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Autoimmune response to transthyretin in juvenile idiopathic arthritis
Cristina C. Clement, … , Steven A. Porcelli, Laura Santambrogio
Cristina C. Clement, … , Steven A. Porcelli, Laura Santambrogio
Published February 25, 2016
Citation Information: JCI Insight. 2016;1(2):e85633. https://doi.org/10.1172/jci.insight.85633.
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Research Article Inflammation

Autoimmune response to transthyretin in juvenile idiopathic arthritis

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Abstract

Juvenile idiopathic arthritis (JIA) is the most common pediatric rheumatological condition. Although it has been proposed that JIA has an autoimmune component, the autoantigens are still unknown. Using biochemical and proteomic approaches, we identified the molecular chaperone transthyretin (TTR) as an antigenic target for B and T cell immune responses. TTR was eluted from IgG complexes and affinity purified from 3 JIA patients, and a statistically significant increase in TTR autoantibodies was observed in a group of 43 JIA patients. Three cryptic, HLA-DR1–restricted TTR peptides, which induced CD4+ T cell expansion and IFN-γ and TNF-α production in 3 out of 17 analyzed patients, were also identified. Misfolding, aggregation and oxidation of TTR, as observed in the synovial fluid of all JIA patients, enhanced its immunogenicity in HLA-DR1 transgenic mice. Our data point to TTR as an autoantigen potentially involved in the pathogenesis of JIA and to oxidation and aggregation as a mechanism facilitating TTR autoimmunity.

Authors

Cristina C. Clement, Halima Moncrieffe, Aditi Lele, Ginger Janow, Aniuska Becerra, Francesco Bauli, Fawzy A. Saad, Giorgio Perino, Cristina Montagna, Neil Cobelli, John Hardin, Lawrence J. Stern, Norman Ilowite, Steven A. Porcelli, Laura Santambrogio

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Figure 4

Transthyretin and anti-transthyretin antibodies in the synovial fluid and sera of juvenile idiopathic arthritis patients and controls.

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Transthyretin and anti-transthyretin antibodies in the synovial fluid an...
(A) Quantification of transthyretin (TTR) autoantibodies, as detected by ELISA, present in the synovial fluid from patients with juvenile idiopathic arthritis (JIA) and controls (data were compiled from 3 separate ELISAs, with each patient’s samples run in quadruplicate). Data were analyzed by 1-way ANOVA and Tukey test. (B) Quantification of TTR autoantibodies, as detected by ELISA, present in the sera of patients with JIA and controls (data were compiled from 3 separate ELISAs, with each patient’s samples run in quadruplicate). Data were analyzed by 1-way ANOVA and Tukey test. (C and D) Amount of TTR present in the synovial fluid and sera from patients with JIA and controls (data were compiled from 3 separate ELISAs, with each patient’s samples run in quadruplicate) Data were analyzed by 1-way ANOVA and Tukey test. (E) Correlation between TTR protein and anti-TTR antibodies (Spearman r = 0.72, ****P < 0.001). The patient ID for each circle is reported in Supplemental Figure 4. Mean ± SD. *P < 0.05; **P < 0.005; ****P < 0.001.

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