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

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 1

Peptidomic profiling of synovial fluid from juvenile idiopathic arthritis patients and controls.

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Peptidomic profiling of synovial fluid from juvenile idiopathic arthriti...
(A) Venn diagram reporting the number of endogenous peptides and their protein substrates (peptidomic data are reported in Supplemental Tables 2 and 3) found in the synovial fluid of patients with juvenile idiopathic arthritis (JIA) and controls (data were compiled from 3 separate proteomic analyses). (B) Hierarchical clustering analysis of the protein substrates of the peptidome found in the synovial fluid of patients with JIA and controls was generated in Scaffold 4 using the log of the normalized spectral abundance factor [ln(NSAF)] values [average of 3 experiments for the ln(NSAF)]. The Ward’s dual-clustering method and the t test were performed comparing 2 controls and 7 JIA patients. Only 43 protein substrates of the peptidome were shown to have more than 1.5-fold difference in expression across all patients, with statistical significance corresponding to a FDR < 0.7 [green corresponds to the lowest ln(NSAF), while red corresponds to the highest ln(NSAF)]. The protein substrates with the highest statistically significant contribution to the peptidome of JIA patients versus controls are shown as cluster (I) (at P < 0.08) (peptidomic data used to compile the heat map are reported in Supplemental Table 2F). (C) Analysis of the unique endogenous peptides derived from the degradation of the acute-phase response and cartilage matrix proteins found in the synovial fluid of patients with JIA and controls (data were compiled from 3 separate proteomic analyses). The enhanced degradation of the proteome from the synovial fluid of JIA patients correlates with the increased number of sequenced endogenous peptides. (D) Selected tandem mass spectrometry fragmentation profiles of peptides derived from collagen I (α 1) and from transthyretin, as mapped in the synovial fluid of patients with JIA.