Severity of post-COVID syndrome may be linked to antibodies involved in auto-immune diseases

A study conducted at the University of São Paulo provides knowledge for use in diagnosing and treating chronic fatigue syndrome, which affects 10%-20% of patients who recover from COVID-19.

By André Julião  |  Agência FAPESP – A study conducted at the University of São Paulo’s Biomedical Sciences Institute (ICB-USP) and reported in an article published in the journal Frontiers in Immunology casts light on the mechanisms involved in post-COVID syndrome, a condition that in some patients follows mild to moderate COVID-19 with persistent symptoms for more than six months. 

The researchers analyzed auto-antibodies (immune proteins that mistakenly target and react with a person’s own tissues or organs) from 80 patients who had had COVID-19 and 78 healthy subjects who were seronegative or asymptomatic.

“Auto-antibodies are part of normal human physiology and are dysregulated in auto-immune diseases. Recent studies have shown that they play a role in regulating several processes in both sick and healthy people,” said Otávio Cabral Marques, a researcher at ICB-USP and penultimate author of the article. The study was supported by FAPESP. 

Auto-antibodies are the organism’s first line of defense against infections and also contribute to immune system homeostasis, Marques explained. In some auto-immune disorders, they may be present before the first symptoms appear, serving as biomarkers and assisting diagnosis and treatment.

Data for the control group comprising seronegative or asymptomatic subjects was compared with data for patients with chronic fatigue syndrome (CFS), also known as myalgic encephalomyelitis, whose symptoms can include profound fatigue, sleep difficulties, memory loss and attention deficit. Since the start of the pandemic, CFS has been detected in 10%-20% of patients who recover from COVID-19.

In subjects with CFS, the researchers observed low prevalence of auto-antibodies directed against vasoregulatory and immunoregulatory receptors, besides others involved in the autonomic nervous system, which controls organ functioning.

“Auto-antibodies are necessary to regulate various functions of the organism. Levels shouldn’t be either too high or too low. In this study, low levels suggested vasoregulatory and immunoregulatory receptor failure, possibly due to loss of auto-antibody function,” said Igor Salerno Filgueiras, who conducted the bioinformatics analysis for the study as part of his master’s research at ICB-USP.

Detection and treatment

Using computational tools, the scientists found that low levels of certain auto-antibodies correlated with the presence and severity of CFS, permitting stratification of patients. The molecules with low levels targeted G protein-coupled receptors (GPCRs), which play an important role in cellular signaling and vital physiological systems.

Among the targets of low-level auto-antibodies in patients with post-COVID syndrome were ADRB2, ADRA2A and STAB1, which were especially useful to classify patients based on post-COVID prognosis and help predict whether patients had CFS.

ADRB2 is associated with cardiac function, while ADRA2A plays a role in the nervous system, activating receptors in blood vessels, heart and kidneys, among other functions. STAB1 is a scavenger receptor that removes cell debris and other remains of damaged tissue, helping maintain tissue balance and resolve inflammation.

Low levels of auto-antibodies targeting ADRB2 also correlated with symptom severity in patients with CFS. With fewer auto-antibodies, other molecules in the organism may be overabundant, impairing its overall functioning.

“These and other auto-antibodies could serve in future as indicators of CFS. Furthermore, certain drugs act as inhibitors of these molecules and could in future be tested as a form of treatment. Physical exercise is currently the only recommendation for mitigating CFS,” Marques said.

Age and COVID-19

In another study, posted to the preprint platform medRxiv and yet to be peer-reviewed, Marques and his group showed how levels of auto-antibodies correlated with age in severe COVID-19 patients. In this case, however, the reverse applied: the older the patient, the more severe the disease and the higher the levels of these molecules. 

Here, the researchers analyzed samples from 159 individuals with different COVID-19 outcomes (71 were mild cases, 61 moderate and 27 severe) as well as 73 healthy controls, and selected 58 molecules associated with auto-immune diseases. They concluded that natural production of auto-antibodies increases with age but is exacerbated by infection by SARS-CoV-2, especially in severe cases. Levels of these molecules served to stratify patients by age (more or less than 50 years old).

“Our analysis showed that the key auto-antibodies for stratifying severe cases are those that target cardiolipin, claudin and platelet glycoprotein, all of which perform important functions in the organism,” said Dennyson Leandro Mathias da Fonseca, first author of the article and a PhD candidate at ICB-USP with a scholarship from FAPESP.

The findings offer novel explanations for the fact that older patients generally display worse responses to COVID-19 than younger patients, reinforcing the role of auto-antibodies in severe cases.

In a previous article, the researchers also reported results showing a correlation between increased levels of auto-antibodies and severe COVID-19 (read more at: agencia.fapesp.br/36945). 

School closures

A third study by Marques and his group has been published recently, analyzing COVID-19 test data for teachers and pupils in public schools in Sergipe, a state in Northeast Brazil, recorded between November 2020 and January 2021. The findings are reported in an article in the journal Heliyon.

The number of asymptomatic cases rose sharply among both students and teachers, as well as other staff, when schools reopened. The test data refers to 2,259 individuals (1,139 students and 1,120 workers) at schools in 28 municipalities across the state. 

“The study was part of a task force set up in March 2020 to test different groups of essential workers. It was supported by the labor law prosecutors’ office (MPT) and the Sergipe state government. More than 180,000 tests were performed altogether,” said Lysandro Borges, first author of the Heliyon article. A physician and a professor at the Federal University of Sergipe (UFS), Borges is currently a postdoctoral fellow at ICB-USP.

Besides teachers and pupils, the study sample from which the test data was drawn also included quilombolas (descendants of runaway African slaves), prisoners and warders, law enforcement personnel, firefighters, and donations to blood banks, all of which will be analyzed in future studies.

The material was collected 30 days after schools reopened and before the start of COVID-19 vaccine rollout. Less than half the school students (408) and staff (431) tested positive for SARS-CoV-2, while 515 students (45%) and 415 staff (37%) tested negative.

However, only 16% of all subjects, including those reinfected, had symptoms and even these were mild, such as headache, sore throat and cough. 

“The results, albeit localized for only one state, show that many infections were asymptomatic during the school reopening period. They underscore the importance of coordinated public health measures to ensure schools are safe and the existing social inequalities don’t get worse,” Marques said.

Brazil kept schools closed for longer than many other countries during the pandemic. The educational harm this caused was worst of all for children belonging to poor families, in addition to the social, mental and economic losses suffered by all pupils and teachers.

The article “Dysregulated autoantibodies targeting vaso- and immunoregulatory receptors in post-COVID syndrome correlate with symptom severity” is at: www.frontiersin.org/articles/10.3389/fimmu.2022.981532/full. 

The article “SARS-CoV-2 infection induces the production of autoantibodies in severe COVID-19 patients in an age-dependent manner” is at: www.medrxiv.org/content/10.1101/2022.12.04.22282902v1. 

The article “Cross-sectional analysis of students and school workers reveals a high number of asymptomatic SARS-CoV-2 infections during school reopening in Brazilian cities” is at: www.cell.com/heliyon/fulltext/S2405-8440(22)02656-1.

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