Written by: Chumeng Wang
Edited by: Esther Melamed
Since the beginning of the COVID-19 pandemic, researchers and clinicians have sought to determine predispositions that may put individuals at higher risk for severe disease. As the virus spread and information became available about typical recovery times, more questions arose as some patients reported symptoms of Long COVID, or Post-acute sequelae of COVID-19 (PASC), in which symptoms like fatigue, headache, and smell/taste changes can persist for weeks-months after initial infection not only in those who had been hospitalized, but also in others who had only experienced mild symptoms.1 Interestingly, PASC symptoms may be better understood by exploring patterns in autoimmunity.
In a recent December review published in The Journal of Clinical Investigation by Jason S. Knight, et al, the intersection between COVID-19 and autoimmunity discussed during the 2021 Noel R. Rose COVID-19 and Autoimmunity Colloquium was further examined to better understand where the scientific community stands regarding autoimmune predispositions of severe infection and de novo, or new, autoimmune diseases emerging post-COVID.2
The first question explored by the researchers was whether autoimmunity could be a risk factor for patients experiencing severe symptoms of COVID-19. Type I interferons (IFNs) are major modulators of the innate immune system and induce other genes necessary for protection against acute viral infections.3 For some patients, COVID-19 infection does not induce full Type I IFN response, which leads to impaired response to disease and poor control of virus replication.4 In an international patient cohort, neutralizing autoantibodies against Type I IFNs were present in at least 10% of patients who experienced life-threatening COVID-19 pneumonia and may have been present prior to infection in some patients.5 Knight et al found these types of neutralizing antibodies also historically present in patients with systemic lupus erythematosus (SLE), autoimmune polyendocrinopathy syndrome type 1, and other autoimmune conditions. Therapies aimed at strengthening Type I IFN signaling in patients with genetic IFN deficiencies and neutralizing autoantibodies could be potentially crucial in early treatment of COVID-19.
Additionally, Knight et al explored the role of COVID-19 in development of de novo autoimmunity. The basis of this argument is rooted in molecular mimicry, a hypothesis that posits that immune responses against pathogens like COVID-19 can cross-react with human proteins sharing similar features and peptide structures with the virus, resulting in severe autoimmune pathologies and chronic conditions reminiscent of Long COVID.6 A potential pathway for de novo autoimmunity in COVID-19 may be through B cell activation through extrafollicular pathways, which lack checkpoints that typically prevent autoreactivity, resulting in double-negative (DN2) B cells. DN2 B cells are also found in SLE and patients with active lupus nephritis.7 Higher circulating DN2 B cells have been correlated with poorer COVID-19 outcomes, suggesting that COVID-19 may contribute to dysregulated humoral immunity.8 Computational modeling also shows that the SARS-CoV-2 spike protein contains a high-affinity motif resembling those of bacterial superantigens.9 These superantigens are unique in their ability to excessively activate immune cells, contributing to hyperinflammation and autoimmunity. These characteristics of COVID-19 may all contribute to de novo autoimmunity, and larger studies are needed to further explore the trends currently found in smaller cohorts and case studies.
Current data strongly suggest a connection between preexisting autoantibodies and COVID-19 severity. Some preliminary findings also make a compelling argument supporting the possibility of molecular mimicry and COVID-19 de novo autoimmunity. Studies at much larger scales will be needed to confirm the trends in data, and more time should be taken to monitor whether de novo antibodies produced during COVID-19 infection persist in patients who experience prolonged symptoms like those characteristic of chronic autoimmune conditions. Future findings will be crucial to both determining the best strategies to approach acute infection and managing long-term care of PASC patients.
References
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2. Knight, J. S., Caricchio, R., Casanova, J.-L., Combes, A. J., Diamond, B., Fox, S. E., Hanauer, D. A., James, J. A., Kanthi, Y., Ladd, V., Mehta, P., Ring, A. M., Sanz, I., Selmi, C., Tracy, R. P., Utz, P. J., Wagner, C. A., Wang, J. Y., & McCune, W. J. (2021). The intersection of covid-19 and autoimmunity. Journal of Clinical Investigation, 131(24). https://doi.org/10.1172/jci154886
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9. Cheng, M. H., Zhang, S., Porritt, R. A., Noval Rivas, M., Paschold, L., Willscher, E., Binder, M., Arditi, M., & Bahar, I. (2020). Superantigenic character of an insert unique to SARS-COV-2 spike supported by skewed TCR repertoire in patients with hyperinflammation. Proceedings of the National Academy of Sciences, 117(41), 25254–25262. https://doi.org/10.1073/pnas.2010722117
