18 September 2023

Auto-antibodies may lie behind the susceptibility of elderly patients to thrombosis triggered by COVID-19, according to a new study.

Research conducted at the University of São Paulo, Brazil, reveals that natural production of auto-antibodies increases with age, and that infection by SARS-CoV-2 can exacerbate production of auto-antibodies relating to auto-immune diseases.

This, write the researchers in NPJ Aging, partly explains why ageing increases the chances of developing severe COVID-19.

The researchers also discovered some of the factors that are associated with the severe form of the disease with blood clotting disorders such as thrombosis.

Researcher Dr Otávio Cabral-Marques, of the University of São Paulo’s Medical School (FM-USP), said: “These findings open the door to a better understanding of many pathological events associated with COVID-19, ranging from memory loss to sudden death from acute thrombosis.

“The hyperinflammation typical of severe COVID-19 and the increase in auto-antibodies produce blood clotting, resulting in the need to reconstruct tissue and recruit a coagulation cascade. Thrombosis and inflammation are closely correlated. Our study is one more confirmation of this important link.”

Dr Cabral-Marque said the rise in levels of auto-antibodies in severe COVID-19 cases could also be true of other pathologies.

“It’s not exclusive to SARS-CoV-2. Other pathogens also raise levels of auto-antibodies, so that they can serve as markers or therapeutic targets to save the lives of patients with almost terminal sepsis, for example,” he said.

For this study, the team analysed auto-antibodies present in 159 COVID-19 patients, of whom 71 had mild disease, 61 moderate, and 27 severe, and compared them to those from 72 healthy individuals.

When they use artificial intelligence (AI) to cross-reference the data, they found two main auto-antibodies that were exacerbated in patients with severe symptoms – those that are associated with blood clotting and thrombocytopenia.

High levels of these auto-antibodies can cause the body to harm itself by producing blood clots and netosis.

First author Dennyson Leandro M. Fonseca, a PhD student at the university, said: “When we divided the data into younger and older patients, we found that although this mechanism may occur in under-50s, it makes the elderly more susceptible to severe COVID-19. This explains why old age is one of the main risk factors for COVID-19.”

While a small increase in production of auto-antibodies is part of the natural ageing process, the team observed that infection by SARS-CoV-2 exacerbates levels of auto-antibodies in patients with severe disease.

Severe COVID-19 patients display a significant age-related increase in auto-antibodies against 16 targets, including amyloid β peptide, β catenin, cardiolipin, claudin, enteric nerve, fibulin, insulin receptor A, and platelet glycoprotein.

Dr Cabral-Marques said: “This discovery provides new avenues for validation of the action mechanism of auto-antibodies and broadens the pool of targets, providing a more comprehensive picture of the underlying pathophysiology of COVID-19 disease progression with the advance of aging and permitting more suitable interventions.”

The study authors say they are unsure if the severity of COVID-19 or the rise in levels of auto-antibodies comes first.

Fonseca said: “We analysed these two directions statistically and believe they’re both mutual and bidirectional. Auto-antibodies may interact, in conjunction with other immune system molecules, in a highly complex network that underlies immunopathological processes in severe COVID-19, or they may be boosted by health problems associated with aging and make the disease progress to a severe condition.”

He added that severe COVID-19 promotes an environment in the body involving tissue injury, cytokine storm and macrophage hyperactivation, all of which fosters the production of auto-antibodies.

This could allow auto-antibodies to act synergistically with multiple metabolites, cytokines, and chemokines, which are naturally dysregulated in elderly patients as part of immunosenescence, resulting in increased susceptibility to infections and auto-immune disorders, added Fonseca.



Fonseca DLM, Filgueiras IS, Marques AHC, Vojdani E, Halpert G, Ostrinski Y, Baiocchi GC, Plaça DR, Freire PP, Pour SZ, Moll G, Catar R, Lavi YB, Silverberg JI, Zimmerman J, Cabral-Miranda G, Carvalho RF, Khan TA, Heidecke H, Dalmolin RJS, Luchessi AD, Ochs HD, Schimke LF, Amital H, Riemekasten G, Zyskind I, Rosenberg AZ, Vojdani A, Shoenfeld Y, Cabral-Marques O.  (2023) “Severe COVID-19 patients exhibit elevated levels of autoantibodies targeting cardiolipin and platelet glycoprotein with age: a systems biology approach.” NPJ Aging, doi: 10.1038/s41514-023-00118-0.

Link: https://www.nature.com/articles/s41514-023-00118-0

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