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

A diet rich in saturated fat and carbohydrates causes low-grade chronic inflammation in several organs, including the liver, ultimately driving nonalcoholic steatohepatitis. In this setting, environment-driven lipotoxicity and glucotoxicity induce liver damage, which promotes dendritic cell activation and generates a major histocompatibility complex class II (MHC-II) immunopeptidome enriched with peptides derived from proteins involved in cellular metabolism, oxidative phosphorylation, and the stress responses. Here, we demonstrated that lipotoxicity and glucotoxicity, as driven by a high-fat and high-fructose (HFHF) diet, promoted MHC-II presentation of nested T and B cell epitopes from protein disulfide isomerase family A member 3 (PDIA3), which is involved in immunogenic cell death. Increased MHC-II presentation of PDIA3 peptides was associated with antigen-specific proliferation of hepatic CD4+ immune infiltrates and isotype switch of anti-PDIA3 antibodies from IgM to IgG3, indicative of cellular and humoral PDIA3 autoreactivity. Passive transfer of PDIA3-specific T cells or PDIA3-specific antibodies also exacerbated hepatocyte death, as determined by increased hepatic transaminases detected in the sera of mice subjected to an HFHF but not control 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. Together, our data indicated that metabolic insults caused by an HFHF diet elicited liver damage and promoted pathogenic immune autoreactivity driven by T and B cell PDIA3 epitopes. Description Metabolic insults elicit epitope-dependent immune autoreactivity to PDIA3, aggravating hepatic damage in type 2 diabetes. Livers beware T and B cells! So-called “American,” high-fat and high-sugar, diets are known to contribute to chronic inflammation in the liver and subsequent autoimmune reactions, yet the immune responses behind this phenomenon are not well characterized. Here, Clement et al. identified PDIA3, a protein involved in immunogenic cell death, as a peptide presented via MHC-II that led to pathogenic T and B cell responses in mice given a high-fat, high-glucose diet. PDIA3-specific T cells and PDIA3-specific antibodies were sufficient to induce liver toxicity. Anti-PDIA3 was detected at high levels in the serum of patients with chronic inflammatory liver conditions. Thus, the American diet induces liver damage through PDIA3-specific T and B cells in mice.