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Clinicopathological value of programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) expression in synovium of patients with rheumatoid arthritis

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Abstract

The etiology of rheumatoid arthritis (RA) is thought to involve dysfunction of the programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) pathway; PD-1 negatively regulates autoimmunity by interacting with its ligand, PD-L1. We therefore investigated PD-1/PD-L1 expression in synovial tissue of patients with RA. We immunohistochemically stained synovial specimens from 51 patients with RA and assessed the association between PD-1/PD-L1 expression and rheumatoid factor (RF), the total count of infiltrating T cells, C-reactive protein (CRP), and Krenn’s synovitis score. PD-1 expression on infiltrating lymphocytes was detected in 34/51 RA cases (66.7%), while PD-1 expression was very mildly correlated only with the number of total infiltrating T cells (R2 = 0.1011, P = 0.0230). On the other hand, PD-L1 expression on synovial lining cells was observed in 37/51 RA cases (72.5%). Furthermore, a higher PD-L1 expression was significantly associated with RF positive state (P = 0.0454), and the correlations between PD-L1 expression and the number of infiltrating T cells (R2 = 0.5571, P < 0.0001), CRP (R2 = 0.4060, P < 0.0001), and Krenn’s synovitis score (R2 = 0.7785, P < 0.0001) were confirmed. PD-1 was expressed on infiltrating lymphocytes, while PD-L1 was expressed on synovial lining cells; the expression of PD-L1 on synovial lining cells was significantly correlated with the active state of the disease. These data suggest that PD-1/PD-L1 pathway may have an important role in the pathogenesis of RA.

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References

  1. Feldmann M, Brennan FM, Maini RN. Rheumatoid arthritis. Cell. 1996;85:307–10.

    Article  CAS  Google Scholar 

  2. Itonaga I, Fujikawa Y, Sabokbar A, Murray DW, Athanasou NA. Rheumatoid arthritis synovial macrophage-osteoclast differentiation is osteoprotegerin ligand-dependent. J Pathol. 2000;192:97–104.

    Article  CAS  Google Scholar 

  3. Guo G, Shang Y, Zhu G, Bao X, Xu S, Chen Y. The expression and distribution of immunomodulatory proteins B7-H1, B7-DC, B7-H3, and B7-H4 in rheumatoid synovium. Clin Rheumatol. 2012;31:271–81.

    Article  Google Scholar 

  4. Yoshida S, Higuchi F, Ishibashi Y, et al. Downregulation of RCAS1 and upregulation of cytotoxic T cells affects synovial proliferation and apoptosis in rheumatoid arthritis. J Rheumatol. 2008;35:1716–22.

    PubMed  Google Scholar 

  5. Griffiths GM, Alpert S, Lambert E, McGuire J, Weissman IL. Perforin and granzyme A expression identifying cytolytic lymphocytes in rheumatoid arthritis. Proc Natl Acad Sci USA. 1992;89:549–53.

    Article  CAS  Google Scholar 

  6. Belfrage H, Bhiladvala P, Hedlund G, Dohlsten M, Kalland T. Combined activation of murine lymphocytes with staphylococcal enterotoxin and interleukin-2 results in additive cytotoxic activity. Cancer Immunol Immunother. 1994;38:265–71.

    CAS  PubMed  Google Scholar 

  7. Ishida Y, Agata Y, Shibahara K, Honjo T. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J. 1992;11:3887–95.

    Article  CAS  Google Scholar 

  8. Agata Y, Kawasaki A, Nishimura H, et al. Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. Int Immunol. 1996;8:765–72.

    Article  CAS  Google Scholar 

  9. Okazaki T, Maeda A, Nishimura H, Kurosaki T, Honjo T. PD-1 immunoreceptor inhibits B cell receptor-mediated signaling by recruiting src homology 2-domain-containing tyrosine phosphatase 2 to phosphotyrosine. Proc Natl Acad Sci USA. 2001;98:13866–71.

    Article  CAS  Google Scholar 

  10. Nishimura H, Nose M, Hiai H, Minato N, Honjo T. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity. 1999;11:141–51.

    Article  CAS  Google Scholar 

  11. Nishimura H, Okazaki T, Tanaka Y, et al. Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science. 2001;291:319–22.

    Article  CAS  Google Scholar 

  12. Dong H, Zhu G, Tamada K, Chen L. B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat Med. 1999;5:1365–9.

    Article  CAS  Google Scholar 

  13. Latchman Y, Wood CR, Chernova T, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol. 2001;2:261–8.

    Article  CAS  Google Scholar 

  14. Keir ME, Liang SC, Guleria I, et al. Tissue expression of PD-L1 mediates peripheral T cell tolerance. J Exp Med. 2006;203:883–95.

    Article  CAS  Google Scholar 

  15. Dong H, Strome SE, Salomao DR, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002;8:793–800.

    Article  CAS  Google Scholar 

  16. Kobayashi M, Kawano S, Hatachi S, et al. Enhanced expression of programmed death-1 (PD-1)/PD-L1 in salivary glands of patients with Sjögren’s syndrome. J Rheumatol. 2005;32:2156–63.

