Abstract
The programmed death-1 (PD-1) pathway has been shown to deliver an inhibitory signal, and aberrant expression of the PD-1 molecule and/or its ligand programmed death ligand 1 (PD-L1) has been demonstrated in human diseases, while its other ligand, programmed death ligand 2 (PD-L2), has rarely been studied. Here, we investigated the expression of PD-L2 in synovial tissue and blood from patients with rheumatoid arthritis (RA). Soluble PD-L2 and inflammatory cytokine levels in serum among healthy controls and patients with RA were compared via enzyme-linked immunosorbent assay (ELISA). Membrane PD-L2 on monocytes in blood was analyzed through flow cytometry (FCM). The different expression levels of PD-L2 between the RA and non-RA synovium were semi-quantified by immunohistochemical (IHC) staining. The soluble PD-L2 levels in serum from patients with RA were significantly lower than those in healthy subjects, correlating with active parameters (rheumatoid factor) and inflammatory cytokine secretion. The FCM results showed that patients with RA had significantly increased percentages of PD-L2-expressing CD14+ monocytes and correlated with inflammatory cytokines. PD-L2 expression on macrophages in the synovium from patients with RA was recorded by IHC staining with a higher score, and its correlation with pathological scores and clinical features was determined. Together, our results revealed aberrant expression of PD-L2 in RA, which may be a promising biomarker and therapeutic target associated with the pathogenesis of RA.
Similar content being viewed by others
Data availability
The data used to support the findings of this study are available from the corresponding author upon request.
References
Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, Healey LA, Kaplan SR, Liang MH, Luthra HS et al (1988) The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 31:315–324
Bittner S, Knoll G, Fullsack S, Kurz M, Wajant H, Ehrenschwender M (2016) Soluble TL1A is sufficient for activation of death receptor 3. FEBS J 283:323–336
Bustamante MF, Garcia-Carbonell R, Whisenant KD, Guma M (2017) Fibroblast-like synoviocyte metabolism in the pathogenesis of rheumatoid arthritis. Arthritis Res Ther 19:110
Greisen SR, Kragstrup TW, Thomsen JS, Hansen AS, Krishnamurthy A, Horslev-Petersen K, Hetland ML, Stengaard-Pedersen K, Ostergaard M, Ornbjerg LM et al (2020) Programmed death ligand 2 - a link between inflammation and bone loss in rheumatoid arthritis. J Transl Autoimmun 3:100028
Guo Y, Walsh AM, Canavan M, Wechalekar MD, Cole S, Yin X, Scott B, Loza M, Orr C, McGarry T et al (2018) Immune checkpoint inhibitor PD-1 pathway is down-regulated in synovium at various stages of rheumatoid arthritis disease progression. PLoS ONE 13:e0192704
Hatachi S, Iwai Y, Kawano S, Morinobu S, Kobayashi M, Koshiba M, Saura R, Kurosaka M, Honjo T, Kumagai S (2003) CD4+ PD-1+ T cells accumulate as unique anergic cells in rheumatoid arthritis synovial fluid. J Rheumatol 30:1410–1419
Inaba K, Yashiro T, Hiroki I, Watanabe R, Kasakura K, Nishiyama C (2020) Dual roles of PU.1 in the expression of PD-L2: direct transactivation with IRF4 and indirect epigenetic regulation. J Immunol 205:822–829
Kanai T, Totsuka T, Uraushihara K, Makita S, Nakamura T, Koganei K, Fukushima T, Akiba H, Yagita H, Okumura K et al (2003) Blockade of B7–H1 suppresses the development of chronic intestinal inflammation. J Immunol 171:4156–4163
Karolova J, Radek M, Helman K, Spacek M, Trneny M, Klener P (2020) PD-1, PD-L1 and PD-L2 expression in mantle cell lymphoma and healthy population. Folia Biol (Praha) 66:117–122
Keir ME, Butte MJ, Freeman GJ, Sharpe AH (2008) PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol 26:677–704
