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

Bharathi Krishnan, Chandirasegaran Massilamany, Rakesh H. Basavalingappa, Arunakumar Gangaplara, Guobin Kang, Qingsheng Li, Francisco A. Uzal, Jennifer L. Strande, Gustavo A. Delhon, Jean-Jack M Riethoven, David J Steffen, N R Jayagopala Reddy

Research output: Contribution to journalArticle

2 Citations (Scopus)

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 (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.

Original languageEnglish (US)
Pages (from-to)421-434
Number of pages14
JournalImmunity Inflammation and Disease
Volume5
Issue number4
DOIs
StatePublished - Jan 1 2017

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3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)
Autoimmune Hepatitis
T-Lymphocyte Epitopes
Myocarditis
Phosphotransferases
Autoantigens
Peptides
T-Lymphocytes
Antigens
Immunodominant Epitopes
Mitochondrial Proteins
Major Histocompatibility Complex
Protein Kinases
Interferons
Hepatitis
Autoimmune Diseases
Liver Diseases
Heart Diseases
Skeletal Muscle
Staining and Labeling

Keywords

  • Autoimmune hepatitis
  • Autoimmune myocarditis
  • Autoreactive T cells
  • Branched chain α-ketoacid dehydrogenase kinase
  • Mouse model

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Branched chain α-ketoacid dehydrogenase kinase 111-130, a T cell epitope that induces both autoimmune myocarditis and hepatitis in A/J mice. / Krishnan, Bharathi; Massilamany, Chandirasegaran; Basavalingappa, Rakesh H.; Gangaplara, Arunakumar; Kang, Guobin; Li, Qingsheng; Uzal, Francisco A.; Strande, Jennifer L.; Delhon, Gustavo A.; Riethoven, Jean-Jack M; Steffen, David J; Reddy, N R Jayagopala.

In: Immunity Inflammation and Disease, Vol. 5, No. 4, 01.01.2017, p. 421-434.

Research output: Contribution to journalArticle

Krishnan, Bharathi ; Massilamany, Chandirasegaran ; Basavalingappa, Rakesh H. ; Gangaplara, Arunakumar ; Kang, Guobin ; Li, Qingsheng ; Uzal, Francisco A. ; Strande, Jennifer L. ; Delhon, Gustavo A. ; Riethoven, Jean-Jack M ; Steffen, David J ; Reddy, N R Jayagopala. / Branched chain α-ketoacid dehydrogenase kinase 111-130, a T cell epitope that induces both autoimmune myocarditis and hepatitis in A/J mice. In: Immunity Inflammation and Disease. 2017 ; Vol. 5, No. 4. pp. 421-434.
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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 M

AU - Steffen, David J

AU - Reddy, N R Jayagopala

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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.

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