Branched chain α-ketoacid dehydrogenase kinase 111–130, a T cell epitope that induces both autoimmune myocarditis and hepatitis in A/J mice

Authors

Bharathi Krishnan, University of Nebraska-LincolnFollow
Chandirasegara Massilamany, University of Nebraska-LincolnFollow
Rakesh H. Basavalingappa, University of Nebraska-LincolnFollow
Arunakumar Gangaplara, University of Nebraska - Lincoln
Guobin Kang, University of Nebraska-LincolnFollow
Qingsheng Li, University of Nebraska - LincolnFollow
Francisco A. Uzal, University of California, Davis
Jennifer L. Strande, Medical College of Wisconsin
Gustavo A. Delhon, University of Nebraska - LincolnFollow
Jean-Jack Riethoven, University of Nebraska - LincolnFollow
David J. Steffen, University of Nebraska - LincolnFollow
Jay Reddy, University of Nebraska-LincolnFollow

Document Type

Article

Date of this Version

2017

Citation

Immunity, Inflammation and Disease 2017; 5(4): pp. 421–434 doi: 10.1002/iid3.177

Comments

© 2017 The Authors. Immunity, Inflammation and Disease Published by John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution License.

Abstract

Introduction: Organ-specific autoimmune diseases are believed to result from immune responses generated against self-antigens specific to each organ. However, when such responses target antigens expressed promiscuously in multiple tissues, then the immune-mediated damage may be wide spread.

Methods: In this report, we describe a mitochondrial protein, branched chain α-ketoacid dehydrogenase kinase (BCKD_k) that can act as a target autoantigen in the development of autoimmune inflammatory reactions in both heart and liver.

Results: We demonstrate that BCKD_k protein contains at least nine immunodominant epitopes, three of which, BCKD_k 71–90, BCKD_k 111–130 and BCKD_k 141–160, were found to induce varying degrees of myocarditis in immunized mice. One of these, BCKD_k 111–130, could also induce hepatitis without affecting lungs, kidneys, skeletal muscles, and brain. In immunogenicity testing, all three peptides induced antigen-specific T cell responses, as verified by proliferation assay and/or major histocompatibility complex class II/IA^k dextramer staining. Finally, the disease-inducing abilities of BCKD_k peptides were correlated with the production of interferon-γ, and the activated T cells could transfer disease to naive recipients.

Conclusions: The disease induced by BCKD_k peptides could serve as a useful model to study the autoimmune events of inflammatory heart and liver diseases.