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New research offers evidence that autoimmunity—in which the body’s immune system targets its own tissues—is a driver in some cases of Long COVID.

Why COVID-19 sometimes leads to Long COVID still confounds doctors, but researchers have several hypotheses to explain its often-debilitating symptoms. These include lingering SARS-CoV-2 remnants, the reactivation of latent viruses such as the Epstein-Barr virus, infection-induced tissue damage, and autoimmunity.

In this new study, researchers transferred antibodies from patients with Long COVID into healthy mice, causing the animals to exhibit symptoms including heightened pain sensation and dizziness. The study is among the first to show a causal link between antibodies and Long COVID symptoms. It was posted as a preprint on medRxiv on June 19.

“We’re very excited to have a mechanism to study and learn more about so we can help people with specific reported symptoms,” says Akiko Iwasaki, PhD, Sterling Professor of Immunobiology and the study’s principal investigator at Yale School of Medicine.

Several factors prompted Iwasaki’s team to zero in on autoimmunity as one of Long COVID’s drivers. First, there was the persistent nature of the condition. “This suggested to us that there is some chronic triggering of an immune response that is pathogenic,” she says.

Second, women between the ages of 30 and 50 are among the most susceptible to Long COVID. Women in this age group also face a greater risk of autoimmune diseases in general. Finally, in earlier research, Iwasaki’s team detected significant levels of autoantibodies in individuals who were infected with SARS-CoV-2. “All of these things were pointing to the possibility of autoimmune responses being one of the triggers of Long COVID,” Iwasaki says.

Human antibodies induced Long COVID symptoms in mice

In their latest study, Iwasaki’s team analyzed blood samples from patients in the Mount Sinai-Yale Long COVID study. This cohort of over 215 Long COVID patients is part of a collaboration between Iwasaki and David Putrino, PhD, professor in the Department of Rehabilitation and Human Performance at Icahn School of Medicine at Mount Sinai in New York City. As part of this joint effort, Putrino’s clinic obtained blood samples from patients enrolled in the study. Iwasaki’s laboratory then purified antibodies from the blood and transferred them into healthy mice.

Next, researchers led by Keyla Sá conducted multiple behavioral experiments to look for Long COVID symptoms. While many experiments found no significant difference between experimental and control mice, some revealed striking changes in those that received antibodies.

In one experiment involving a heated plate test for pain sensitivity, some mice that received antibodies reacted significantly more quickly than controls. Researchers identified these patients' antibodies as belonging mostly to those reporting pain as one symptom.

Another experiment was the rotarod test for coordination and balance; mice receiving certain antibodies struggled more compared to controls—these antibodies came from patients reporting dizziness as a symptom.

A grip strength test showed reduced muscle strength among mice injected with antibodies from patients experiencing tinnitus or headache-related symptoms.

Treatments targeting autoimmunity may help some Long COVID patients

Developing diagnostic tools and therapies for Long COVID will require knowledge about its underlying disease mechanisms. The new study offers important evidence that autoimmunity contributes significantly here. Recently supporting this hypothesis is research led by Jeroen den Dunnen at Amsterdam University Medical Center showing similar links between patient-derived antibodies and corresponding mouse symptoms.

Intravenous immunoglobulin (IVIg) therapy used for various autoimmune disorders may also promise treatment efficacy against autoimmune-driven cases within long-COVID contexts according to another Yale-led 2024 investigation focusing specifically upon small fiber neuropathy-linked long-covid manifestations led primarily through Lindsey McAlpine alongside Serena Spudich suggesting potential symptomatic relief following said interventions—a sentiment echoed by co-investigator Iwasaki emphasizing clinical trials' necessity further elucidating therapeutic potentials across additional painful symptomologies exhibited therein while noting biologics development endeavors aimed toward enhancing recovery prospects FcRn inhibitors designed reduce circulating antibody levels achieved FDA approval concerning myasthenia gravis presenting hopeful analogs applying respective therapeutics applicable herein exploring expanded treatment avenues encompassing broad-ranging strategies potentially addressing varying subsets unique individual circumstances presenting targeted effective solutions possible treating implicated diverse underlying causes respectively necessitating differentiated approaches ensuring optimal outcomes realized per case-specific considerations pivotal maximizing successful interventions afforded evolving scientific insights guiding continued research efforts moving forward accordingly underscored throughout ongoing collaborative investigatory initiatives fostering cumulative knowledge growth benefiting collective medical community pursuits advancing understanding mitigating impacts consequentially improving affected patient populations' quality life comprehensively envisioned

Future studies focusing upon causative mechanisms alongside therapeutic innovations

Exploring further how/why involved contributing pathogenesis remains paramount imperative detailed investigations elucidate precisely molecular interactions underpinning observed phenomena comprehensive insights derived enable targeted treatments enhance efficacy pursuing wide-ranging drug classes spanning IVIg B-cell depletion plasmapheresis amongst others collectively representing multi-faceted approach adapting tailored solutions necessary diverse presentations encountered ultimately delivering personalized care effectively managing condition intricacies anticipated progressively unraveled through continued dedicated scholarly endeavors highlighting shared commitment advancing field holistically addressing public health challenges posed ameliorating associated burdens experienced worldwide aiming betterment humanity overall envisioned concerted sustained coordinated efforts promoting beneficial outcomes aligned overarching goals pursued ardently jointly collaboratively within broader scientific community context facilitating progress realization towards future envisioned positively transformed enhanced medical paradigms universally benefitting all humankind inclusively equitably aspiring achieve collectively###