In rare cases, myocarditis can occur, especially in young men, after an mRNA vaccination against Sars-CoV-2. A German medical team has now identified a cause for this. Accordingly, special autoantibodies are behind these vaccine-related myocarditis cases, which are formed against a central, anti-inflammatory molecule. Normally, this interleukin-1 receptor antagonist (IL-Ra) inhibits excessive inflammatory reactions through the messenger substance interleukin-1. In those affected, however, this receptor antagonist is slightly altered by attachment and therefore triggers the erroneous formation of antibodies against itself. This also occurs in severe cases of Covid-19 and the inflammatory syndrome MIS-C, which occurs in children.
Thanks to the vaccines against Sars-CoV-2, the corona pandemic has lost much of its horror. Because the vaccinations arm our immune system against the corona virus and thus prevent the most severe courses of Covid-19. However, in rare cases, side effects of the vaccination can occur. With the vector vaccines from AstraZeneca and Johnson & Johnson, the dangerous sinus vein thrombosis caused a stir at the beginning of 2021 and ultimately led to the fact that these vaccines are hardly used today. The side effects are less severe with the mRNA vaccines. In very rare cases, however, the vaccination can lead to heart muscle inflammation in about one to ten cases in 100,000, especially in young men. Unlike the much more common myocarditis after Covid-19 or other viral infections, this "vaccination myocarditis" is usually mild.
Anti-inflammatory autoantibodies
Lorenz Thurner from the Saarland University Hospital in Homburg and his colleagues have now found out something new about why this vaccination-related myocarditis occurs and what mechanism is behind it. For their study, they immunologically examined 40 patients between the ages of 14 and 79 with biopsy-confirmed myocarditis after a Sars-CoV-2 vaccination. They compared these data with those of 214 vaccinated healthy controls and 125 patients with myocarditis of other causes. The researchers were primarily looking for a special autoantibody that had previously been increasingly found in patients with a severe course of Covid-19 and in children with multisystem inflammatory syndrome (MIS-C). MIS-C, also known as PIMS - Pediatric Inflammatory Multisystem Syndrome - is a severe body-wide inflammation that can occur a few weeks after acute coronavirus infection.
The analyzes showed that the autoantibodies that frequently occur in these cases were also present in the blood of the vaccinees with myocarditis. In 75 percent of patients under the age of 21, the blood contained autoantibodies against a central endogenous anti-inflammatory called interleukin-1 receptor antagonist (IL-Ra). IL-Ra is a molecule that blocks the docking sites of the inflammatory messenger interleukin-1 on the surface of the cells and can thus stop excessive inflammatory immune reactions. "Especially with regard to inflammation of the pericardium, heart muscle and blood vessels, we already know how important interleukin-1 is," explains co-author Christoph Kessel from the University Hospital in Münster. "However, our immune system normally regulates itself and highly potent interleukins in particular have natural opponents." However, in at least some patients with vaccination-related myocarditis, the immune system apparently mistakenly fights these important opponents and thus promotes inflammation.
Atypical attachments on the molecule
Thurner and his colleagues have now been able to clarify one possible reason for this misdirected autoimmune reaction by examining the interleukin-1 receptor antagonist in these patients more closely: "Patients with myocarditis usually have an atypical form of IL-Ra with additional phosphorylation." , reports Thurner. In them, the molecule carries an additional phosphorus group at one point in its protein chain – something similar has already been demonstrated in children with MIS-C and adults with a severe course of Covid-19. This attachment to the IL-Ra molecule disrupts the recognition systems of the immune system: "The immune system then evaluates this as a foreign structure and mistakenly forms antibodies against it," explains Thurner. "These then neutralize the important anti-inflammatory agent and thus promote the effect of pro-inflammatory messenger substances."
The detection of the autoantibodies and the atypical IL-Ra molecules thus sheds a first light on the processes by which a vaccination can cause myocarditis in some people. However, it is still unclear why only some people temporarily develop attachments to their interleukin-1 receptor antagonists and thus irritate the immune system. This question now needs to be further explored. "In this context, however, it must be made clear that vaccinations against Sars-CoV-2 have prevented countless serious illnesses and saved many lives," emphasizes co-author Karin Klingel from the University Hospital in Tübingen. "We firmly believe that the benefit of mRNA vaccinations with the resulting protection against severe Sars-CoV-2 infections and serious complications far outweighs the risk of mild myocarditis."
Source: Lorenz Thurner (Saarland University Hospital, Homburg) et al., New England Journal of Medicine, doi: 10.1056/NEJMc2205667