Long COVID may involve more than lingering inflammation or viral persistence. A new study in Acta Neuropathologica reports evidence that antibodies circulating in some patients with persistent neurological symptoms can directly affect peripheral sensory neurons and produce short-lived pain-like responses when transferred into mice. The findings point toward an autoimmune component in at least a subset of people with post-acute sequelae of SARS-CoV-2 infection, particularly those experiencing hypersensitivity to touch, heat, or cold. At the same time, the experiments did not reproduce cognitive impairment, anxiety, depression, or fatigue in the animals, underscoring the biological complexity of long COVID and the likelihood that different symptoms arise through different mechanisms.
Long COVID, also known as post-acute sequelae of COVID-19 or PASC, affects people who continue to experience symptoms weeks or months after the initial infection. Estimates vary across studies, but neurological complaints are among the most frequently reported. Patients describe “brain fog,” difficulties with attention and memory, chronic fatigue, headaches, burning or prickling sensations, muscle and joint pain, and abnormal sensitivity to pressure or temperature. The causes remain uncertain. Proposed explanations include persistent viral material, abnormal immune activation, vascular dysfunction, reactivation of latent viruses, and damage to the nervous system. Autoimmunity—the mistaken targeting of the body’s own proteins by immune defenses—has become one of the leading hypotheses, although no single long-COVID autoantibody has yet been consistently identified.
To test whether antibodies might actively contribute to symptoms, researchers in Belgium recruited 13 adults with long COVID and neurological complaints and compared them with 10 age- and sex-matched individuals without persistent symptoms. The long-COVID participants had been infected with SARS-CoV-2 an average of roughly three years before enrollment. All reported pain, fatigue, and cognitive difficulties, while a substantial proportion met questionnaire-based criteria for neuropathic pain. The participants underwent detailed neuropsychological testing, including assessments of memory, attention, executive function, anxiety, depression, and pain. People with previous neurological or autoimmune disorders were excluded, reducing the possibility that the antibody findings were caused by an unrelated pre-existing disease.
The investigators isolated immunoglobulin G, or IgG, from the participants’ blood using protein G purification. IgG is the most abundant antibody class in human circulation and normally helps identify and neutralize pathogens. In autoimmune disease, however, some IgG molecules can bind to self-antigens and alter the behavior of cells, activate immune receptors, or promote tissue injury. The purified antibodies were injected into female C57BL/6J mice at a dose of 8 milligrams per day for four consecutive days. Each human antibody preparation was administered to a separate group of animals, allowing the researchers to compare the effects of antibodies from long-COVID patients with those from healthy controls. The mice were then monitored for two weeks using behavioral tests designed to measure pain sensitivity, memory, anxiety, depressive-like behavior, and general well-being.
The clearest effect appeared in tests of sensory sensitivity. Mice receiving IgG from long-COVID patients withdrew their paws more rapidly from a radiant heat stimulus in the Hargreaves test, indicating thermal hypersensitivity. They also responded to weaker mechanical stimulation in the Von Frey test, a standard assay for mechanical allodynia—the experience of normally harmless touch as painful. These changes were strongest during the first several days after antibody administration and faded during the following week. A facial-grimace assessment, used as an indirect measure of discomfort in laboratory mice, also showed a temporary increase in abnormal facial expressions on the first day. Not every pain assay produced the same result: the hot-plate test did not reveal a significant difference between the groups, illustrating how distinct experimental measures can capture different aspects of nociception.
Additional experiments strengthened the argument that the pain-like responses were caused by intact IgG rather than by another component of the blood preparation. When the researchers injected serum from which IgG had been removed, the hypersensitivity was largely abolished. The same occurred after the antibodies were treated with papain, an enzyme that cuts IgG molecules into antigen-binding Fab fragments and an Fc fragment. Although the digestion was incomplete, the treated material no longer produced the same behavioral effects as native purified IgG. The result suggests that the structural integrity of the antibody is important for the response, although it does not by itself reveal whether the critical activity depends on antigen binding, Fc-receptor signaling, or a combination of both.
