The immune system stuck in overdrive, unable to return to rest
En los laboratorios de dos universidades madrileñas, investigadores han encontrado lo que la medicina llevaba años buscando: una huella biológica medible del COVID persistente. Dos marcadores —anticuerpos elevados en saliva y proteínas inmunitarias disminuidas en sangre— revelan un sistema inmune atrapado en un estado de activación crónica, incapaz de volver al reposo. Para los aproximadamente dos millones de españoles que viven con esta condición, el hallazgo representa algo más que un avance científico: es la posibilidad de que su sufrimiento quede, por fin, anclado en una realidad biológica objetiva.
- Dos millones de personas en España llevan años con síntomas incapacitantes —fatiga, niebla mental, dolor articular, arritmias— sin que ninguna prueba pudiera confirmar lo que sus cuerpos sentían.
- Investigadores de la Universidad Complutense y la Rey Juan Carlos han identificado un patrón inmunológico común: anticuerpos IgA elevados contra la nucleocápside del virus en saliva y niveles reducidos de C3, una proteína clave del sistema del complemento.
- El mecanismo descubierto sugiere que los anticuerpos desencadenan una activación excesiva y crónica del sistema inmune, convirtiendo la defensa del organismo en una fuente persistente de inflamación.
- Por primera vez, ambos marcadores se han vinculado como parte de una misma respuesta inmune desregulada, abriendo la puerta a un panel diagnóstico de sangre y saliva comparable al que existe para la diabetes o las enfermedades tiroideas.
- El estudio, publicado en Frontiers in Immunology y apoyado por la asociación de pacientes AMACOP, conecta la ciencia de laboratorio directamente con quienes han vivido durante años sin validación médica de su enfermedad.
En dos universidades de Madrid, un equipo de inmunólogos ha dado con algo que la medicina llevaba tiempo buscando: una señal biológica concreta del COVID persistente. Estudiando a 104 pacientes con síntomas prolongados frente a 34 personas que se habían recuperado sin secuelas, los investigadores de la Complutense y la Rey Juan Carlos encontraron un patrón claro. En los pacientes con COVID persistente, los niveles de anticuerpos IgA contra la proteína nucleocápside del coronavirus —un componente viral ausente en las vacunas administradas en España— estaban anormalmente elevados en saliva. Al mismo tiempo, presentaban niveles reducidos de C3, una pieza fundamental del sistema del complemento, esa cascada de proteínas que el cuerpo activa cuando detecta una amenaza.
Lo que hace relevante este hallazgo no es solo la identificación de cada marcador por separado —algo que investigaciones previas ya habían apuntado—, sino la conexión entre ambos. Los anticuerpos elevados parecen desencadenar una activación excesiva del complemento, que a su vez moviliza células inmunes en un ciclo inflamatorio que no se apaga. El resultado es la inflamación crónica que explica la fatiga, la niebla mental, el dolor y las alteraciones cardíacas que caracterizan la enfermedad. Según Narcisa Martínez, profesora de inmunología en la Complutense, la combinación de IgA y C3 podría convertirse en la base de un panel diagnóstico: una prueba de sangre y saliva que permitiría identificar y monitorizar la condición con la misma objetividad con que se mide el azúcar o la función tiroidea.
La magnitud del problema que este avance intenta abordar es considerable. Aproximadamente dos millones de personas en España viven con COVID persistente, una condición que afecta a múltiples sistemas —vascular, neurológico, inmunológico— y que ha documentado cerca de doscientos síntomas distintos. Se estima que al menos el diez por ciento de los adultos infectados por SARS-CoV-2 desarrollan alguna forma de secuela prolongada. Los factores de riesgo identificados incluyen mayor gravedad durante la infección aguda, sexo femenino, enfermedades previas e infección antes de la vacunación.
El estudio fue publicado en Frontiers in Immunology y contó con la colaboración de AMACOP, una asociación madrileña de pacientes con COVID persistente, que facilitó las muestras y tendió un puente entre el laboratorio y las personas que llevan años esperando que la ciencia les devuelva lo que la incredulidad médica les negó: un diagnóstico.
In laboratories at two Madrid universities, researchers have identified something that has eluded medicine for years: a measurable fingerprint of long COVID in the body. The discovery centers on two biological markers—elevated antibodies in saliva and depleted immune proteins in the blood—that together paint a picture of an immune system stuck in overdrive, unable to return to rest.
