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

Author:

Clement Cristina C.1ORCID,Osan Jaspreet1ORCID,Buque Aitziber1ORCID,Nanaware Padma P.2ORCID,Chang Yoke-Chen3ORCID,Perino Giorgio1,Shetty Madhur1ORCID,Yamazaki Takahiro1ORCID,Tsai Wanxia Li4,Urbanska Aleksandra M.1,Calvo-Calle J. MauricioORCID,Ramsamooj Shakti12,Ramsamooj Shakti5,Vergani Diego67ORCID,Mieli-Vergani Giorgina67ORCID,Terziroli Beretta-Piccoli Benedetta67,Gadina Massimo4ORCID,Montagna Cristina3ORCID,Goncalves Marcus DaSilva5ORCID,Sallusto Federica6ORCID,Galluzzi Lorenzo189ORCID,Soni Rajesh K.10ORCID,Stern Lawrence J.211ORCID,Santambrogio Laura189ORCID

Affiliation:

1. Department of Radiation Oncology, Weill Cornell Medicine, New York, NY 10065, USA.

2. Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01605, USA.

3. Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08901, USA.

4. Translational Immunology Section, National Institute of Arthritis Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 10916, USA.

5. Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA.

6. Institute for Research in Biomedicine, Faculty of Biomedical Sciences, Università della Svizzera Italiana and Epatocentro Ticino, Lugano 6900, Switzerland.

7. King’s College London Faculty of Life Sciences and Medicine, King’s College Hospital, London WC2R 2LS, UK.

8. Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA.

9. Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY 10065, USA.

10. Proteomics and Macromolecular Crystallography Shared Resource, Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA.

11. Immunology and Microbiology Program, University of Massachusetts Medical School, Worcester, MA 01605, USA.

Abstract

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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

General Medicine,Immunology

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