METABOLIC INSULTS ELICIT EPITOPE-DEPENDENT IMMUNE AUTOREACTIVITY AGGRAVATING HEPATIC DAMAGE IN TYPE 2 DIABETES

Abstract

Abstract A diet rich in saturated fat and carbohydrates causes low-grade chronic inflammation in several organs including the liver, ultimately driving non-alcoholic steatohepatitis. The environment-driven lipotoxicity and glucotoxicity induces liver damage, which promotes dendritic cell adjuvanticity and generates an MHC-II immunopeptidome enriched of peptides derived from proteins involved in cellular metabolism, oxidative phosphorylation, and stress responses. Here, we demonstrate that metabolic insults promote the presentation of nested T and B cell epitopes from protein disulfide isomerase family A member 3 (PDIA3, which is involved in immunogenic cell death) on MHC Class II, ultimately supporting pathogenic autoreactivity. Additionally, PDIA3-driven T cell responses infiltrating the hepatic parenchyma, favored the release of TH1 and TH17 pro-inflammatory cytokines and, PDIA3-driven B cell responses were associated with antibodies that aggravated hepatic toxicity in mice subjected to high-fat and high-sucrose diet. Increased humoral responses to PDIA3 were also observed in patients with chronic inflammatory liver conditions including autoimmune hepatitis, primary biliary cholangitis and type 2 diabetes. Altogether our data indicate that metabolic insult caused by high-sucrose diet, cause tissue damage, which, by supplying PDIA3 T cell and B cell epitopes further contributes to epitope-dependent pathogenic immune autoreactivity Supported by NIHAI146180 and NIH AI137198