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Autoantibodies against interleukin-21 correlate with disease activity in patients with rheumatoid arthritis

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Abstract

The objective of this study is to investigate the levels of interleukin (IL)-21 and autoantibodies (AAbs) against IL-21 and their association with clinical characteristics and laboratory parameters in patients with rheumatoid arthritis (RA). One hundred twenty-six patients with RA, 69 patients with osteoarthritis (OA), and 88 healthy controls (HC) were included in this study. The levels of IL-21 and AAbs against IL-21 in the serum were measured using enzyme-linked immunosorbent assay (ELISA). The correlation between the levels of IL-21 and anti-IL-21 AAbs with clinical and laboratory parameters was evaluated. The results showed that the concentration of IL-21 was significantly higher in the serum of patients with RA (15.58 ± 3.22 ng/ml) than OA (1.80 ± 0.99 ng/ml) and HC (0.07 ± 0.03 ng/ml, p < 0.01). The levels of IL-21 in the serum correlated with erythrocyte sedimentation rate (ESR) in patients with RA (r = 0.435, p < 0.01). Anti-IL-21 AAbs could be detected in RA patients. The median AU value of AAbs against IL-21 was significantly higher in serum of RA (47.90) than in that of OA (15.17) and HC (8.19, p < 0.01). The titers of AAbs against IL-21 correlated with Disease Activity Score-28 (DAS28) (r = 0.449, p < 0.001), ESR (r = 0.386, p < 0.001), and CRP (r = 0.241, p = 0.03). Both IL-21 and AAbs against IL-21 are elevated in RA. The levels of AAbs against IL-21 correlate with disease activity, which suggests that anti-IL-21 AAbs may play a role in the pathogenesis of RA.

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References

  1. Firestein GS, McInnes IB (2017) Immunopathogenesis of rheumatoid arthritis. Immunity 46:183–196. https://doi.org/10.1016/j.immuni.2017.02.006

    Article  CAS  PubMed  Google Scholar 

  2. Noack M, Miossec P (2017) Selected cytokine pathways in rheumatoid arthritis. Semin Immunopathol 39:365–383. https://doi.org/10.1007/s00281-017-0619-z

  3. Ignatenko S, Skrumsager BK, Mouritzen U (2016) Safety, PK, and PD of recombinant anti-interleukin-21 monoclonal antibody in a first-in-human trial. Int J Clin Pharmacol Ther 54:243–252. https://doi.org/10.5414/CP202474

    Article  CAS  PubMed  Google Scholar 

  4. Spolski R, Leonard WJ (2014) Interleukin-21: a double-edged sword with therapeutic potential. Nat Rev Drug Discov 13:379–395. https://doi.org/10.1038/nrd4296

    Article  CAS  PubMed  Google Scholar 

  5. Ettinger R, Kuchen S, Lipsky PE (2008) Interleukin 21 as a target of intervention in autoimmune disease. Ann Rheum Dis 67(Suppl 3):iii83–iii86. https://doi.org/10.1136/ard.2008.098400

    Article  CAS  PubMed  Google Scholar 

  6. Rasmussen TK, Andersen T, Hvid M et al (2010) Increased interleukin 21 (IL-21) and IL-23 are associated with increased disease activity and with radiographic status in patients with early rheumatoid arthritis. J Rheumatol 37:2014–2020. https://doi.org/10.3899/jrheum.100259

    Article  CAS  PubMed  Google Scholar 

  7. Sglunda O, Mann HF, Hulejová H et al (2014) Decrease in serum interleukin-21 levels is associated with disease activity improvement in patients with recent-onset rheumatoid arthritis. Physiol Res 63:475–481

    CAS  PubMed  Google Scholar 

  8. Xing R, Yang L, Jin Y et al (2016) Interleukin-21 induces proliferation and proinflammatory cytokine profile of fibroblast-like synoviocytes of patients with rheumatoid arthritis. Scand J Immunol 83:64–71. https://doi.org/10.1111/sji.12396

