Letter to the Editor: Autoantibodies to Type I Interferons: The Chicken or the Egg?

Dear Editor:

Manry et al (2022) recently published in The Proceedings of the National Academy of Sciences (PNAS) that type-1 interferon (IFN) autoantibodies (AABs) lead to a higher risk of death in patients with COVID-19. This is one among many articles from the group that support the idea of AABs neutralizing natural IFN responses and leading to more severe forms of COVID-19. The findings have been observed across multiple cohorts and thousands of patients. Before the COVID-19 pandemic these AABs were found to be almost nonexistent in available blood samples from general population.

The authors show that these AABs were only detected in patients with severe COVID-19 and were not seen in asymptomatic or paucisymptomatic patients. The group highlights that these AABs are pre-existing in severe COVID-19 patients and levels increase with age. While this contributes to death, other factors are also at play.

In a recent publication by authors of this letter, surprisingly high levels of AABs were found during major systemic inflammation, in this case, a ruptured abdominal aortic aneurysm (rAAA) (Hakovirta et al, 2022). The finding was discovered during a trial assessing if IFN beta could reduce multiorgan failure and mortality in this often fatal condition. The increased levels of AABs were seen at baseline after rAAA and subsequent to emergency surgery before IFN beta therapy, thus concluding that AABs were pre-existing and not therapy related.

Similar to what has been seen in COVID-19, AABs were associated with a doubling in mortality in comparison with patients without. Interestingly, in this study of rAAA patients with longitudinal samples, the levels of AABs decreased over time together with the attenuation of systemic inflammation, despite receiving IFN beta therapy. Unfortunately, the study in rAAA patients does not reveal, whether the patients had elevated AAB levels already before the rupture and were subsequent to aortic cross-clamping, or did the elevated levels appear after the onset of major systemic inflammation.

During COVID-19 it has been seen that an early IFN response is necessary to reduce the disease burden and keep it within mild symptoms. However, patients who have a delayed IFN response or are given type I IFNs as a therapy late in the disease had worst outcomes compared with patients who received early IFN beta (Kaili et al, 2021). Early IFN responses and the induction of IFN-stimulated genes, including CD73, are critical for survival. However, some of the pro-inflammatory properties of the same response are detrimental in the later stages of the disease. Based on the aforementioned findings, the origin of the AABs seems to be a chicken-and-egg scenario. Are AABs a reaction to viral infections, with naturally higher levels in elderly patients? Or are AABs our endogenous response, that is, the last attempt trying to control major systemic inflammation?

We concur with the conclusions of Manry et al, and align with their work on AABs and the deleterious effects they have in COVID-19. Moreover, we would like to emphasize the importance of studying AABs against type I IFNs over time and in additional systemic inflammatory conditions, not just COVID-19.