New ETSU researcher Yang investigates immune system’s dangerous imbalance

Contributed/ETSU
Kun Yang

For many sepsis survivors, the battle doesn’t end when the infection is defeated. The immune system, after going into overdrive to fight a life-threatening infection, can swing too far in the opposite direction. Instead of returning to normal, it may remain suppressed for months or even years, leaving survivors vulnerable to secondary infections. The body’s own defense system, designed to protect against infection, can lose its balance long after the original threat is gone.

This dangerous imbalance lies at the heart of Kun Yang’s research at ETSU. Yang is launching his independent laboratory after receiving his first R01 grant from the National Institutes of Health earlier this year, a competitive award that placed his proposal in the top 1% of applications. His official start date was July 27, positioning him to explore how the immune system’s protective responses can overshoot or fail entirely. But sepsis is only part of the story Yang is investigating.

One discovery emerging from Yang’s research builds on recent findings: Lactate, a metabolic byproduct that can accumulate in septic patients, may alter how immune B cells behave, prompting them to produce gamma-aminobutyric acid, or GABA. While scientists have discovered that immune cells can produce the molecule, Yang’s team identified another potential connection.

“We identified that lactate can actually be a major regulator of B cell function,” Yang said.

If those B cells produce GABA, they may suppress other immune cells such as macrophages, monocytes and neutrophils, potentially contributing to the prolonged immune suppression experienced by sepsis survivors. This cascading immune dysfunction may help explain why survivors remain vulnerable to secondary infections months or even years later.

Yang’s path to understanding these failures began in cancer research. After earning a medical degree in China in 2013, Yang moved to the University of Cincinnati for his doctorate, where he studied how tumors manipulate surrounding tissue to fuel their own growth. During four years of postdoctoral training at ETSU, Yang’s focus shifted to investigating why sepsis leaves survivors vulnerable to secondary infections.

His research has since expanded to another major health challenge: cardiovascular disease.

Collagen is often associated with skin, wound healing and strong tissue. But in the heart, collagen can play a different role. When the heart is injured, the immune system activates fibroblasts, cells responsible for generating collagen and other structural proteins. In small amounts, this response is protective because collagen helps repair damaged tissue.

Under sustained inflammation, however, fibroblasts can continue producing and depositing collagen in heart tissue, creating scar tissue that stiffens the heart’s chambers. The body’s own repair mechanism can eventually become harmful, making it increasingly difficult for the heart to function normally.

Yang’s team is also investigating how abnormal immune responses contribute to cardiac damage and fibrosis. Their research suggests that communication among immune cells, blood vessels and fibroblasts may play an important role in determining how the heart responds to injury. By identifying the signals that drive excessive inflammation and scar formation, the team hopes to uncover mechanisms that could inform future therapeutic strategies to protect the heart and prevent progression to heart failure.

These two seemingly different problems — prolonged immune suppression after sepsis and excessive inflammation and scarring in the heart — share a common theme: an immune system that has lost its balance.

The urgency of Yang’s work resonates particularly in Appalachia. Heart disease mortality in Appalachian Tennessee is 21% higher than the national rate, and rural counties in the region have heart disease mortality rates 27% higher than large metropolitan counties.

Meanwhile, sepsis accounts for 15 out of every 100 rural hospitalizations and causes 50% of in-hospital deaths. Yang has already assembled his team with a first-year doctoral student and a third-year doctoral candidate who transferred from his postdoctoral laboratory.

As equipment arrives and the lab takes shape over the next four or five years, Yang and his growing team will work to map the mechanisms that tip the immune system from protective to destructive. The research could ultimately contribute to new approaches for helping sepsis survivors recover immune function and preventing harmful cardiac scarring.

Key terms

Lactate: A byproduct of glucose metabolism that can accumulate in the blood during intense exercise or severe illnesses such as sepsis. Elevated levels can be associated with inadequate tissue oxygenation or other metabolic stress.

GABA (gamma-aminobutyric acid): A neurotransmitter best known for reducing activity in the nervous system. Research has also shown that immune cells can produce GABA, which may play a role in regulating immune responses.

Sepsis: A life-threatening condition caused by the body’s extreme response to an infection, which can lead to tissue damage and organ dysfunction. Some sepsis survivors experience prolonged immune suppression.