With the publication of a recent study, Jay Reddy continues to unravel the mysteries of the heart while driven by the memories of those dearest to his own.

As a teenager, and without warning, Reddy lost his mother to suspected heart failure. The tragedy would later inspire his decision to study heart maladies, especially those that can develop with few symptoms. Several decades and many discoveries later, a heart attack took his sister.

Now, Reddy and his colleagues have reported new findings that reveal more about the stealthy but potent ways that autoimmune responses can target the heart. The team’s study has pinpointed a segment of the mitochondria’s most abundant protein – a strand of 20 amino acids to which the immune system’s T-cells can bind – that appears to trigger inflammation in heart tissue.

Known as myocarditis, this inflammation can damage cells and disrupt the electrical impulses that maintain the steady tempo of a heartbeat. In some cases, it becomes chronic and can lead to dilated cardiomyopathy: an enlargement of heart chambers that weakens the muscle’s capacity to pump blood and introduces the risk of heart failure. About half of those patients, lacking other treatment options, must resort to a heart transplant.

Though T-cells typically recognize and attack only foreign invaders such as viruses, autoimmune diseases can occur when the body instead targets its own short and long chains of amino acids – better known as peptides and proteins. But the T-cells that help activate the damaging autoimmune responses can bind to only certain segments of those chains.

Reddy’s team decided to examine which segments of adenine nucleotide translocator 1, or ANT1, a protein crucial to mitochondrial functioning but implicated in the onset of myocarditis, might be subject to this unhealthy attachment in mice. Though the researchers identified four segments capable of alarming the T-cells that initiate inflammation, they found that one in particular – the 21st through 40th links in the chain – contributed to more severe myocarditis in a larger proportion of mice.

The 21-40 segment also thickened the wall of the heart’s left ventricle, suggesting that it could contribute to dilated cardiomyopathy. And when the researchers introduced the ANT1-associated T-cells to normal tissue, they discovered that it, too, began displaying hallmarks of inflammation.

“We saw T-cells specific to the heart, but we needed to demonstrate that these T-cells can in fact cause the disease,” said Reddy, professor of veterinary medicine and biomedical sciences. “After seeing that they can cause damage, this could be one mechanism through which the so-called enlarged hearts can develop.”

Because ANT1 features the same 21-40 sequence of amino acids in both mice and humans, Reddy said it could prove relevant to the diagnosis and eventual treatment of myocarditis – potentially reducing cases of dilated cardiomyopathy in the process. Clinicians have traditionally attempted to combat autoimmune responses by administering general immune suppressants, he said. While sometimes effective, they can also inflict collateral damage.

“The biggest challenge for clinicians and clinical scientists is that we don’t like to hit all of the cells,” Reddy said. “If the heart-reactive T-cells are only one of many (types) – say, one of 100 – we want to spare the other 99 cell (types) and affect only the bad guy.”

A newer, more targeted approach involves altering the composition of familiar amino acid chains to intercept and modify the behavior of T-cells that might otherwise drive autoimmune responses. Identifying which culprits are triggering the alarms – in this case, ANT1 21-40 – could inform and accelerate those efforts, Reddy said.

“In that way, we could target the (offending) T-cells while sparing the normal guys,” he said. “That’s the ultimate goal that we and other people are trying to reach.”

The team’s study appeared in The American Journal of Pathology. Reddy authored the paper with Rakesh Basavalingappa, graduate student in integrative biomedical sciences; Chandirasegaran Massilamany, research assistant professor of veterinary medicine and biomedical sciences; Bharathi Krishnan, graduate student in integrative biomedical sciences; Guobin Kang, research technologist with the Nebraska Center for Virology; Vahid Khalilzad-Sharghil and Zhongji Han, postdoctoral researchers in biological systems engineering; Shadi Othman, a former Nebraska researcher now at the University of the Pacific; Qingsheng Li, professor of biological sciences; Jean-Jack Riethoven, research assistant professor with the Center for Biotechnology; David Steffen, professor of veterinary medicine and biomedical sciences; and researchers from Stanford University and the National Institute of Allergy and Infectious Diseases.

The researchers received support from the National Institutes of Health via the National Heart, Lung and Blood Institute (grant HL114669) and National Institute of General Medical Science (grant P20GM104320). The latter funded the formation of the Nebraska Center for the Prevention of Obesity Diseases.

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