatoid arthritis (RA).

Subjects and methods. The investigation enrolled 45 patients with early RA (2010 ACR/EULAR criteria) who had not previously received treatment with methotrexate, including 39 women; median age was 52.0 [32.5; 57.5] years; disease duration, 5 [4; 6] months, DAS28 5.01 [4.18; 5.8]; 71.1% of the patients were rheumatoid factor (RF) positive and 88.9% were anti-cyclic citrullinated peptide positive. The relative and absolute counts of Treg (FoxP3+CD25+; CD152+surface; CD152+intracellular; FoxP3+CD127-; CD25+CD127-; FoxP3+ICOS+; FoxP3+CD154+; FoxP3+CD274+) were measured by immunofluorescence staining and multicolor flow cytometry. A control group consisted of 20 healthy donors who were matched for sex and age with the examined patients.

Results and discussion. DАS28 was high, moderate, and low in 22 (48.9%), 20 (44.4%), and 3 (6.7%) patients, respectively. As compared with the healthy donors, the patients with early RA were observed to have lower values in the percentage of FoxP3+CD25+ cells, in the percentage and absolute count of FoxP3+ICOS+ cells, in the percentage and absolute count of FoxP3+CD154+ and FoxP3+ CD274+ T cells; p<0.05 in all cases. Negative correlation was recorded between the percentage of FoxP3+CD25+ and C-reactive protein (CRP) (r=-0.4); that of CD152+intracellular and DAS28 (r=-0.35), ESR (r=-0.46), CRP (r=-0.54); that of FoxP3+CD127 and CRP (r=-0.42); that of CD25+CD127 and DAS28 (r=-0.38), SDAI (r=-0.41), CDAI (r=-0.36), ESR (r=-0.39), CRP (r=-0.47); p<0.05 in all cases.

The patients who were seronegative for RF were found to have higher values in the percentage of CD25+CD127, in the percentage and absolute count of Foxp3+CD154+ and Foxp3+CD274+ T lymphocytes.

Conclusion. The given data may indicate that the count and functional activity of Treg were decreased in early RA, which is associated with higher disease activity, the systemic manifestations of the disease and which is also accompanied by antibody hyperproduction.

About the Authors

A. S. Avdeeva
V.A. Nasonova Research Institute of Rheumatology, Moscow
Russian Federation
34A, Kashirskoe Shosse, Moscow 115522


Yu. P. Rubtsov
M.V. Lomonosov Moscow State University
Russian Federation

Department of Biochemistry and Molecular Medicine, Faculty of Fundamental Medicine

31, Lomonosovsky Prospect, Build. 5, Moscow 119192



D. T. Dyikanov
M.V. Lomonosov Moscow State University
Russian Federation

Department of Biochemistry and Molecular Medicine, Faculty of Fundamental Medicine

31, Lomonosovsky Prospect, Build. 5, Moscow 119192



T. V. Popkova
V.A. Nasonova Research Institute of Rheumatology, Moscow
Russian Federation
34A, Kashirskoe Shosse, Moscow 115522


E. L. Nasonov
V.A. Nasonova Research Institute of Rheumatology, Moscow; I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia, Moscow
Russian Federation

Department of Rheumatology, Institute of Professional Education

34A, Kashirskoe Shosse, Moscow 115522

8, Trubetskaya St., Build. 2, Moscow 119991 



References

1. Быковская СН, Насонов ЕЛ. Роль дефектов иммуносупрессии в развитии аутоиммунных заболеваний. Научно-практическая ревматология. 2005;43(4):81-4 [Bykovskaya SN, Nasonov EL. Role of immunosupression defects in the development of autoimmune diseases. NauchnoPrakticheskaya Revmatologiya = Rheumatology Science and Practiсе. 2005;43(4):81-4 (In Russ.)]. doi: 10.14412/1995-4484- 2005-623

2. 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

3. 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

4. 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.

5. 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

6. 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

7. 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].

8. Firestein G. Evolving concepts of rheumatoid arthritis . Nature. 2003;423:356-61. doi: 10.1038/nature01661

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

10. 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.

11. 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

12. 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

13. 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-R346. doi: 10.1186/ar1192

14. 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

15. 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

16. 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

17. 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

18. 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

19. 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

20. 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

21. 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

22. 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

23. 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

24. 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

25. 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

26. 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.

