PMID- 34031570 OWN - NLM STAT- MEDLINE DCOM- 20220321 LR - 20221207 IS - 1530-0447 (Electronic) IS - 0031-3998 (Linking) VI - 90 IP - 4 DP - 2021 Oct TI - Juvenile idiopathic arthritis: lymphocyte activation gene-3 is a central immune receptor in children with oligoarticular subtypes. PG - 744-751 LID - 10.1038/s41390-021-01588-2 [doi] AB - BACKGROUND: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. IMPACT: 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. CI - (c) 2021. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc. FAU - Sag, Erdal AU - Sag E AD - Department of Biomedicine, Aarhus University, Aarhus, Denmark. sag.erdal@gmail.com. AD - Division of Pediatric Rheumatology, Department of Pediatrics, Hacettepe University, Ankara, Turkey. sag.erdal@gmail.com. AD - Pediatric Rheumatology Unit, Translational Medicine Laboratories, Hacettepe University, Ankara, Turkey. sag.erdal@gmail.com. FAU - Demir, Selcan AU - Demir S AD - Division of Pediatric Rheumatology, Department of Pediatrics, Hacettepe University, Ankara, Turkey. AD - Pediatric Rheumatology Unit, Translational Medicine Laboratories, Hacettepe University, Ankara, Turkey. FAU - Aspari, Maithri AU - Aspari M AD - Department of Biomedicine, Aarhus University, Aarhus, Denmark. FAU - Nielsen, Morten Aagaard AU - Nielsen MA AD - Department of Biomedicine, Aarhus University, Aarhus, Denmark. FAU - Skejo, Caecilie AU - Skejo C AD - Department of Biomedicine, Aarhus University, Aarhus, Denmark. FAU - Hvid, Malene AU - Hvid M AD - Department of Biomedicine, Aarhus University, Aarhus, Denmark. AD - Department of Clinical Medicine, Aarhus University, Aarhus, Denmark. FAU - Turhan, Egemen AU - Turhan E AD - Department of Orthopedics and Traumatology, Hacettepe University, Ankara, Turkey. FAU - Bilginer, Yelda AU - Bilginer Y AD - Division of Pediatric Rheumatology, Department of Pediatrics, Hacettepe University, Ankara, Turkey. AD - Pediatric Rheumatology Unit, Translational Medicine Laboratories, Hacettepe University, Ankara, Turkey. FAU - Greisen, Stinne AU - Greisen S AD - Department of Biomedicine, Aarhus University, Aarhus, Denmark. FAU - Ozen, Seza AU - Ozen S AD - Division of Pediatric Rheumatology, Department of Pediatrics, Hacettepe University, Ankara, Turkey. AD - Pediatric Rheumatology Unit, Translational Medicine Laboratories, Hacettepe University, Ankara, Turkey. FAU - Deleuran, Bent AU - Deleuran B AD - Department of Biomedicine, Aarhus University, Aarhus, Denmark. AD - Department of Rheumatology, Aarhus University Hospital, Aarhus, Denmark. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210524 PL - United States TA - Pediatr Res JT - Pediatric research JID - 0100714 RN - 0 (Antigens, CD) RN - 0 (Receptors, Immunologic) RN - 0 (Lymphocyte Activation Gene 3 Protein) RN - 0 (Lag3 protein, human) SB - IM MH - Antigens, CD/*genetics MH - Arthritis, Juvenile/*immunology MH - Child MH - Humans MH - Joint Diseases/*immunology MH - Receptors, Immunologic/*genetics MH - T-Lymphocytes/immunology MH - Lymphocyte Activation Gene 3 Protein EDAT- 2021/05/26 06:00 MHDA- 2022/03/22 06:00 CRDT- 2021/05/25 06:38 PHST- 2021/03/26 00:00 [received] PHST- 2021/04/28 00:00 [accepted] PHST- 2021/04/27 00:00 [revised] PHST- 2021/05/26 06:00 [pubmed] PHST- 2022/03/22 06:00 [medline] PHST- 2021/05/25 06:38 [entrez] AID - 10.1038/s41390-021-01588-2 [pii] AID - 10.1038/s41390-021-01588-2 [doi] PST - ppublish SO - Pediatr Res. 2021 Oct;90(4):744-751. doi: 10.1038/s41390-021-01588-2. Epub 2021 May 24.