Neutralizing Autoantibodies Predict COVID-19 Disease Course and Severity

OCTOBER 8, 2020 BY PARKER DAVIS

Though the disease course of COVID-19 follows a relatively predetermined and predictable progression, any number of comorbidities that a patient possesses may serve to derail or modify the patient’s clinical trajectory. From hypertension, to diabetes, to various cardiac and cerebrovascular diseases, these underlying pathologies are some of the prime factors that denote a propensity for more severe COVID-19 (Wang et al., 2020; Guan et al., 2020). Even 9 months into the pandemic, light is being shed on a new condition that is placing individuals in the ICU at higher rates than those with COVID-19 alone. Jean-Laurent Casanova’s group out of Paris, in collaboration with others, has elucidated an underlying autoimmune condition that diminishes the body’s ability to produce interferons upon infection (Bastard et al., 2020). These patients were more likely to end up in the ICU, had longer ICU stays, and had more severe COVID-19. Bastard et al. summarize their findings from 987 patients hospitalized for “life-threatening” COVID-19 pneumonia, compared with 663 individuals who were SARS-CoV-2 positive but were asymptomatic or had mild disease, and 1,227 healthy control plasma samples collected prior to December 2019.

Interferons are molecules that play a critical role in the body’s immune response to many pathogens (but especially viruses) by alerting nearby cells to infection. Inhibition of interferon signaling “blinds” host cells to viral infiltration, and is one mechanism by which some viruses avoid immune recognition. Of the hospitalized patients in the Casanova study, 135 (roughly 13.7%) had auto-antibodies against at least one type I interferon. Additionally, in 101 of the 135 patients, these autoantibodies were neutralizing for the type I interferon – in other words, the autoantibodies  completely eliminated the functionality of the interferons. Of these 101 patients with neutralizing autoantibodies, 95 of them (94%) were males. For comparison, only 4 of the 1,227 healthy controls, and 0 of the 663 asymptomatic/mild COVID-19 patients, were found to have  autoantibodies. The patients who developed  autoantibodies against interferon-alpha-2 also developed  autoantibodies against all interferon-alpha subsets. The authors demonstrated in vitro that the neutralizing antibodies against interferon-alpha subsets expressed by critical patients significantly blocked the protective action of these interferons by allowing infection of Huh7.5 cells. In addition, all patients with autoantibodies against pan-interferon-alpha had low or undetectable plasma levels of all 13 interferon-alpha subsets. It is worthy to  reiterate here that  94% of the patients with critical COVID-19 and neutralizing autoantibodies against interferons were male! The authors note that this finding suggests an X-linked mutation is responsible for the development of the neutralizing antibodies in males , especially given the fact that in their healthy control cohort of 1,227, the prevalence of autoantibodies against type I interferons was a mere 0.33%.

This is a great paper with profound implications for COVID-19 severity and progression, and for how we may go about treating COVID-19  in the future. The authors state that their findings suggest the development of autoantibodies against type I interferons is a significant cause of severe COVID-19. If this is true, it may provide not only alternate therapeutic routes, but also some insight on the disparate sex differences that have characterized disease course and severity since the very first cases of COVID-19 . The work performed by this group will no doubt become a strong foothold on the ascent toward ultimate COVID-19 treatment and prevention, and because its implications and complexities are too immense to be adequately captured in a blog post, I encourage everybody to read this paper  for themselves and draw their own conclusions.