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GITRL is associated with increased autoantibody production in patients with rheumatoid arthritis

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Abstract

The study aimed to determine the serum level of glucocorticoid-induced tumor necrosis factor receptor family-related protein ligand (GITRL) in patients with rheumatoid arthritis (RA) and investigate its clinical significance. GITRL levels were measured by enzyme-linked immunosorbent assay (ELISA) in 88 RA patients, 20 osteoarthritis (OA) patients, and 20 healthy controls (HCs). Anti-cyclic citrullinated peptide (anti-CCP) antibodies and rheumatoid factor immunoglobulin G (RF-IgG) were also tested by ELISA. RF-IgM, anti-keratin antibody (AKA), and anti-perinuclear factor (APF) antibodies and the erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and immunoglobulins were measured by standard laboratory techniques. The disease activity was evaluated by the 28-joint count Disease Activity Score (DAS28). GITRL concentrations were significantly elevated in both serum and synovial fluid (SF) of RA patients. GITRL levels in RA sera were significantly higher than those in matched SFs. Positive correlations were found between serum GITRL levels and inflammation parameters or autoantibody production. GITRL levels are significantly elevated in RA serum and SF and are positively correlated with autoantibody production in RA, suggesting a role of GITRL in the development of RA.

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References

  1. Ikeda M, Takeshima F, Ohba K, Ohnita K, Isomoto H, Yamakawa M et al (2006) Flow cytometric analysis of expression of transforming growth factor-β and glucocorticoid-induced tumor necrosis factor receptor on CD4+ CD25+ T cells of patients with inflammatory bowel disease. Dig Dis Sci 51(1):178–184

    Article  CAS  PubMed  Google Scholar 

  2. Li Z, Mahesh SP, Kim BJ, Buggage RR, Nussenblatt RB (2003) Expression of glucocorticoid induced TNF receptor family related protein (GITR) on peripheral T cells from normal human donors and patients with non-infectious uveitis. J Autoimmun 21(1):83–92

    Article  CAS  PubMed  Google Scholar 

  3. Kim J, Choi WS, Kang H, Kim HJ, Suh JH, Sakaguchi S et al (2006) Conversion of alloantigen-specific CD8+ T cell anergy to CD8+ T cell priming through in vivo ligation of glucocorticoid- induced TNF receptor. J Immunol 176(9):5223–5231

    Article  CAS  PubMed  Google Scholar 

  4. Liu B, Li Z, Mahesh SP, Pantanelli S, Hwang FS, Siu WO et al (2008) Glucocorticoid-induced tumor necrosis factor receptor negatively regulates activation of human primary natural killer (NK) cells by blocking proliferative signals and increasing NK cell apoptosis. J Biol Chem 283(13):8202–8210

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Kim WJ, Bae EM, Kang YJ, Bae HU, Hong SH, Lee JY et al (2006) Glucocorticoid-induced tumour necrosis factor receptor family related protein (GITR) mediates inflammatory activation of macrophages that can destabilize atherosclerotic plaques. Immunology 119(3):421–429

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Gurney AL, Marsters SA, Huang RM, Pitti RM, Mark DT, Baldwin DT et al (1999) Identification of a new member of the tumor necrosis factor family and its receptor, a human ortholog of mouse GITR. Curr Biol 9(4):215–218

    Article  CAS  PubMed  Google Scholar 

  7. Kwon B, Yu KY, Ni J, Yu GL, Jang IK, Kim YJ et al (1999) Identification of a novel activation-inducible protein of the tumor necrosis factor receptor superfamily and its ligand. J Biol Chem 274(10):6056–6061

    Article  CAS  PubMed  Google Scholar 

  8. Kim BJ, Li Z, Fariss RN, Shen DF, Mahesh SP, Egwuagu C et al (2004) Constitutive and cytokine induced GITR ligand expression on human retinal pigment epithelium and photoreceptors. Investig Ophthalmol Vis Sci 45(9):3170–3176

    Article  Google Scholar 

  9. Howie D, Garcia Rueda H, Brown MH, Waldmann H (2013) Secreted and transmembrane 1A is a novel co-stimulatory ligand. PLoS One 8(9):e73610. doi:10.1371/journal.pone.0073610, eCollection 2013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Gan X, Feng X, Gu L, Tan W, Sun X, Lv C, Zhang M (2013) Correlation of increased blood levels of GITR and GITRL with disease severity in patients with primary Sjögren’s syndrome. Clin Dev Immunol 2013:340751. doi:10.1155/2013/340751, Epub 2013 Jul 7