27. 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

28. 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

29. 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.

30. 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

31. 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

32. 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

33. 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

34. Kim CH, Rott LS, Clark-Lewis I, et al. Subspecialization of CXCR5+ T cells: B helper activity is focused in a germinal centerlocalized subset of CXCR5+ T cells. J Exp Med. 2001;193:1373- 81. doi: 10.1084/jem.193.12.1373

35. Odegard JM, Marks BR, DiPlacido LD, et al. ICOS-dependent extrafollicular helper T cells elicit IgG production via IL-21 in systemic autoimmunity. J Exp Med. 2008;205:2873-86. doi: 10.1084/jem.20080840

36. Radbruch A, Muehlinghaus G, Luger EO, et al. Competence and competition: the challenge of becoming a long-lived plasma cell. Nat Rev Immunol. 2006;6:741-50. doi: 10.1038/nri1886

37. Slifka MK, Antia R, Whitmire JK, Ahmed R. Humoral immunity due to long-lived plasma cells. Immunity. 1998;8:363-72. doi: 10.1016/S1074-7613(00)80541-5

38. Hoyer BF, Moser K, Hauser AE, et al. Short-lived plasmablasts and long-lived plasma cells contribute to chronic humoral autoimmunity in NZB/Wmice. J Exp Med. 2004;199:1577-84. doi: 10.1084/jem.20040168

39. Silverman GJ, Weisman S. Rituximab therapy and autoimmune disorders: prospects for anti-B cell therapy. Arthritis Rheum. 2003;48:1484-92. doi: 10.1002/art.10947

40. Zhao DM, Thornton AM, DiPaolo RJ, Shevach EM. Activated CD4+CD25+ T cells selectively kill B lymphocytes. Blood. 2006;107:3925-32. doi: 10.1182/blood-2005-11-4502

41. Iikuni N, Lourenco EV, Hahn BH, La Cava A. Cutting edge: regulatory T cells directly suppress B cells in systemic lupus erythematosus. J Immunol. 2009;183:1518-22. doi: 10.4049/jimmunol.0901163

42. Grossman WJ, Verbsky JW, Barchet W, et al. Human T regulatory cells can use the perforin pathway to cause autologous target cell death. Immunity. 2004;21:589-601. doi: 10.1016/j.immuni.2004.09.002

43. Seo SJ, Fields ML, Buckler JL, et al. The impact of T helper and T regulatory cells on the regulation of anti-double stranded DNA B cells. Immunity. 2002;16:535-46. doi: 10.1016/S1074- 7613(02)00298-4

44. Morgan ME, Sutmuller RP, Witteveen HJ, et al. CD25+ cell depletion hastens the onset of severe disease in collagen-induced arthritis. Arthritis Rheum. 2003;48:1452-60. doi: 10.1002/art.11063

45. Jang E, Cho W, Cho M, et al. Foxp3+ Regulatory T Cells Control Humoral Autoimmunity by Suppressing the Development of Long-Lived Plasma Cells. J Immunol. 2011;186:1546-53. doi: 10.4049/jimmunol.1002942

46. Hunt L, Hensor EM, Nam J, et al. T cell subsets: an immunological biomarker to predict progression to clinical arthritis in ACPApositive individuals. Ann Rheum Dis. 2016;75:1884-9. doi: 10.1136/annrheumdis-2015-207991

47. Janssen K, Westra J, Chalan P, et al. Regulatory CD4+ T-Cell Subsets and AntiCitrullinated Protein Antibody Repertoire: Potential Biomarkers for Arthritis Development in Seropositive Arthralgia Patients? PLoS ONE 2016;11(9):e0162101. doi: 10.1371/journal.pone.0162101PLoS


Review

For citations:


Avdeeva A.S., Rubtsov Yu.P., Dyikanov D.T., Popkova T.V., Nasonov E.L. THE RELATIONSHIP OF FoxP3+ T REGULATORY CELLS TO DISEASE ACTIVITY AND ANTIBODY LEVELS IN EARLY RHEUMATOID ARTHRITIS. Rheumatology Science and Practice. 2017;55(3):245-251. (In Russ.) https://doi.org/10.14412/1995-4484-2017-245-251

Views: 761


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


ISSN 1995-4484 (Print)
ISSN 1995-4492 (Online)