Serum cytokine profile in early and established rheumatoid arthritis

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Abstract

Background: An important characteristic of immune pathology in rheumatoid arthritis (RA) is a B-cell tolerance defect, associated with autoantibodies production, and antigen-specific activation of Th-1 CD4+ T lymphocytes with an excess production of pro-inflammatory cytokines compared to anti-inflammatory ones. Pro-inflammatory cytokines contribute to the development of local inflammatory effects, induce bone destruction and pannus formation, and contribute to the development of autoimmune abnormalities and systemic manifestations. Anti-inflammatory cytokines are able to reduce the rate of joint destruction. There is evidence of the involvement of Th2 cytokines in the development of early RA. These facts suggest the need for a thorough investigation into the balance between the Th1 and Th2 types of immune response at different stages of the disease.

Aim: To assess the importance of сytokine profiling in the evaluation of immune abnormalities in RA.

Materials and methods: In this descriptive, controlled, retrospective study, we examined 118 patients with RA and 33 healthy donors as a control group. Serum IgM rheumatoid factor (RF) and C-reactive protein (CRP) levels were measured by immunonephelometry; anti-cyclic citrullinated peptide antibodies (anti-CCP) and anti-mutated citrullinated vimentin antibodies (anti-MCV) were determined by an enzyme immunoassay, cytokines levels with "xMAP" technique.

Results: Serum cytokine levels vary depending on RA duration. The cytokine profile in early RA, unlike that in established RA with a duration of more than 6 months, is characterized by higher levels of pro-inflammatory (MIP-1α), Th1 (IFN-γ), and Th17 (IL-17) cytokines, colony-stimulating factors (IL-7, G-CSF), and chemokines (IL-8, IP-10) (p < 0.05 for all parameters). In established RA, the levels of pro-inflammatory (IL-1β, -6, -15, TNF-α), anti-inflammatory (IL-1ra, IL-10, IL-13, IL-5), Th1 (IL-2, IL-12), Th2 (IL-9) cytokines and colony-stimulating factors (G-CSF, GM-CSF) correlate with the concentrations of IgM RF and antibodies to citrullinated proteins (antiCCP, anti-MCV) (all p < 0.05). There was also а correlation between CRP and pro-inflammatory (IL-1β, IL-6, TNF-α), Th1 (IL-12), Th2 (IL-5, IL-9) cytokine levels and between DAS28 and pro-inflammatory cytokine (IL-6) and colony-stimulating factor (G-CSF) levels (all p < 0.05). Conclusion: In RA, cytokines, chemokines and colony-stimulating factors mirror the inflammatory activity of the disease. Changes in blood concentrations of cytokines enable to get an insight into the complex interplay of numerous mediators of innate and acquired immunity.

About the authors

A. A. Novikov

Loginov Moscow Clinical Scientific Center, Moscow Healthcare Department

Author for correspondence.
Email: a.novikov@mknc.ru
ORCID iD: 0000-0002-2738-2956

Aleksander A. Novikov – Doctor of Biol. Sci., PhD, Leading Research Fellow, Laboratory of Clinical Immunology

86 Shosse Entuziastov, Moscow, 111123

Russian Federation

Е. N. Aleksandrova

Loginov Moscow Clinical Scientific Center, Moscow Healthcare Department

Email: e.aleksandrova@mknc.ru
ORCID iD: 0000-0003-4074-5907

Elena N. Aleksandrova – MD, PhD, Head of Laboratory of Clinical Immunology

86 Shosse Entuziastov, Moscow, 111123

G. V. Lukina

Loginov Moscow Clinical Scientific Center, Moscow Healthcare Department;
V.A. Nasonova Research Institute of Rheumatology, Russian Academy of Medical Sciences

Email: g.lukina@mknc.ru

Galina V. Lukina – MD, PhD, Professor, Head of Rheumatology Department Loginov Moscow Clinical Scientific Center, Moscow Healthcare Department; Leading Research Fellow, Safety of Anti-rheumatic Therapy Monitoring Laboratory V.A. Nasonova Research Institute of Rheumatology, Russian Academy of Medical Sciences

