TY - JOUR
T1 - Autoimmune response to transthyretin in juvenile idiopathic arthritis
AU - Clement, Cristina C.
AU - Moncrieffe, Halima
AU - Lele, Aditi
AU - Janow, Ginger
AU - Becerra, Aniuska
AU - Bauli, Francesco
AU - Saad, Fawzy A.
AU - Perino, Giorgio
AU - Montagna, Cristina
AU - Cobelli, Neil
AU - Hardin, John
AU - Stern, Lawrence J.
AU - Ilowite, Norman
AU - Porcelli, Steven A.
AU - Santambrogio, Laura
N1 - Funding Information:
This work was supported by NIH grants AG045223 (to L. Santambrogio), AI38996 (to L.J. Stern), and AI48833 (to L.J. Stern). We acknowledge the Laboratory for Macromolecular Analysis and Proteomics (NIH grant 1S10RR019352) at Albert Einstein College of Medicine. We thank Monica Tsoras of the CCHMC Pediatric Rheumatology Tissue Core for excellent technical support and database management. This research was supported in part by the Cincinnati Children’s Research Foundation and its Cincinnati Genomic Control Cohort. All flow cytometry data were acquired using equipment maintained by the Research Flow Cytometry Core in the Division of Rheumatology at CCHMC, supported in part by NIH grants AR-47363, DK78392, and DK90971. H. Moncrieffe was supported in part by NIH grants AR-47363 and AR-48929.
Publisher Copyright:
© 2016 American Society for Clinical Investigation. All rights reserved.
PY - 2016/2/25
Y1 - 2016/2/25
N2 - 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.
AB - 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.
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U2 - 10.1172/jci.insight.85633
DO - 10.1172/jci.insight.85633
M3 - Article
AN - SCOPUS:85057026254
SN - 2379-3708
VL - 1
JO - JCI insight
JF - JCI insight
IS - 2
M1 - e85633
ER -