A surprising suspect behind concussion trouble: Your own immune system

From football fields to military training grounds, head injuries are leaving lasting marks on the brain in ways we’re only beginning to understand. Repeated concussions can increase the risk of mood issues, memory loss and movement problems as well as long-term diseases like Chronic Traumatic Encephalopathy (CTE), which has affected many former NFL players, such as Aaron Hernandez, with tragic consequences. Scientists know these problems exist, but the exact biological reasons behind them are still being investigated.

A team led by Stephen Tomlinson, Ph.D., professor of Pharmacology and Immunology at MUSC, and Silvia Guglietta, Ph.D., associate professor of Regenerative Medicine and Cell Biology, has found that the immune system plays a central role. The team, including Khalil Mallah, Ph.D., the first author and assistant professor of Pharmacology and Immunology; Carsten Krieg, Ph.D., assistant professor of Pathology and Laboratory Medicine; expert in science technologies and Devin Hatchell, a South Carolina Clinical & Translational Research (SCTR) Institute TL1 trainee, published a study in Signal Transduction and Targeted Therapy, linking a part of the immune system, known as the complement system, to some of the most serious long-term effects of repeated concussions.

The complement system is a group of more than 50 proteins that help the body to fight infection. It does this by tagging harmful microbes and creating inflammation to remove them. While this process protects the body, too much inflammation can harm healthy tissue, especially in the brain. Scientists already knew that complement activation is involved in severe traumatic brain injury (TBI) and stroke, but its role in repeated mild concussions was unclear.

Microglia: Helpful cleaners that can sometimes go too far

Microglia are the brain’s built-in immune cells. When the brain is injured, they quickly respond by clearing out dead or damaged cells through a process called phagocytosis, often described as “cell eating.” This cleanup is important for healing.

However, if microglia become too active, they may start removing weakened but still living neurons and synapses. This “over-cleaning” can disrupt how brain cells communicate, which may cause long-term cognitive problems. The team wanted to know whether complement activation encourages this harmful over-cleaning after repeated concussions. To answer this question, the researchers developed a new murine model designed to mimic repeated concussions in humans, the first in-depth study of its kind. “One of the key findings wasn’t just the biology – it was actually the development of the model itself,” said Tomlinson.

“Most studies have focused on severe injuries. There were no studies specifically looking at the role of the complement system in these mild, repetitive injuries,” explained Guglietta. After creating the model, the team used an experimental complement inhibitor called CR2-Crry – a drug that blocks complement activation – to see whether it could protect the brain.

The results showed clear benefits. When complement activity was reduced, microglia became less aggressive. As a result, synapses and neurons were better preserved, and injured cells had a greater chance of recovery. Levels of inflammation in the brain also returned to normal, and the test subjects had reduced cognitive impairments. These findings suggest that complement-driven inflammation is a major cause of ongoing damage after repeated concussions.

Why these findings matter – and what comes next

Concerns about concussions continue to rise, especially in contact sports. Many athletes playing football, soccer and other high-impact sports are exposed to repeated hits that can have long- lasting consequences, including neurodegenerative diseases.

“The scary part is that contact sports are very popular and even start at younger ages,” said Mallah. Because complement proteins also play important roles in brain functions, understanding how concussions disrupt the normal brain activity is becoming a major public health priority.

Today, treatments for TBI focus mainly on managing symptoms. There are still no therapies that can stop or reverse the inflammation that follows a concussion, Guglietta said. However, complement inhibitors similar to the one used in this study are already being tested for other diseases, which could make it easier to repurpose them for concussion treatment in the future. “This approach shows real therapeutic promise,” Tomlinson said.

The current study focused on short-term outcomes. However, the research team continues to follow its test subjects for longer periods of time to watch for signs of long-lasting inflammation leading to neurodegeneration. As scientists learn more about how the brain responds to repeated injury, this study offers strong evidence that the immune system plays a key role. By identifying a pathway that drives lasting damage, the MUSC team has opened the door to new strategies that could one day help to protect athletes, service members and anyone at risk for repeated concussions.

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About the Medical University of South Carolina

Founded in 1824 in Charleston, MUSC is the state’s only comprehensive academic health system, with a mission to preserve and optimize human life in South Carolina through education, research and patient care. Each year, MUSC educates over 3,300 students in six colleges and trains more than 1,060 residents and fellows across its health system. MUSC leads the state in federal, National Institutes of Health and other research funding. For information on our academic programs, visit musc.edu.

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MUSC has a total enterprise annual operating budget of $8.2 billion. The nearly 34,000 MUSC members include world-class faculty, physicians, specialty providers, scientists, contract employees, affiliates and care team members who deliver groundbreaking education, research and patient care.