Six years after the first reports of long COVID emerged, scientists may have uncovered a key mechanism behind the mysterious condition: in a subset of patients, the immune system appears to launch an autoimmune attack against the brain and nervous system. A groundbreaking study published in Cell reveals that autoantibodies—immune proteins that mistakenly target the body’s own tissues—are present in long COVID patients and can reproduce hallmark symptoms when transferred to mice.

The findings, led by Yale immunobiologist Akiko Iwasaki and collaborators from Mount Sinai and other institutions, suggest that long COVID may overlap with autoimmune diseases, even though it doesn’t perfectly match any known condition. “This is one possible cause of long COVID, but it will likely have other trigger causes as well,” Iwasaki emphasized, noting that the study does not explain all cases of the syndrome.

For millions of people worldwide still suffering from long COVID, the discovery offers both hope and new questions. While no approved treatments exist yet, the research opens doors to repurposing therapies used for other autoimmune diseases, though the team stresses that much more investigation is needed.

Autoantibodies as the Missing Link in Long COVID

Since the COVID-19 pandemic began in 2020, long COVID has confounded researchers with its elusive origins. Symptoms like fatigue, brain fog, and chronic pain persist for months or years after acute infection, but the biological mechanisms have remained unclear. The new study, published in Cell, provides the strongest evidence yet that in a subset of patients, the immune system’s misfiring may be to blame.

Using tissue-based immunofluorescence, ELISA assays, and mass spectrometry, the Yale-led team analyzed blood samples from long COVID patients, healthy controls, and recovered individuals without lingering symptoms. They found that patients with neurocognitive symptoms—such as memory problems, dizziness, and headaches—had significantly higher levels of autoantibodies targeting central and peripheral nervous system proteins.

When researchers purified these autoantibodies and exposed them to human and mouse tissues, they observed strong reactions in critical brain regions, including the locus coeruleus (involved in attention and arousal), the thalamus (a relay station for sensory and motor signals), and the adrenal glands (which regulate stress responses). The antibodies also cross-reacted with mouse sciatic nerves and meninges, suggesting widespread nervous system involvement.

Keyla Santos Guedes de Sá, a postdoctoral associate in Iwasaki’s lab and lead author of the study, described the findings as “fascinating.” “We were able to find antibodies that, when transferred to mice, caused the same type of symptoms reported by long COVID patients—fatigue, impaired balance, and heightened pain sensitivity,” she said.

The team further screened the autoantibodies against over 21,000 human proteins, identifying targets linked to neurons, nerve communication, inflammation, and hormone signaling. Notably, antibodies from patients with long COVID showed enhanced antibody-dependent phagocytosis—a process where immune cells engulf and destroy targeted cells—when exposed to the protein MED20.

Mouse Study Reproduces Human Symptoms

To test the functional impact of these autoantibodies, the researchers transferred them into healthy mice. Within weeks, the mice developed:

• Increased pain sensitivity (thermal hyperalgesia)
• Fatigue-like behavior
• Loss of balance and coordination
• Damage to small nerve fibers
• Abnormal neuronal activation in brain regions controlling pain, memory, and emotional regulation

These symptoms closely mirror those reported by long COVID patients, providing compelling evidence that autoantibodies may drive at least some cases of the condition. The study also highlights the diversity of autoantibody targets, which may explain why long COVID symptoms vary so widely among patients.

Implications for Treatment and Research

The findings suggest that therapies targeting autoantibodies—such as intravenous immunoglobulin (IVIG), plasma exchange, or B-cell depletion—could be explored for long COVID. However, the researchers caution that these approaches would need to be carefully tested, as not all long COVID cases may involve autoimmunity.

Iwasaki noted that the study aligns with historical patterns observed after other pandemics. “Every major pandemic is accompanied by a long-version, chronic illness,” she said. “This happens when a human population is exposed to a new pathogen—or even an existing one like EBV [Epstein-Barr virus]. Many viral infections can trigger chronic diseases after the acute phase.”

The team plans to investigate how these autoantibodies cause damage at the neurological and immunological levels. “Now that we’ve identified a subgroup of patients whose condition might be driven by autoantibodies, we want to understand the mechanisms behind this process,” said de Sá.

Who Is Affected and What Happens Next?

While the study focuses on a subset of long COVID patients—particularly those with neurological symptoms—it raises important questions about the broader population. The World Health Organization estimates that up to 20% of COVID-19 survivors experience long COVID, though the exact prevalence varies by study and region.

For now, the research offers a potential path forward. If validated, it could lead to:

• Better diagnostic tools to identify autoimmune-driven long COVID cases.
• Clinical trials for existing autoimmune therapies.
• A deeper understanding of how viral infections can trigger chronic autoimmune-like conditions.

Expert Perspective: Why This Matters

As a physician and medical journalist, I’ve followed long COVID research closely since 2020. This study stands out because it provides a plausible biological mechanism for a condition that has largely remained a mystery. While more work is needed to confirm these findings and explore treatment options, the discovery is a critical step toward unraveling the complexity of long COVID.

“The fact that You can reproduce symptoms in mice using human autoantibodies is a game-changer,” said Iwasaki. “It gives us a tangible target to study and potentially treat.”

For patients still struggling with long COVID, the study offers a glimmer of hope. As Iwasaki emphasized, “We’re all driven by the desire to help people with long COVID. Right now, there is no approved treatment for these individuals, and they really need help.”