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.

The ability to extract somatic cells from a patient and reprogram them to pluripotency opens up new possibilities for personalized medicine. Induced pluripotent stem cells (iPSCs) have been employed to generate beating cardiomyocytes from a patient's skin or blood cells. Here, iPSC methods were used to generate cardiomyocytes starting from the urine of a patient with Duchenne muscular dystrophy (DMD). Urine was chosen as a starting material because it contains adult stem cells called urine-derived stem cells (USCs). USCs express the canonical reprogramming factors c-myc and klf4, and possess high telomerase activity. Pluripotency of urine-derived iPSC clones was confirmed by immunocytochemistry, RT-PCR and teratoma formation. Urine-derived iPSC clones generated from healthy volunteers and a DMD patient were differentiated into beating cardiomyocytes using a series of small molecules in monolayer culture. Results indicate that cardiomyocytes retain the DMD patient's dystrophin mutation. Physiological assays suggest that dystrophin-deficient cardiomyocytes possess phenotypic differences from normal cardiomyocytes. These results demonstrate the feasibility of generating cardiomyocytes from a urine sample and that urine-derived cardiomyocytes retain characteristic features that might be further exploited for mechanistic studies and drug discovery.