Microscopic analysis provided a possible anatomical explanation. Human IgG from long-COVID patients accumulated in the lumbar dorsal root ganglia, clusters of sensory-neuron cell bodies located outside the spinal cord. These structures are unusually accessible to circulating molecules because they contain fenestrated blood vessels, which are more permeable than the vessels that normally protect the brain. In mice given patient-derived IgG, the human antibodies were detected directly on sensory neurons and overlapped with the neuronal marker NeuN. They did not substantially colocalize with satellite glial cells, the support cells that surround sensory neurons. The antibodies appeared to recognize several neuronal populations, including neurons marked by NF200 and, to a lesser extent, peripherin and calcitonin gene-related peptide. These markers broadly represent large myelinated fibers involved in mechanosensation and proprioception, as well as smaller fibers involved in pain and temperature detection.
The researchers also tested whether the antibodies could bind human nervous tissue. When purified IgG was applied to post-mortem human dorsal root ganglia, samples from long-COVID patients showed more punctate staining on sensory-neuron cell bodies than samples from healthy controls. Antibodies from both groups could bind satellite glial cells, but the neuron-associated pattern was more prominent in the long-COVID preparations. The punctate appearance may reflect antibodies attaching to clusters of membrane proteins, ion channels, or receptors, although the precise target remains unknown. A commercial microarray containing 120 neurological and brain-associated antigens failed to identify a common autoreactivity profile. The result does not rule out autoimmunity: conformational epitopes, which depend on a protein’s three-dimensional structure, can be destroyed or hidden when antigens are immobilized on an array. The study therefore leaves open the possibility that the relevant targets are unusual, intracellular, or structurally dependent proteins.
The absence of central nervous system effects was equally important. Human IgG was not detected in the brain parenchyma or spinal cord, apart from antibody staining in vascular or connective tissues such as the meninges and choroid plexus. Mice that received long-COVID IgG performed similarly to control animals in Barnes-maze and Y-maze tasks assessing spatial memory and working memory. They also showed no meaningful differences in elevated-plus-maze or light-dark-box tests of anxiety, or in the tail-suspension test used to measure depressive-like behavior. Locomotor activity and nest-building behavior were unchanged. Examination of the brain, spinal cord, and dorsal root ganglia found no clear increase in microglia or astrocytes, and gene-expression analyses detected no significant rise in the inflammatory markers Iba1 or Gfap. These observations suggest that the transferred antibodies produced a functional change in sensory signaling without triggering widespread neuroinflammation.
The findings do not establish that all long-COVID pain is autoimmune, nor do they show that antibodies cause brain fog or other cognitive symptoms in patients. The study involved only 13 affected participants, most of them women, and relied on a short-term, high-dose passive-transfer model in female mice. Human antibodies may recognize mouse proteins differently from human proteins, and human IgG does not necessarily interact with mouse immune receptors in the same way it does with human receptors. The researchers also measured behavior for only two weeks, whereas long COVID can persist for years. Nevertheless, the work offers a mechanistic bridge between patient blood samples and pain-related biology: IgG from a carefully selected neurological long-COVID cohort bound sensory neurons and temporarily induced hypersensitivity in animals, while antibody depletion or enzymatic disruption prevented the effect. Identifying the responsible antibody targets will be the next major challenge. Future studies using unbiased antibody profiling, cultured human sensory neurons, electrophysiology, and cell-based assays may determine whether these antibodies alter ion-channel activity, activate neuronal Fc receptors, or interfere with signaling pathways that regulate nociception. If confirmed in larger cohorts, the results could help define an immune-mediated subtype of long-COVID pain and guide treatments aimed at neutralizing or removing pathogenic antibodies.
Subject of Research: The potential role of IgG autoantibodies in neurological long COVID, particularly pain-related sensory dysfunction.
Article Title: Pathogenic IgG from long COVID patients with neurological sequelae triggers sensitive but not cognitive impairments upon transfer into mice
Article References: Mignolet M, Deroux C, Florkin T, et al. “Pathogenic IgG from long COVID patients with neurological sequelae triggers sensitive but not cognitive impairments upon transfer into mice.” Acta Neuropathologica 151, article 50 (2026).
Image Credits: AI Generated
DOI: 10.1007/s00401-026-03019-0
Keywords: Long COVID; SARS-CoV-2; post-acute sequelae of COVID; IgG antibodies; autoimmunity; neuropathic pain; mechanical allodynia; thermal hypersensitivity; dorsal root ganglia; sensory neurons; neuroimmunology; passive antibody transfer
Tags: animal models of long COVIDautoimmune responseimmune-mediated painLong COVIDlong COVID symptom variabilityneuroimmune interactionsneurological mechanism differentiationneurological symptomspersistent sensory neuropathypost-viral neurological sequelaeSARS-CoV-2 antibodiessensory neuron hypersensitivity