    Article  PubMed  PubMed Central  Google Scholar 

  11. Gu L, Xu L, Zhang X, Tan W, Wang H, Zhang M (2012) Correlation of circulating glucocorticoid-induced TNFR-related protein ligand levels with disease activity in patients with systemic lupus erythematosus. Clin Dev Immunol 2012:265868. doi:10.1155/2012/265868, Epub 2012 Dec 4

    Article  PubMed  PubMed Central  Google Scholar 

  12. Liu Y, Tang X, Tian J, Zhu C, Peng H, Rui K et al (2014) Th17//Treg cells imbalance and GITRL profile in patients with Hashimoto’s thyroiditis. Int J Mol Sci 15(12):21674–21686. doi:10.3390/ijms151221674

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Baltz KM, Krusch M, Bringmann A, Brossart P, Mayer F, Kloss M et al (2007) Cancer immunoediting by GITR (glucocorticoid-induced TNF-related protein) ligand in humans: NK cell/tumor cell interactions. FASEB J 21(10):2442–2454

    Article  CAS  PubMed  Google Scholar 

  14. Baessler T, Krusch M, Schmiedel BJ, Kloss M, Baltz KM, Wacker A et al (2009) Glucocorticoid-induced tumor necrosis factor receptor-related protein ligand subverts immunosurveillance of acute myeloid leukemia in humans. Cancer Res 69(3):1037–1045

    Article  CAS  PubMed  Google Scholar 

  15. Li R, Sun J, Ren LM, Wang HY, Liu WH, Zhang XW et al (2012) Epidemiology of eight common rheumatic diseases in China: a large-scale cross-sectional survey in Beijing. Rheumatology (Oxford) 51(4):721–729. doi:10.1093/rheumatology/ker370, Epub 2011 Dec 16

    Article  Google Scholar 

  16. Patel M, Xu D, Kewin P, Choo-Kang B, McSharry C, Thomson NC et al (2005) Glucocorticoid-induced TNFR family-related protein (GITR) activation exacerbates murine asthma and collagen-induced arthritis. Eur J Immunol 35(12):3581–3590

    Article  CAS  PubMed  Google Scholar 

  17. Cuzzocrea S, Ayroldi E, Di Paola R, Agostini M, Mazzon E, Bruscoli S et al (2005) Role of glucocorticoid-induced TNF receptor family gene (GITR) in collagen-induced arthritis. FASEB J 19(10):1253–1265

    Article  CAS  PubMed  Google Scholar 

  18. Bae E, Kim WJ, Kang YM, Suk K, Koh EM, Cha HS et al (2007) Glucocorticoid- induced tumour necrosis factor receptor-related protein-mediated macrophage stimulation may induce cellular adhesion and cytokine expression in rheumatoid arthritis. Clin Exp Immunol 148(3):410–418, Epub 2007 Mar 15

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Wang S, Shi Y, Yang M, Ma J, Tian J, Chen J et al (2012) Glucocorticoid-induced tumor necrosis factor receptor family-related protein exacerbates collagen-induced arthritis by enhancing the expansion of Th17 cells. Am J Pathol 180(3):1059–1067. doi:10.1016/j.ajpath.2011.11.018, Epub 2011 Dec 31

    Article  CAS  PubMed  Google Scholar 

  20. Liu YY, Chang LL, Li ZG (2007) GITR/GITRL expression in peripheral blood of rheumatoid arthritis. J Peking Univ Health Sci 39(2):163–166

    CAS  Google Scholar 

  21. Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS et al (1988) The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 31(3):315–324

    Article  CAS  Google Scholar 

  22. Prevoo ML, Van T, Hof MA, Kuper HH, Van Leeuwen MA, Van De Putte LB, Van Riel PL (1995) Modified disease activity scores that include twenty-eight-joint counts. Development and validation in prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum 38(1):44–48

    Article  CAS  PubMed  Google Scholar 

  23. Ronchetti S, Ricci E, Petrillo MG, Cari L, Migliorati G, Nocentini G et al (2015) Glucocorticoid-induced tumour necrosis factor receptor-related protein: a key marker of functional regulatory T cells. J Immunol Res 2015:171520. doi:10.1155/2015/171520, Epub 2015 Apr 15