    Article  CAS  PubMed  Google Scholar 

  9. Xing R, Jin Y, Sun L et al (2016) Interleukin-21 induces migration and invasion of fibroblast-like synoviocytes from patients withrheumatoid arthritis. Clin Exp Immunol 184:147–158. https://doi.org/10.1111/cei.12751

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Xing R, Zhang Y, Li C et al (2016) Interleukin-21 promotes osteoclastogenesis in RAW264.7 cells through the PI3K/AKT signaling pathway independently of RANKL. Int J Mol Med 38:1125–1134. https://doi.org/10.3892/ijmm.2016.2722

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kwok SK, Cho ML, Park MK et al (2012) Interleukin-21 promotes osteoclastogenesis in humans with rheumatoid arthritis and in mice with collagen-induced arthritis. Arthritis Rheum 64:740–751. https://doi.org/10.1002/art.33390

    Article  CAS  PubMed  Google Scholar 

  12. Young DA, Hegen M, Ma HL et al (2007) Blockade of the interleukin-21/interleukin-21 receptor pathway ameliorates disease in animal models of rheumatoid arthritis. Arthritis Rheum 56:1152–1163

    Article  CAS  PubMed  Google Scholar 

  13. Cappellano G, Orilieri E, Woldetsadik AD et al (2012) Anti-cytokine autoantibodies in autoimmune diseases. Am J Clin Exp Immunol 1:136–146

    PubMed  PubMed Central  Google Scholar 

  14. McInnes IB, Buckley CD, Isaacs JD (2016) Cytokines in rheumatoid arthritis—shaping the immunological landscape. Nat Rev Rheumatol 12:63–68. https://doi.org/10.1038/nrrheum.2015.171.

    Article  CAS  PubMed  Google Scholar 

  15. Vincent T, Plawecki M, Goulabchand R, Guilpain P, Eliaou JF (2015) Emerging clinical phenotypes associated with anti-cytokine autoantibodies. Autoimmun Rev 14:528–535. https://doi.org/10.1016/j.autrev.2015.01.015

    Article  CAS  PubMed  Google Scholar 

  16. Watanabe M, Uchida K, Nakagaki K et al (2007) Anti-cytokine autoantibodies are ubiquitous in healthy individuals. FEBS Lett 581:2017–2021

    Article  CAS  PubMed  Google Scholar 

  17. Puel A, Döffinger R, Natividad A et al (2010) Autoantibodies against IL-17A, IL-17F, and IL-22 in patients with chronic mucocutaneous candidiasis and autoimmune polyendocrine syndrome type I. J Exp Med 207:291–297

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Sjowall C, Ernerudh J, Bengtsson AA, Sturfelt G, Skogh T (2004) Reduced anti-TNF alpha autoantibody levels coincide with flare in systemic lupus erythematosus. J Autoimmun 22:315–323

    Article  PubMed  Google Scholar 

  19. Morimoto AM, Flesher DT, Yang J et al (2011) Association of endogenous anti-interferon-alpha autoantibodies with decreased interferon pathway and disease activity in patients with systemic lupus erythematosus. Arthritis Rheum 63:2407–2415

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Slavikova M, Schmeisser H, Kontsekova E, Mateicka F, Borecky L, Kontsek P (2003) Incidence of autoantibodies against type I and type II interferons in a cohort of systemic lupus erythematosus patients in Slovakia. J Interf Cytokine Res 23:143–147

    Article  CAS  Google Scholar 

  21. Price JV, Haddon DJ, Kemmer D et al (2013) Protein microarray analysis reveals BAFF-binding autoantibodies in systemic lupus erythematosus. J Clin Invest 123:5135–5145

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Watanabe M, Uchida K, Nakagaki K, Trapnell BC, Nakata K (2010) High avidity cytokine autoantibodies in health and disease: pathogenesis and mechanisms. Cytokine Growth Factor Rev 21:263–273

