Background/Purpose: Activated T cells are involved in the pathogenesis of the synovitis in oligoarticular Juvenile Idiopathic Arthritis (o-JIA). T cell activation is counter-balanced via co-inhibitory receptors (co-IRs) such as CTLA-4, PD-1, LAG-3, and TIM-3. Here we identify the role of co-IRs in the pathogenesis of o-JIA.

Methods: Paired synovial fluid (SF) and plasma, PBMCs and SFMCs, were obtained from o-JIA patients together with clinical data (n=14). Plasma from healthy controls (HC, n=14) and paired SF and plasma from 5 children requiring arthroscopy for non-inflammatory orthopaedic problems (OC, n=5) served as controls. Soluble levels of co-IRs were measured by ELISA and their cellular expression by flow cytometry. Spontaneously differentiated fibroblast-like synoviocytes (FLS) from SFMCs were co-cultured with autologous PBMCs/SFMCs and used as an ex-vivo disease models. Functional effects of co-IRs were evaluated via blocking them with checkpoint inhibitors in these ex-vivo disease models.

Results: o-JIA patients had increased soluble levels (Figure 1A) and CD3+CD4+CD45RO+ T cell surface expressions of sPD-1, sLAG-3, sTIM-3, but not sCTLA-4 in SF compared with plasma (Figure 1B). Plasma and SF levels of sLAG-3 and TIM-3, but not sPD-1 levels were higher in o-JIA patients compared with controls. (Figure 1A) None of the soluble co-IR levels correlated with disease activity. As CD4 T cell exhaustion is an outcome of continued antigen presentation, we examined if MHC-class II expression was present on these FLS. FLS expressed nearly no MHC-class II molecules in monocultures, but this was readily detected when co-cultured with PBMCs and SFMCs together with an increased Monocyte Chemoattractant Protein-1 (MCP-1) production. (Figure 2A) Only anti-LAG3 antibodies significantly increased the MCP-1 production in PBMC monocultures and FLS+PBMC co-cultures. (Figure 2B) PBMCs and SFMCs produced significantly higher levels of IFN-ɣ after CD3/CD28 activation (p< 0.001), but they were not affected by the addition of antibody towards the other checkpoint inhibitors. Conclusion: This is the first report studying the effects of different co-IRs in o-JIA. Both the soluble levels and the surface expressions of co-IRs were higher at the site of inflammation in o-JIA. SFMCs and PBMCs of o-JIA patients are not exhausted, based on their ability to respond to CD3/CD28 activation. This is opposite to what has been shown in adult inflammatory arthritis. Co-cultures of autologous FLSs and PBMCs/SFMCs may serve as an ex-vivo arthritis model to perform functional analysis. LAG-3 might play a role in o-JIA pathogenesis and maybe a potential therapeutic option.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/oligoarticular-juvenile-idiopathic-arthritis-displayed-increased-expression-of-co-inhibitory-receptors-without-signs-of-t-cell-exhaustion/