AUTOIMMUNITY

Evidence is growing that self-attacking ‘autoantibodies’ could be the key to understanding some of the worst cases of SARS-CoV-2 infection.   More than a year after COVID-19 emerged, many mysteries persist about the disease: why do some people get so much sicker than others? Why does lung damage sometimes continue to worsen well after the body seems to have cleared the SARS-CoV-2 virus? And what is behind the extended, multi-organ illness that lasts for months in people with ‘long COVID’? A growing number of studies suggest that some of these questions might be explained by the immune system mistakenly turning against the body — a phenomenon known as autoimmunity. “This is a rapidly evolving area, but all the evidence is converging,” says Aaron Ring, an immunologist at the Yale School of Medicine in New Haven, Connecticut.

 

Early in the pandemic, researchers suggested that some people have an overactive immune response to COVID infection. Immune-system signalling proteins called cytokines can ramp up to dangerous levels, leading to ‘cytokine storms’ and damage to the body’s own cells. Clinical trials have now shown that some drugs that broadly dampen immune activity seem to reduce death rates in critically ill people, if administered at the right time. But scientists studying COVID are increasingly also highlighting the role of autoantibodies: rogue antibodies that attack either elements of the body’s immune defences or specific proteins in organs such as the heart. In contrast to cytokine storms, which tend to cause systemic, short-duration problems, autoantibodies are thought to result in targeted, longer-term damage, says immunologist Akiko Iwasaki, a colleague of Ring’s at Yale.  Even healthy people make autoantibodies, but not generally in large amounts, and the molecules don’t usually seem to cause damage or attack the immune system. Yet researchers also have evidence that nefarious autoantibodies do have a role in many infectious diseases. There are several theories to explain how autoimmunity might emerge from COVID and other infections. Some people might be predisposed to producing autoantibodies that can then wreak havoc during an infection. Alternatively, infections could even trigger the production of autoantibodies. If researchers can establish the link, they might be able to come up with avenues for treatment, both for the repercussions of COVID and for other diseases caused by viruses.

Finding autoantibodies

In late September, a group led by Jean-Laurent Casanova at the Rockefeller University in New York City reported that more than 10% of 987 individuals with severe COVID-19 had antibodies that attacked and blocked the action of type 1 interferon molecules, which normally help to bolster the immune response against foreign pathogens1. That was a striking proportion, the researchers say, because people’s antibody repertoires are normally very dissimilar, and no one in a control group for the study had these antibodies. The researchers also saw the antibodies in people before their COVID-19 infection, so Casanova thinks that some people could be genetically predisposed to produce them. And the autoantibodies were more common in men than women — a possible factor in why COVID seems to hit men harder. The first evidence suggesting that autoantibodies against interferon might put people at higher risk of infectious disease was published in 1984, and evidence has accumulated since then, Casanova says. But now COVID is drawing more attention to the connection. “Now people understand the problem,” he says, “and all of a sudden they realize that what my lab has been doing for 25 years is actually pretty meaningful.” Casanova is now screening 40,000 people to see how many have pre-existing autoantibodies and determine whether their distribution by age, ancestry and gender matches that of severe COVID. Other research groups have supported Casanova’s autoantibody connection. Iwasaki, Ring and others screened 194 patients and hospital workers with varying severities of COVID for a wide range of autoantibodies. Their study, which was posted online in December and has not yet been peer reviewed, found a higher prevalence of autoantibodies against the immune system in infected individuals than in uninfected people. They found autoantibodies that attacked B cells, as well as some that attacked interferon.....

 

Published in Nature (Jan. 19, 2021):

https://doi.org/10.1038/d41586-021-00149-1

Via Juan Lama

Coate et al. examined expression of canonical SARS-CoV-2 entry proteins ACE2 and TMPRSS2
in the human pancreas and report ACE2 expression in the microvasculature, including
islet pericytes, whereas both ACE2 and TMPRSS2 are expressed in some ducts.

Coagulopathy in Critical Illness with Covid-19 The authors describe a 69-year-old man with Covid-19 diagnosed in January 2020 in Wuhan, China, along with two other critically ill patients with Covi...

To the Editor, Recently in the Journal of Thrombosis and Haemostasis, Harzallah and colleagues report the results of antiphospholipid antibody testing in a series of 56 patients with confirmed or suspected SARS‐CoV‐2 infection. 1 Twenty‐five patients were found to be positive for lupus anticoagulants, while five patients had either anticardiolipin or anti–β2‐glycoprotein 1 antibodies. The isotypes for the anticardiolipin and anti–β2‐glycoprotein 1 antibodies were reportedly IgG and IgM, although specific antibody titers and details of which were found in combination with a lupus anticoagulant in three overlap patients were not reported. The authors also reference published work by Zhang and colleagues, who reported three patients with SARS‐CoV‐2 infection, coagulopathy, thrombocytopenia, and the presence of anticardiolipin IgA and anti–β2‐glycoprotein 1 IgA and IgG antibodies who developed cerebral infarcts. 2 Harzallah and colleagues suggest the presence of these antibodies should be used as evidence for early anticoagulation of patients with COVID‐19. Antiphospholipid antibodies are common in the general population, especially during infection. 3 , 4 Whether the IgA isotype alone, noted by Zhang and colleagues, invokes thrombosis remains controversial, with only high titer IgG and IgM isotypes included as diagnostic criteria for the antiphospholipid syndrome. 5 Lack of IgG and/or IgM titers in these case series precludes any evaluation of their role in the thrombotic sequelae described. Thrombosis is common during critical illness and all patients in the Zhang series had preexisting cardiovascular disease, further increasing risk for arterial thrombosis. A key question remains whether COVID‐19 patients experience arterial thrombotic events at a higher rate compared to critically ill patients without SARS‐CoV‐2. The findings presented by Zhang and colleagues cannot confirm anticardiolipin antibodies as the causal agent for the arterial thrombosis observed in their series. False positive lupus anticoagulant testing might be expected in patients with COVID‐19 given the marked elevation in measured C‐reactive protein (CRP) levels seen in patients with significant pulmonary or systemic inflammation. Many assays to detect lupus anticoagulants are sensitive to the presence of CRP, resulting in false positive results, further limiting interpretation of this test in the acute inflammatory state. 6 COVID‐19 appears to induce a hypercoagulable state, with elevated fibrinogen, and minimal prolongation of prothrombin time and activated partial thromboplastin time, as seen in these patients. The exact mechanisms underlying the coagulopathy are unclear. 7 We urge clinicians who are evaluating coagulation parameters in patients with COVID‐19 to be cognizant of the pre‐analytic and analytic variables that affect the validity and interpretation of coagulation testing and to adhere to established anticoagulation protocols and guidelines until clinical studies demonstrating efficacy and safety of various anticoagulation strategies are published.