Khan M, Zhao Z, Arooj S, Fu Y, Liao G (2020) Soluble PD-1: predictive, prognostic, and therapeutic value for cancer immunotherapy. Front Immunol 11:587460
Lazar-Molnar E, Yan Q, Cao E, Ramagopal U, Nathenson SG, Almo SC (2008) Crystal structure of the complex between programmed death-1 (PD-1) and its ligand PD-L2. Proc Natl Acad Sci U S A 105:10483–10488
Meng W, Zhu Z, Jiang X, Too CL, Uebe S, Jagodic M, Kockum I, Murad S, Ferrucci L, Alfredsson L et al (2017) DNA methylation mediates genotype and smoking interaction in the development of anti-citrullinated peptide antibody-positive rheumatoid arthritis. Arthritis Res Ther 19:71
Messal N, Serriari NE, Pastor S, Nunes JA, Olive D (2011) PD-L2 is expressed on activated human T cells and regulates their function. Mol Immunol 48:2214–2219
Pawlowska A, Kwiatkowska A, Suszczyk D, Chudzik A, Tarkowski R, Barczynski B, Kotarski J, Wertel I (2021) Clinical and prognostic value of antigen-presenting cells with PD-L1/PD-L2 expression in ovarian cancer patients. Int J Mol Sci 22
Smolen JS, Aletaha D, Barton A, Burmester GR, Emery P, Firestein GS, Kavanaugh A, McInnes IB, Solomon DH, Strand V, Yamamoto K (2018) Rheumatoid arthritis. Nat Rev Dis Primers 4:18001
Smolen JS, Aletaha D, McInnes IB (2016) Rheumatoid arthritis. Lancet 388:2023–2038
Sun C, Mezzadra R, Schumacher TN (2018) Regulation and Function of the PD-L1 Checkpoint. Immunity 48:434–452
Tong M, Fang X, Yang J, Wu P, Guo Y, Sun J (2020) Abnormal membrane-bound and soluble programmed death ligand 2 (PD-L2) expression in systemic lupus erythematosus is associated with disease activity. Immunol Lett 227:96–101
Yamazaki T, Akiba H, Iwai H, Matsuda H, Aoki M, Tanno Y, Shin T, Tsuchiya H, Pardoll DM, Okumura K et al (2002) Expression of programmed death 1 ligands by murine T cells and APC. J Immunol 169:5538–5545
Yasuoka H, Asai A, Ohama H, Tsuchimoto Y, Fukunishi S, Higuchi K (2020) Increased both PD-L1 and PD-L2 expressions on monocytes of patients with hepatocellular carcinoma was associated with a poor prognosis. Sci Rep 10:10377
Zhang G, Hou J, Shi J, Yu G, Lu B, Zhang X (2008) Soluble CD276 (B7–H3) is released from monocytes, dendritic cells and activated T cells and is detectable in normal human serum. Immunology 123:538–546
Zhong X, Tumang JR, Gao W, Bai C, Rothstein TL (2007) PD-L2 expression extends beyond dendritic cells/macrophages to B1 cells enriched for V(H)11/V(H)12 and phosphatidylcholine binding. Eur J Immunol 37:2405–2410
Funding
This work was funded by Grants from Jiangsu Commission of Health (grant No. H2019063), Qinglan Project of Jiangsu Province of China, Jiangsu 333 talent project and Youth Science and Technology Project of Suzhou Vocational Health College (No. SZWZY202114).
Author information
Authors and Affiliations
Contributions
XJ analyzed the date, and wrote the manuscript. YJ conducted the most assays, contributed equally to this work, and listed as first co-author. SYL, CYC, GYD, and LCP collected the clinical samples including serum and synovium needed in this study. SJ participated and designed the study and reviewed the manuscript.
Corresponding authors
Ethics declarations
Ethical approval
This study was approved by the Ethics Committee of Suzhou Vocational Health College (approval No. SZHCTEC-2020-002).
Conflicts of interest
The authors declare that they have no conflict of interest.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Xiong, J., Yang, J., Sun, Y. et al. Dysregulated PD-L2 is correlated with disease activity and inflammation in rheumatoid arthritis. Immunogenetics 75, 425–431 (2023). https://doi.org/10.1007/s00251-023-01307-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00251-023-01307-7