86 Shosse Entuziastov, Moscow, 111123, 

34A Kashirskoe shosse, Moscow, 115522

References

  1. Harris ED Jr. Rheumatoid arthritis. Pathophysiology and implications for therapy. N Engl J Med. 1990;322(18): 1277–89. doi: 10.1056/NEJM199005033221805.
  2. Ревматология. Национальное руководство. М.: ГЭОТАР-Медиа; 2008. 737 с.
  3. McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med. 2011;365(23): 2205–19. doi: 10.1056/NEJMra1004965.
  4. Samuels J, Ng YS, Coupillaud C, Paget D, Meffre E. Impaired early B cell tolerance in patients with rheumatoid arthritis. J Exp Med. 2005;201(10): 1659–67. doi: 10.1084/jem.20042321.
  5. Brennan FM, McInnes IB. Evidence that cytokines play a role in rheumatoid arthritis. J Clin Invest. 2008;118(11): 3537–45. doi: 10.1172/JCI36389.
  6. Naka T, Nishimoto N, Kishimoto T. The paradigm of IL-6: from basic science to medicine. Arthritis Res. 2002;4 Suppl 3:S233–42. doi: 10.1186/ar565.
  7. Paleolog EM. Angiogenesis in rheumatoid arthritis. Arthritis Res. 2002;4 Suppl 3:S81–90. doi: 10.1186/ar575.
  8. Lally F, Smith E, Filer A, Stone MA, Shaw JS, Nash GB, Buckley CD, Rainger GE. A novel mechanism of neutrophil recruitment in a coculture model of the rheumatoid synovium. Arthritis Rheum. 2005;52(11): 3460–9. doi: 10.1002/art.21394.
  9. Firestein GS. Immunologic mechanisms in the pathogenesis of rheumatoid arthritis. J Clin Rheumatol. 2005;11(3 Suppl):S39–44.
  10. Burska A, Boissinot M, Ponchel F. Cytokines as biomarkers in rheumatoid arthritis. Mediators Inflamm. 2014;2014:545493. doi: 10.1155/2014/545493.
  11. McInnes IB, Schett G. Cytokines in the pathogenesis of rheumatoid arthritis. Nat Rev Immunol. 2007;7(6): 429–42. doi: 10.1038/nri2094.
  12. Alex P, Szodoray P, Knowlton N, Dozmorov IM, Turner M, Frank MB, Arthur RE, Willis L, Flinn D, Hynd RF, Carson C, Kumar A, El-Gabalawy HS, Centola M. Multiplex serum cytokine monitoring as a prognostic tool in rheumatoid arthritis. Clin Exp Rheumatol. 2007;25(4): 584–92.
  13. Meyer PW, Hodkinson B, Ally M, Musenge E, Wadee AA, Fickl H, Tikly M, Anderson R. Circulating cytokine profiles and their relationships with autoantibodies, acute phase reactants, and disease activity in patients with rheumatoid arthritis. Mediators Inflamm. 2010;2010:158514. doi: 10.1155/2010/158514.
  14. Sivalingam SP, Thumboo J, Vasoo S, Thio ST, Tse C, Fong KY. In vivo proand anti-inflammatory cytokines in normal and patients with rheumatoid arthritis. Ann Acad Med Singapore. 2007;36(2): 96–9.
  15. Hitchon CA, Alex P, Erdile LB, Frank MB, Dozmorov I, Tang Y, Wong K, Centola M, El-Gabalawy HS. A distinct multicytokine profile is associated with anti-cyclical citrullinated peptide antibodies in patients with early untreated inflammatory arthritis. J Rheumatol. 2004;31(12): 2336–46.
  16. Kokkonen H, Soderstrom I, Rocklov J, Hallmans G, Lejon K, Rantapaa Dahlqvist S. Up-regulation of cytokines and chemokines predates the onset of rheumatoid arthritis. Arthritis Rheum. 2010;62(2): 383–91. doi: 10.1002/art.27186.
  17. Deane KD, O'Donnell CI, Hueber W, Majka DS, Lazar AA, Derber LA, Gilliland WR, Edison JD, Norris JM, Robinson WH, Holers VM. The number of elevated cytokines and chemokines in preclinical seropositive rheumatoid arthritis predicts time to diagnosis in an age-dependent manner. Arthritis Rheum. 2010;62(11): 3161–72. doi: 10.1002/art.27638.
  18. Jorgensen KT, Wiik A, Pedersen M, Hedegaard CJ, Vestergaard BF, Gislefoss RE, Kvien TK, Wohlfahrt J, Bendtzen K, Frisch M. Cytokines, autoantibodies and viral antibodies in premorbid and postdiagnostic sera from patients with rheumatoid arthritis: case-control study nested in a cohort of Norwegian blood donors. Ann Rheum Dis. 2008;67(6): 860–6. doi: 10.1136/ard.2007.073825.
  19. Hueber W, Tomooka BH, Zhao X, Kidd BA, Drijfhout JW, Fries JF, van Venrooij WJ, Metzger AL, Genovese MC, Robinson WH. Proteomic analysis of secreted proteins in early rheumatoid arthritis: anti-citrulline autoreactivity is associated with up regulation of proinflammatory cytokines. Ann Rheum Dis. 2007;66(6): 712–9. doi: 10.1136/ard.2006.054924.
  20. Ridgley LA, Anderson AE, Pratt AG. What are the dominant cytokines in early rheumatoid arthritis? Curr Opin Rheumatol. 2018;30(2): 207–14. doi: 10.1097/BOR.0000000000000470.
  21. Hughes-Austin JM, Deane KD, Derber LA, Kolfenbach JR, Zerbe GO, Sokolove J, Lahey LJ, Weisman MH, Buckner JH, Mikuls TR, O'Dell JR, Keating RM, Gregersen PK, Robinson WH, Holers VM, Norris JM. Multiple cytokines and chemokines are associated with rheumatoid arthritis-related autoimmunity in first-degree relatives without rheumatoid arthritis: Studies of the Aetiology of Rheumatoid Arthritis (SERA). Ann Rheum Dis. 2013;72(6): 901–7. doi: 10.1136/annrheumdis-2012-201505.
  22. Chung SJ, Kwon YJ, Park MC, Park YB, Lee SK. The correlation between increased serum concentrations of interleukin6 family cytokines and disease activity in rheumatoid arthritis patients. Yonsei Med J. 2011;52(1): 113–20. doi: 10.3349/ymj.2011.52.1.113.

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Copyright (c) 2019 Novikov A.A., Aleksandrova Е.N., Lukina G.V.

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