The work emerged from a collaboration between the Complutense University of Madrid and Rey Juan Carlos University, where immunologists studied 104 patients living with persistent COVID symptoms alongside 34 people who had recovered cleanly from infection. What they found was a pattern: in the long COVID patients, levels of IgA antibodies targeting the coronavirus's nucleocapsid protein were abnormally high in saliva. This protein was never included in the vaccines administered in Spain, suggesting the immune system was still mounting a response to a viral component it had never been trained to recognize. Simultaneously, these patients showed depleted levels of C3, a crucial component of the complement system—a cascade of roughly fifty proteins that activate in sequence when the body detects a threat.
The mechanism appears to work like this: the elevated antibodies against the nucleocapsid trigger excessive activation of the complement system, which then summons immune cells to attack. This cascade, meant to be temporary and targeted, becomes chronic and widespread. The result is persistent inflammation—the body's own defense mechanisms turned inward, creating the exhaustion, brain fog, joint pain, and cardiac irregularities that characterize long COVID.
What makes this research novel is the correlation itself. Previous work had identified these markers separately. This team linked them together, showing that the antibodies and the complement depletion are not independent phenomena but part of a single dysregulated immune response. According to Narcisa Martínez, an immunology professor at the Complutense's medical faculty, the two markers considered together—IgA antibodies and C3 levels—could form the basis of a diagnostic panel, a blood and saliva test that would finally give doctors a concrete way to identify and monitor the condition.
The scale of the problem is staggering. Approximately two million people in Spain are living with long COVID. The condition is classified as a post-viral syndrome, and its effects ripple across multiple systems: vascular, neurological, immunological. Around two hundred distinct symptoms have been documented, ranging from loss of smell and taste to orthostatic tachycardia syndrome, from cognitive impairment to incapacitating fatigue. Current estimates suggest that at least ten percent of adults infected with SARS-CoV-2 develop some form of persistent sequelae, with rates between one and four percent in children.
Why some people develop long COVID while others recover fully remains unclear, though risk factors have begun to emerge: greater severity during acute infection, female sex, pre-existing illness, and infection before vaccination all appear to increase vulnerability. Martínez emphasized that the underlying mechanisms are increasingly understood to involve immune dysregulation—the body's defense system losing its ability to distinguish between genuine threat and harmless viral remnants.
The research was conducted across multiple departments: immunology and biochemistry at the Complutense, immunology and microbiology at Rey Juan Carlos. The patient samples came through AMACOP, a long COVID patient association in Madrid, connecting laboratory science directly to the people living with the condition. The findings were published in Frontiers in Immunology, a peer-reviewed venue, lending credibility to what has long been dismissed or minimized.
For the millions of Spanish patients who have spent years without a diagnosis, without a test, without medical validation of their suffering, this represents a threshold moment. A biomarker panel would mean long COVID could be diagnosed like diabetes or thyroid disease—through objective measurement rather than symptom checklist. It would mean monitoring treatment efficacy, tracking disease progression, and finally anchoring the condition in biological reality rather than medical skepticism.
Notable Quotes
Both parameters considered together—IgA anti-nucleocapsid and C3—could contribute to a biomarker panel for diagnosis and monitoring of patients— Narcisa Martínez, immunology professor, Complutense University of Madrid
The causes of why some infected individuals develop the syndrome are not known with exactitude, though risk factors include greater severity during acute infection, female sex, pre-existing illness, and infection before vaccination— Narcisa Martínez
The Hearth Conversation Another angle on the story
Why does it matter that these antibodies are against the nucleocapsid specifically, rather than other viral proteins?
Because the nucleocapsid wasn't in the vaccines. So the immune system is still reacting to something it was never trained to recognize and neutralize. It's like the body never got the memo that the infection is over.
And the complement system—why does its depletion cause inflammation rather than preventing it?
Depletion means it's being consumed faster than the body can replenish it. The antibodies are triggering the complement to activate in overdrive, which recruits immune cells that then cause tissue damage. It's the activation itself, not the absence, that drives the inflammation.
So this is an autoimmune-like process?
Not quite autoimmune in the classical sense, but it shares the mechanism—the immune system attacking the body's own tissues. Except here it's triggered by persistent viral components or molecular mimicry, not a fundamental breakdown in self-tolerance.
If they can measure these markers, can they treat based on them?
That's the next question. Right now this is diagnostic. But if you can measure what's driving the inflammation, you have a target. You could theoretically dampen complement activation or reduce antibody production. The test itself doesn't cure anything, but it gives you something to aim at.
Why has this taken so long to find?
Long COVID was politically and medically contentious for years. Resources went elsewhere. And the condition is heterogeneous—not everyone has the same markers or the same symptoms. You need large, well-characterized patient cohorts to see the pattern. This team had access to that through the patient association.