PDIA3 epitope-driven immune autoreactivity contributes to hepatic damage in type 2 diabetes

• DOI: 10.1126/sciimmunol.abl3795
• Publication Date: 2022-08-19T17:58:21Z
• Authors: Cristina C. Clement; Jaspreet Osan; Aitziber Buque; Padma P. Nanaware; Yoke-Chen Chang; Giorgio Perino; Madhur Shetty; Takahiro Yamazaki; Wanxia Li Tsai; Aleksandra M. Urb...; J. Mauricio Calvo...; Shakti Ramsamooj; Shakti Ramsamooj; Diego Vergani; Giorgina Mieli-Ve...; Benedetta Terziro...; Massimo Gadina; Cristina Montagna; Marcus DaSilva Go...; Federica Sallusto; Lorenzo Galluzzi; Rajesh K. Soni; Lawrence J. Stern; Laura Santambrogio
• Keywords: Lipotoxicity; Steatohepatitis; Steatosis

A diet rich in saturated fat and carbohydrates causes low-grade chronic inflammation several organs, including the liver, ultimately driving nonalcoholic steatohepatitis. In this setting, environment-driven lipotoxicity glucotoxicity induce liver damage, which promotes dendritic cell activation generates a major histocompatibility complex class II (MHC-II) immunopeptidome enriched with peptides derived from proteins involved cellular metabolism, oxidative phosphorylation, stress responses. Here, we demonstrated that glucotoxicity, as driven by high-fat high-fructose (HFHF) diet, promoted MHC-II presentation of nested T B epitopes protein disulfide isomerase family member 3 (PDIA3), is immunogenic death. Increased PDIA3 was associated antigen-specific proliferation hepatic CD4+ immune infiltrates isotype switch anti-PDIA3 antibodies IgM to IgG3, indicative humoral autoreactivity. Passive transfer PDIA3-specific cells or also exacerbated hepatocyte death, determined increased transaminases detected sera mice subjected an HFHF but not control diet. responses were observed patients inflammatory conditions, autoimmune hepatitis, primary biliary cholangitis, type 2 diabetes. Together, our data indicated metabolic insults caused elicited damage pathogenic autoreactivity epitopes.