    Article  PubMed  PubMed Central  Google Scholar 

  24. Galuppo M, Nocentini G, Mazzon E, Ronchetti S, Esposito E, Riccardi L et al (2011) The glucocorticoid-induced TNF receptor family-related protein (GITR) is critical to the development of acute pancreatitis in mice. Br J Pharmacol 162(5):1186–1201. doi:10.1111/j.1476-5381.2010.01123.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Motta AC, Vissers JL, Gras R, Van Esch BC, Van Oosterhout AJ, Nawijn MC (2009) GITR signaling potentiates airway hyperresponsiveness by enhancing Th2 cell activity in a mouse model of asthma. Respir Res 10:93. doi:10.1186/1465-9921-10-93

    Article  PubMed  PubMed Central  Google Scholar 

  26. Krill KT, Csencsits Smith K, Wood SC, Faust S, Lu G, Bishop DK (2013) Glucocorticoid-induced TNFR-related protein stimulation reverses cardiac allograft acceptance induced by CD40-CD40L blockade. Clin Dev Immunol 2013:986859. doi:10.1155/2013/986859.Epub2013Apr17

    Article  PubMed  PubMed Central  Google Scholar 

  27. Adlowitz DG, Barnard J, Biear JN, Cistrone C, Owen T, Wang W, Palanichamy A et al (2015) Expansion of activated peripheral blood memory B cells in rheumatoid arthritis, impact of B cell depletion therapy, and biomarkers of response. PLoS One 10(6):e0128269. doi:10.1371/journal.pone.0128269.eCollection2015

    Article  PubMed  PubMed Central  Google Scholar 

  28. Nocentini G, Riccardi C (2009) GITR: a modulator of immune response and inflammation. Adv Exp Med Biol 647:156–173

    Article  CAS  PubMed  Google Scholar 

  29. Ray A, Basu S, Williams CB, Salzman NH, Dittel BN (2012) A novel IL-10-independent regulatory role for B cells in suppressing autoimmunity by maintenance of regulatory T cells via GITR ligand. J Immunol 188(7):3188–3198. doi:10.4049/jimmunol.1103354, Epub 2012 Feb 24

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Zong M, Lu T, Fan S, Zhang H, Gong R, Sun L et al (2015) Glucose-6-phosphate isomerase promotes the proliferation and inhibits the apoptosis in fibroblast-like synoviocytes in rheumatoid arthritis. Arthritis Res Ther 17:100. doi:10.1186/s13075-015-0619-0

    Article  PubMed  PubMed Central  Google Scholar 

  31. Bloom BJ, Alario AJ, Miller LC (2009) Persistent elevation of fibrin D-dimer predicts long-term outcome in systemic juvenile idiopathic arthritis. J Rheumatol 36(2):422–426. doi:10.3899/jrheum.070600

    PubMed  Google Scholar 

  32. Nakashima M, Aoyagi T, Aratake K, Kawabe Y, Eguchi K (1998) The levels of FDP, FDP-E and D-dimer in patients with rheumatoid arthritis. Ryumachi 38(6):793–800, Japanese

    CAS  PubMed  Google Scholar 

  33. Zhao J, Sun L, Zhang X, Liu X (2011) Detection and clinical significance of blood D-Dimer in rheumatoid arthritis. Chin J Rheumatol 15(3):168–171, Chinese

    CAS  Google Scholar 

  34. Boilard E, Blanco P, Nigrovic PA (2012) Platelets: active players in the pathogenesis of arthritis and SLE. Nat Rev Rheumatol 8(9):534–542. doi:10.1038/nrrheum.2012.118, Epub 2012 Aug 7

    Article  CAS  PubMed  Google Scholar 

  35. Placke T, Salih HR, Kopp HG (2012) GITR ligand provided by thrombopoietic cells inhibits NK cell antitumor activity. J Immunol 189(1):154–160. doi:10.4049/jimmunol.1103194, Epub 2012 May 30

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by grants from Ministry of Science and Technology of China (2014BAI07B01, 2014AA020527), National Natural Science Foundation of China (81471601), Beijing Natural Science Foundation (7152150), Beijing Municipal Science & Technology Commission (Z141107002514064), and Research and Development Fund of Peking University People’s Hospital (RDB2014–03, RDB2014–04).

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Correspondence to Xiaolin Sun or Zhanguo Li.

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Li, L., Wen, W., Jia, R. et al. GITRL is associated with increased autoantibody production in patients with rheumatoid arthritis. Clin Rheumatol 35, 2195–2202 (2016). https://doi.org/10.1007/s10067-016-3280-3

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