    Article  CAS  PubMed  Google Scholar 

  23. Gupta S, Tatouli IP, Rosen LB et al (2016) Distinct functions of autoantibodies against interferon in systemic lupus erythematosus: a comprehensive analysis of anticytokine autoantibodies in common rheumatic diseases. Arthritis Rheumatol 68:1677–1687. https://doi.org/10.1002/art.39607

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Jouvenne P, Fossiez F, Banchereau J, Miossec P (1997) High levels of neutralizing autoantibodies against IL-1 alpha are associated with a better prognosis in chronic polyarthritis: a follow-up study. Scand J Immunol 46:413–418

    Article  CAS  PubMed  Google Scholar 

  25. Graudal NA, Svenson M, Tarp U, Garred P, Jurik AG, Bendtzen K (2002) Autoantibodies against interleukin 1alpha in rheumatoid arthritis: association with long term radiographic outcome. Ann Rheum Dis 61:598–602

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Sakata M, Tsuruha JI, Masuko-Hongo K et al (2001) Autoantibodies to osteopontin in patients with osteoarthritis and rheumatoid arthritis. J Rheumatol 28:1492–1495

    CAS  PubMed  Google Scholar 

  27. Peichl P, Pursch E, Broll H, Lindley IJ (1998) Anti-IL-8 autoantibodies and complexes in rheumatoid arthritis: polyclonal activation in chronic synovial tissue inflammation. Rheumatol Int 18:141–145

    Article  Google Scholar 

  28. Hellmich B, Csernok E, Schatz H, Gross WL, Schnabel A (2002) Autoantibodies against granulocyte colony-stimulating factor in Felty’s syndrome and neutropenic systemic lupus erythematosus. Arthritis Rheum 46:2384–2391

    Article  CAS  PubMed  Google Scholar 

  29. Yang L, Bai L, Wei F et al (2016) Elevated autoantibodies against interleukin-17F correlate with disease activity in patients with early rheumatoid arthritis. Int J Rheum Dis 19:644–650

    Article  CAS  PubMed  Google Scholar 

  30. Maniwa K, Ogushi F, Tani K, Ohmoto Y, Muraguchi M, Sone S (2000) Increased incidence of autoantibodies to interleukin-1a in rheumatoid arthritis with interstitial lung disease. Respirology 5:315–320

    CAS  PubMed  Google Scholar 

  31. Jüngel A, Distler JH, Kurowska-Stolarska M et al (2004) Expression of interleukin-21 receptor, but not interleukin-21, in synovial fibroblasts and synovial macrophages of patients with rheumatoid arthritis. Arthritis Rheum 50:1468–1476

    Article  PubMed  Google Scholar 

  32. Li J, Shen W, Kong K, Liu Z (2006) Interleukin-21 induces T-cell activation and proinflammatory cytokine secretion in rheumatoid arthritis. Scand J Immunol 64:515–522

    Article  CAS  PubMed  Google Scholar 

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Funding

This work was supported by the National Natural Science Foundation of China (Grant No. 81571573, 81471599).

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Authors and Affiliations

  1. Department of Rheumatology and Immunology, Peking University Third Hospital, No. 49, North Garden Road, Beijing, 100191, China

    Rui Xing, Lin Sun, Dong Wu, Yinji Jin, Changhong Li, Xiangyuan Liu & Jinxia Zhao

  2. Department of Rheumatology and Immunology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430000, China

    Rui Xing

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  1. Rui Xing
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  2. Lin Sun
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Correspondence to Jinxia Zhao.

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Xing, R., Sun, L., Wu, D. et al. Autoantibodies against interleukin-21 correlate with disease activity in patients with rheumatoid arthritis. Clin Rheumatol 37, 75–80 (2018). https://doi.org/10.1007/s10067-017-3862-8

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  • DOI: https://doi.org/10.1007/s10067-017-3862-8

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