    CAS  PubMed  Google Scholar 

  17. Wan B, Nie H, Liu A, et al. Aberrant regulation of synovial T cell activation by soluble costimulatory molecules in rheumatoid arthritis. J Immunol. 2006;177:8844–50.

    Article  CAS  Google Scholar 

  18. 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.

    CAS  PubMed  Google Scholar 

  19. Greisen SR, Rasmussen TK, Stengaard-Pedersen K, et al. Increased soluble programmed death-1 (sPD-1) is associated with disease activity and radiographic progression in early rheumatoid arthritis. Scand J Rheumatol. 2014;43:101–8.

    Article  CAS  Google Scholar 

  20. Li S, Liao W, Chen M, et al. Expression of programmed death-1 (PD-1) on CD4+ and CD8+ T cells in rheumatoid arthritis. Inflammation. 2014;37:116–21.

    Article  Google Scholar 

  21. Aletaha D, Neogi T, Silman AJ, et al. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum. 2010;62:2569–81.

    Article  Google Scholar 

  22. Krenn V, Morawietz L, Burmester GR, et al. Synovitis score: discrimination between chronic low-grade and high-grade synovitis. Histopathology. 2006;49:358–64.

    Article  CAS  Google Scholar 

  23. Yoshida S, Arakawa F, Higuchi F, et al. Gene expression analysis of rheumatoid arthritis synovial lining regions by cDNA microarray combined with laser microdissection: up-regulation of inflammation-associated STAT1, IRF1, CXCL9, CXCL10, and CCL5. Scand J Rheumatol. 2012;41:170–9.

    Article  CAS  Google Scholar 

  24. Gianchecchi E, Delfino DV, Fierabracci A. Recent insights into the role of the PD-1/PD-L1 pathway in immunological tolerance and autoimmunity. Autoimmun Rev. 2013;12:1091–100.

    Article  CAS  Google Scholar 

  25. Iwai Y, Terawaki S, Ikegawa M, Okazaki T, Honjo T. PD-1 inhibits antiviral immunity at the effector phase in the liver. J Exp Med. 2003;198:39–50.

    Article  CAS  Google Scholar 

  26. Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci USA. 2002;99:12293–7.

    Article  CAS  Google Scholar 

  27. Lin SC, Yen JH, Tsai JJ, et al. Association of a programmed death 1 gene polymorphism with the development of rheumatoid arthritis, but not systemic lupus erythematosus. Arthritis Rheum. 2004;50:770–5.

    Article  CAS  Google Scholar 

  28. Wherry EJ. T cell exhaustion. Nat Immunol. 2011;12:492–9.

    Article  CAS  Google Scholar 

  29. Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372:320–30.

    Article  CAS  Google Scholar 

  30. Cush JJ, Splawski JB, Thomas R, et al. Elevated interleukin-10 levels in patients with rheumatoid arthritis. Arthritis Rheum. 1995;38:96–104.

    Article  CAS  Google Scholar 

  31. Anaya JM, Correa PA, Herrera M, Eskdale J, Gallagher G. Interleukin 10 (IL-10) influences autoimmune response in primary Sjögren’s syndrome and is linked to IL-10 gene polymorphism. J Rheumatol. 2002;29:1874–6.

    CAS  PubMed  Google Scholar 

  32. Bertorello R, Cordone MP, Contini P, et al. Increased levels of interleukin-10 in saliva of Sjögren’s syndrome patients. Correlation with disease activity. Clin Exp Med. 2004;4:148–51.

    Article  CAS  Google Scholar 

  33. Brookes SM, Price EJ, Venables PJ, Maini RN. Interferon-gamma and epithelial cell activation in Sjögren’s syndrome. Br J Rheumatol. 1995;34:226–31.

    Article  CAS  Google Scholar 

  34. Dolhain RJ, ter Haar NT, Hoefakker S, et al. Increased expression of interferon (IFN)-gamma together with IFN-gamma receptor in the rheumatoid synovial membrane compared with synovium of patients with osteoarthritis. Br J Rheumatol. 1996;35:24–32.

    Article  CAS  Google Scholar 

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Acknowledgments

We offer our special thanks to Mayumi Miura, Kanoko Miyazaki, Yuki Morotomi, Chie Kuroki, Kaoruko Nagatomo, Kensaku Sato, and Kazutaka Nakashima for their technical support. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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Authors and Affiliations

  1. Department of Pathology, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka, 830-0011, Japan

    Kotaro Matsuda, Hiroaki Miyoshi & Koichi Ohshima

  2. Department of Orthopedic Surgery, Kurume University School of Medicine, Kurume, Fukuoka, Japan

    Kotaro Matsuda, Koji Hiraoka, Tetsuya Hamada, Shiro Yoshida, Yukinao Ishibashi, Toshiaki Haraguchi & Naoto Shiba

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  1. Kotaro Matsuda
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Correspondence to Hiroaki Miyoshi.

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Matsuda, K., Miyoshi, H., Hiraoka, K. et al. Clinicopathological value of programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) expression in synovium of patients with rheumatoid arthritis. Clin Exp Med 18, 487–494 (2018). https://doi.org/10.1007/s10238-018-0515-4

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