Effect of T-cell exhaustion profiles of synovial fluid and peripheral blood from JIA patients on disease pathogenesis and prognosis

Concept

Juvenile idiopathic arthritis (JIA) is a chronic inflammatory disease that can cause severe disability and even mortality with joint swelling, sensitivity, loss of motion and synovial tissue damage. JIA is one of the most common inflammatory joint disease.

Chronicity in autoimmune diseases depends on the balance between pro-inflammatory and anti-inflammatory responses. One of the main factors in achieving this equilibrium is T-cell co-inhibitor receptors, which are highly expressed by exhausted-T-cells.

Previous studies revealed that T cells play an important and central role in the pathogenesis of especially the oligoarticular and polyarticular forms of the disease. We aim to define the role of T cell co-inhibitory receptors (co-IRs) for predicting the outcome of JIA and try to find a novel therapeutic target molecule.

Facts and Figures

Project Lead
E Sag
Hacettepe University
sag.erdal@gmail.com
FOREUM research grant: € 150.000
2018–2021

Meet the Team

Project Lead

E Sag
Hacettepe University
sag.erdal@gmail.com
S Ozen
Hacettepe University
B Deleuran
Aarhus University

Final Results

This is the first study showing the role of co-inhibitory receptors (checkpoint proteins) in the pathogenesis of JIA. Both the soluble levels and the surface expressions of these co-IRs are higher atsynovium which is the site of inflammation in JIA. Co-cultures of autologous fibroblasts and PBMCs/SFMCs may serve as an important ex-vivoarthritis modelfor JIA. Polyarticular JIA patients had a different coIR profile, having more CTLA-4, PD-1 and 4-1BB in their plasma than the other subtypes of JIA. Lag-3 is a central immune receptor in the oligoarticular JIA pathogenesis and LAG-3 agonists mightbe a novel therapeutic option for oligoarticular JIA patients.

Lay Summary

In this project we aimed to investigate the role of checkpoint proteins, also known as co-inhibitory receptors (co-IRs), in the pathogenesis of childhood arthritis (juvenile idiopathic arthritis (JIA)). These molecules were found to be higher in the synovium which is the site of inflammation in JIA patients. We have shown that LAG-3 is an important molecule in the pathogenesis of oligoarticular JIA. We have shown that LAG3 agonists might be a novel therapeutic option for oligoarticular JIA patients in the future. Furthermore, during this study, we designed a novel ex-vivo arthritis models for JIA and performed our functional analysis with this model.We also analysed the co-inhibitory receptor profiles in different JIA subtypes,  showing that patients who have a polyarticular course have a unique pattern with elevated CTLA-4, PD-1 and 4-1BB, which was different from the other forms of JIA. This is the first study analysing these proteins in childhood arthritis and is hoped to lead to more work in the relevant area.

Publications

  • Sag E, Demir S, Aspari M, Nielsen MA, Skejø C, Hvid M, Turhan E, Bilginer Y, Greisen S, Ozen S, Deleuran B. Juvenile idiopathic arthritis: lymphocyte activation gene-3 is a central immune receptor in children with oligoarticular subtypes. Pediatr Res. 2021 May 24. doi: 10.1038/s41390-021-01588-2. Epub ahead of print. PMID: 34031570
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  • Sag, E. ECI Biocommentary: Erdal Sag. Pediatr Res 90, 711 (2021). https://doi.org/10.1038/s41390-021-01636-x. PMID:34175892
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EULAR Abstracts

2019

  • OP0152 : Oligoarticular Juvenile Idiopathic Arthritis does not show signs of T-cell exhaustion, in spite of increased expression of co-inhibitory receptors
    Go to EULAR Abstract Archive

Paediatric Rheumatology European Society PReS Abstracts

  • ABS-1140: Lag-3 is a central immune receptor in oligoarticular Juvenile Idiopathic Arthritis

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