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JCI Insight. 2016 Feb;1(2). pii: 85633. doi: 10.1172/jci.insight.85633. Epub 2016 Feb 25.

Autoimmune response to transthyretin in juvenile idiopathic arthritis.

Author information

1
Department of Pathology, Albert Einstein College of Medicine, New York, New York, USA.
2
Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
3
Department of Pediatric Rheumatology, Montefiore Medical Center, New York, New York, USA.
4
Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
5
Department of Pathology, Hospital for Special Surgery, New York, New York, USA.
6
Department of Genetics, Albert Einstein College of Medicine, New York, New York, USA.
7
Department of Orthopedic Surgery, Montefiore Medical Center, New York, New York, USA.
8
Department of Microbiology and Immunology, Albert Einstein College of Medicine, New York, New York, USA.

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.

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