TY - JOUR
T1 - Branched chain α-ketoacid dehydrogenase kinase 111-130, a T cell epitope that induces both autoimmune myocarditis and hepatitis in A/J mice
AU - Krishnan, Bharathi
AU - Massilamany, Chandirasegaran
AU - Basavalingappa, Rakesh H.
AU - Gangaplara, Arunakumar
AU - Kang, Guobin
AU - Li, Qingsheng
AU - Uzal, Francisco A.
AU - Strande, Jennifer L.
AU - Delhon, Gustavo A.
AU - Riethoven, Jean Jack
AU - Steffen, David
AU - Reddy, Jay
N1 - Publisher Copyright:
© 2017 The Authors.
PY - 2017/12
Y1 - 2017/12
N2 - 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 (BCKDk) that can act as a target autoantigen in the development of autoimmune inflammatory reactions in both heart and liver. Results: We demonstrate that BCKDk protein contains at least nine immunodominant epitopes, three of which, BCKDk 71-90, BCKDk 111-130 and BCKDk 141-160, were found to induce varying degrees of myocarditis in immunized mice. One of these, BCKDk 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/IAk dextramer staining. Finally, the disease-inducing abilities of BCKDk 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 BCKDk peptides could serve as a useful model to study the autoimmune events of inflammatory heart and liver diseases.
AB - 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 (BCKDk) that can act as a target autoantigen in the development of autoimmune inflammatory reactions in both heart and liver. Results: We demonstrate that BCKDk protein contains at least nine immunodominant epitopes, three of which, BCKDk 71-90, BCKDk 111-130 and BCKDk 141-160, were found to induce varying degrees of myocarditis in immunized mice. One of these, BCKDk 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/IAk dextramer staining. Finally, the disease-inducing abilities of BCKDk 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 BCKDk peptides could serve as a useful model to study the autoimmune events of inflammatory heart and liver diseases.
KW - Autoimmune hepatitis
KW - Autoimmune myocarditis
KW - Autoreactive T cells
KW - Branched chain α-ketoacid dehydrogenase kinase
KW - Mouse model
UR - http://www.scopus.com/inward/record.url?scp=85034635299&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85034635299&partnerID=8YFLogxK
U2 - 10.1002/iid3.177
DO - 10.1002/iid3.177
M3 - Article
C2 - 28597552
AN - SCOPUS:85034635299
SN - 2050-4527
VL - 5
SP - 421
EP - 434
JO - Immunity, inflammation and disease
JF - Immunity, inflammation and disease
IS - 4
ER -