Immunologists around the world have refocused their efforts to fight SARS-CoV-2. They work hard to try to answer the question of why, while some people fall seriously ill, others come out unscathed. It is a very complex issue, but we are already learning some clear guidelines.
One of the aspects that has received the most attention has been the production of antibodies (proteins capable of neutralizing and killing invading pathogens such as viruses). The identification in some patients of so-called “autoreactive antibodies”, which in the most severe cases of COVID-19 are directed against the patient’s own tissues instead of fighting against the microbes that cause the infection, has caused great concern.
At first, certain studies linked these autoantibodies to the dangerous blood clots that form in some patients with Covid-19 in intensive care. However, there are more recent studies that link them to a worsening of the disease. The reason is that, in a significant percentage of severe cases, these autoantibodies deactivate essential components of defenses against viruses.
As an immunologist at the Lowance Center for Human Immunology at Emory University, I have been investigating the immune response responsible for the production of antibodies in COVID-19 patients. In the past, our research group, led by Ignacio Sanz, has investigated the immune responses that contribute to the production of autoantibodies against autoimmune diseases, such as lupus.
More recently, we have focused on that same aspect in severe cases of Covid-19. However, and although we were able to classify the response of the organism of these patients as autoimmune, we could not confirm that, camouflaged among other types of responses to viruses, in this case there was also a production of autoantibodies.
But now we can confirm it.
In a recent study (although it is still awaiting a peer review) we have made an alarming discovery: in the most severe cases of COVID-19, the production of autoantibodies is common. This is a finding that could potentially have a huge impact, both in terms of applying the precise treatments and in terms of recovering from the infection.
Serious infections are linked to the production of autoantibodies
There are several types of autoantibodies, which generally target specific diseases. Lupus patients, for example, will typically develop antibodies that target their own DNA (the molecules that make up the human genome).
Patients with the autoimmune disease of rheumatoid arthritis are less likely to generate these types of antibodies , although they are more likely to test positive for rheumatoid factor (a variety of antibodies that face other antibodies).
In this study, our group analyzed the medical records of 52 COVID-19 patients who were receiving intensive care. None of them had a history of autoimmune disease. However, as long as the infection was still active in them, it was detected by tests that they had autoantibodies similar to those generated in a wide range of diseases.
The results were overwhelming. More than half of the 52 patients tested positive for autoantibodies. And of the patients with the highest blood level of C-reactive protein (a marker of inflammation), more than two-thirds had indicators consistent with the fact that their immune system was producing antibodies that attacked their own tissues.
Although this finding is concerning, there are aspects that our data does not reveal. Although there is no doubt that the most serious patients generate an immune response that involves autoantibodies, the data does not tell us to what extent these autoantibodies contribute to aggravating the most severe symptoms of COVID-19.
It could be that serious viral diseases had the normal effect of autoantibody production with little consequence. In this case, it would simply be the first time we have seen it. On the other hand, we also don’t know how long these autoantibodies last. Our data suggest that their presence remains relatively stable for a few weeks, but we need follow-up studies to find out if they usually remain after the infection is over.
As an important piece of information, it should be noted that, in our opinion, the self-reactive responses that we have identified in these cases are specific to the infection caused by SARS-CoV-2. Thus, there is no reason to believe that similar effects could occur when vaccinating against the virus.
Understanding the role of autoantibodies in covid-19
Now, although it is possible that these autoantibodies are benign, or that they may even help our body in some way yet to be determined, it is also possible that they are not. It is possible that these antibody responses that target the patient himself, in fact, exacerbate the disease. This would help to explain the late appearance of severe symptoms of the disease in some patients, since the appearance of these symptoms would coincide with the production of antibodies.
This could be the reason why treatments with dexamethasone (an immunosuppressant commonly used to alleviate the worsening caused by autoimmune diseases) seem effective only for the treatment of the most severe cases.
It is also possible that these immune responses are not short-lived, but rather survive the infection and contribute to the permanent symptoms experienced by more and more long-lasting COVID-19 sufferers.
Most worryingly, it is possible that these responses could be self-perpetuating in some patients, potentially leading to new and permanent autoimmune diseases.
Both my colleagues and I believe that this is not the case. On the contrary, we believe that the appearance of autoantibodies in these patients is a red herring, a singularity within the framework of the immune response generated by some patients that would end up resolving on its own. But we need more than an opinion, and for that we have to ask ourselves the right questions and be able to answer them. Fortunately, our study also gives us the tools to do so.
Autoreactive antibody tests should lead to better treatments
The tests that were carried out on these patients to determine their “self-reactive profile” were not specialized tests. You can find them in most hospitals in the United States. In fact, the two types of antibodies that we most frequently detect in these types of patients (antinuclear antibodies and rheumatoid factor) can be detected with the standard tests that rheumatologists do.
Our study shows that, by only doing tests focused on these two types of autoantibodies and the C-reactive inflammation marker protein, we could be able to diagnose with greater confidence those patients who are more prone to develop potentially dangerous immune responses. In this way, these patients could benefit from a more aggressive immune response modulation treatment.
What’s more, self-reactivity tests could help identify those patients who might benefit the most from rheumatological follow-up to monitor their recovery. And, in the same way, they would help us to understand to what extent some cases of long-term covid-19 patients could be related to the persistence of autoantibodies in them.
If this were the case, these patients could be given the same immune therapies that have already been applied successfully in cases of multisystemic inflammatory syndrome (MIS-C), a disease where the generation of autoantibodies is documented.
Finally, if we test patients for covid-19 immediately after their recovery, we could establish starting points and begin to track the possible appearance of new cases of autoimmunity that derive from this terrible disease (and, if necessary, initiate an early rheumatological intervention).
We already have the necessary tools. Now it is a matter of starting to use them.
Matthew Woodruff, Instructor, Lowance Center for Human Immunology, Emory University
This article was originally published on The Conversation. Read the original.
