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Juvenile idiopathic arthritis: lymphocyte activation gene-3 is a central immune receptor in children with oligoarticular subtypes



We investigated the role of inhibitory receptors (IRs) and especially lymphocyte activation gene-3 (LAG-3) in the pathogenesis of oligoarticular juvenile idiopathic arthritis (o-JIA).


Paired samples of synovial fluid (SF) and plasma and peripheral blood (PBMCs) and synovial fluid mononuclear cells (SFMCs) were collected from o-JIA patients along with their clinical data (n = 24). Plasma from healthy controls (n = 14) and paired SF and plasma samples from five non-arthritic juvenile orthopedic patients (n = 5) served as controls. Spontaneously differentiated fibroblast-like synoviocytes (FLSs) from SFMCs were co-cultured with autologous PBMCs/SFMCs and used as ex vivo disease model. Soluble levels and cellular expressions of IRs together with their functional properties in the ex vivo model were analyzed.


In patients with o-JIA, soluble levels of LAG-3 and expression of LAG-3 and T cell immunoglobulin mucin03 (TIM-3) on CD3+CD4+CD45RO+ T cells were increased, especially in SF. Major histocompatibility complex (MHC) class II expression was induced on FLSs when these were co-cultured with autologous PBMCs/SFMCs, together with an increased monocyte chemoattractant protein-1 (MCP-1) production. In PBMC and FLS + PBMC co-cultures, neutralizing antibodies to IRs were added. Only anti-LAG-3 antibodies significantly increased MCP-1 secretion. The addition of agonistic LAG-3 antibody resulted in decreased effector cytokine secretion.


This is the first report comparing the effects of different IRs in o-JIA and suggests that LAG-3 might contribute to the pathogenesis of this disease.


  • This is the first study addressing the role of different co-IRs in o-JIA.

  • We showed that LAG-3 and TIM-3 seem more important in juvenile arthritis in contrast to adult rheumatoid arthritis, where cytotoxic T-lymphocyte-associated antigen-4 and programmed cell death-1 were reported to be more important.

  • We designed an ex vivo disease model for o-JIA, examined the effects of co-IRs in this model, and demonstrated that they might contribute to the pathogenesis of the disease.

  • LAG-3 might play a role in o-JIA pathogenesis and might be a potential therapeutic option for o-JIA patients.

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Fig. 1: Soluble (s) levels of PD-1, LAG-3, and TIM-3 in plasma and SF in oligoarticular JIA, non-arthritis juvenile orthopedic controls, and healthy controls.
Fig. 2: Surface expressions of IRs, CTLA-4, PD-1, LAG-3, and TIM-3, in JIA PBMC and SFMC (n = 11).
Fig. 3: MHC class II expressions on CD45-PDPN + FLS (n = 4).
Fig. 4: MCP-1 levels in the co-culture supernatants of ex vivo arthritis model (n = 6).
Fig. 5: Different cytokine levels in the FLS + PBMC co-cultures (n = 5) after 48 h.

Data availability

All data generated or analyzed during this study are included in this paper and in its Supplementary information files.


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We would like to thank Karin Skovgaard Sørensen for her technical assistance during this study; to Aarhus University FACS core facility for their advice on the flow cytometry analyses, to Bahar Guclu, the patient/parent research partner, for her contribution. LAG-3 agonist (IMP761) was generously provided by Immutep and Dr. Triebel, CSO and CMO—per clause 10.2 of the MTA. This study was supported by a research grant from FOREUM Foundation for Research in Rheumatology. This study was also supported by the Danish Rheumatoid Association, Aarhus University, The Scientific and Technological Research Council of Turkey (TUBITAK), and the Hacettepe University Scientific Research Unit.

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Authors and Affiliations



E.S., S.O., and B.D. designed the study, collected the data, contributed to the data interpretation, and wrote the manuscript; E.S., S.D., E.T., Y.B., and S.O. collected patients’ data and samples, contributed the data interpretation, revised the manuscript; E.S., M.A., M.A.N., C.S., M.H., S.G., and B.D. designed and performed the experiments, contributed the data interpretation, and revised the manuscript. All authors made substantial contributions to either the conception and design of this study or to the generation, analysis, and/or interpretation of data. They agree to be accountable for the integrity of the work herein. All authors reviewed the manuscript and approved the submitted version.

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Correspondence to Erdal Sag.

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The authors declare no competing interests.

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Written informed written consent for publication was obtained from the parents and patients.

Ethical approval and consent to participate

This study was approved by the Hacettepe University Ethics Committee for Non-Interventional Clinical Trials (GO 18/277-35), and informed written consent to participate in the study was obtained from the parents and patients.

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Sag, E., Demir, S., Aspari, M. et al. Juvenile idiopathic arthritis: lymphocyte activation gene-3 is a central immune receptor in children with oligoarticular subtypes. Pediatr Res 90, 744–751 (2021).

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