Antibody-activated endothelial cells increase the risk of blood clots with Covid-19
Antibody-activated endothelial cells increase the risk of blood clots with Covid-19

Antibody-activated endothelial cells increase the risk of blood clots with Covid-19

The activity of antiphospholipid antibodies may help explain hypercoagulation associated with late stages of Covid-19 and long-term post-acute sequelae of SARS-CoV-2 infection (PASC), also known as long-distance Covid-19. One recently examination found that at least 45 individuals out of every thousand infected with Covid-19, regardless of age, gender, race, and prevalence of pre-existing conditions, experience severe cardiovascular consequences, including widespread blood clots. Forty-five out of a thousand may seem small, but given that an estimated 140 million Covid-19 cases nationwide, over six million people may be at risk. Shi et al., writes for Arthritis and Rheumatology, analyzed blood samples from nearly 250 people admitted for Covid-19 and found that Covid-19-induced blood clots can be triggered in part by “red” autoantibodies.

Unlike other antibodies, natural autoantibodies can be generated outside the immune system and bind to a variety of unrelated antigens. These antibodies by definition attack the body’s own cells. Exposure to SARS-CoV-2 virus appears to induce a strong antibody response, including an increased recruitment of autoantibodies that can attack uninfected cells and tissues.

Covid-19-induced thrombosis or blood clots are common among people hospitalized for serious infection, with estimates suggesting that nearly 60% of those who die from the virus are affected. New research reveals that SARS-CoV-2 activates endothelial cells lining blood vessels, making them vulnerable to coagulation. As Dr. Hui Shi, lead author and rheumatology research fellow at Michigan Medicine, explains, “When endothelial cells are activated, the healthy blood vessels become ‘sticky’, attracting other cells to the vessel walls and becoming more prone to thrombosis. This can affect many of the body’s essential organs. ”

How are endothelial cells activated in the first place? Shi et al. 2022 suggests that there may be an association between increased circulation of antiphospholipid autoantibodies and endothelial activation. In an earlier study, the team intriguingly found that exposing mice to autoantibodies from the blood of Covid-19 patients produced a “striking amount of coagulation.”

Their interest in autoantibodies as potential biomarkers for Covid-19 was further supported by evidence that antiphospholipid antibodies mediate a rare autoimmune disorder called antiphospholipid syndrome (APS). In this state, the body produces antibodies that target its own fat molecules – phospholipids – involved in the formation of blood clots. This study not only sheds light on how Covid-19 induces thrombosis, but may also explain the underlying mechanisms behind this life-threatening disease.

Shi et al. began their study by confirming that Covid-19 actually activates endothelial cells. Using blood samples from 118 individuals hospitalized with Covid-19, serum collected after blood cells revealed increased expression of cell adhesion molecules, E-selectin, VCAM-1 and ICAM-1. These surface proteins are upregulated during immune responses to facilitate the binding and activation of white blood cells on endothelial cells. However, overexpression of E-selectin, VCAm-1 and ICAM-1 surface proteins may mean that endothelial cells become overpowered and subsequently weakened by immune activity.

In fact, increased expression of these adhesion proteins was shown to correlate with worse Covid-19 results. For example, after receiving additional serum samples from 126 admitted Covid-19 patients, Shu et al. 2020 found that individuals in need of oxygen ventilation experienced greater upregulation of ICAM-1 compared to unventilated controls.

How much does Covid-19 contribute to these effects? Could endothelial activation simply be a symptom of any serious illness? To answer these questions, the researchers compared plasma samples from 100 people admitted to intensive care for sepsis infections with plasma from their Covid-19 cohort. Unlike serum, plasma is extracted after anti-coagulants have been added to blood samples. Although people with sepsis more often required mechanical ventilation, their ICAM-1 levels were significantly lower compared to plasma samples from people hospitalized for Covid-19. This suggests that increased expression of surface adhesion molecules, as well as the corresponding activation of endothelial cells, may be specific for SAR-CoV-2.

The team then asked how antiphospholipid antibodies can mediate these effects. Interestingly, they found a strong association between endothelial activation and the presence of autoantibody subtypes, anticardiolipin and anti-phosphatidylserine / prothrombin (anti-PS / PT), in immunoglobulin assays. In particular, significantly high levels of anticardiolipin and anti-PS / PT autoantibodies were detected in IgG assays from their Covid-19 cohort with increased expression of ICAM-1 compared to healthy controls and sepsis patients. Depletion of the IgG samples of anticardiolipin and anti-PS / PT also prevented the upregulation of E-selectin, VCAM-1 and ICAM-1 surface proteins

Although the researchers conclude that the presence of antiphospholipid antibodies in Covid-19 IgG samples can activate endothelial cells, the underlying mechanism remains unclear. Further studies are needed to determine if the presence of these autoantibodies may be a useful biomarker to identify the risks of an infected individual for severe Covid-19 compilations, such as thrombosis and respiratory failure.

How such large amounts of autoantibodies are created in the first place is also a mystery. A new theory suggests that the increased activity of autoantibodies may be associated with the immune response of circulating B cells during Covid-19. Naive B cells generated from bone marrow stem cells circulate the body looking for foreign pathogens, without first being “trained” by the follicles in the lymph nodes. When the body is exposed to SARS-Cov-2, it appears that naive B cells take an extrafollicular pathway, bypassing the lymphoids, to quickly be converted into antibodies. As seen in the autoimmune disease lupus, antibodies created outside lymphoid follicles do not benefit from counter-selection against those that can react against the body, also known as autoantibodies. As a recent examination reports, extrafollicular maturation of B cells may be a hallmark of Covid-19 infection. However, our understanding of this mechanism is limited.

Given the very high incidence of Covid-19-induced coagulation, as well as short- and long-term cardiovascular disease, it is increasingly important to understand the contribution of antiphospholipid autoantibodies. Several likely mechanisms appear to contribute to spectator damage to blood vessels exposed to SARS-CoV-2, including direct infection and excessive activation of the immune system via a “cytokine storm.” Autoantibodies are perhaps just one piece in a much larger puzzle.

Leave a Reply

Your email address will not be published.