Human autoantibodies neutralizing type I IFNs: From 1981 to 2023

Abstract

Human autoantibodies (auto-Abs) neutralizing type I IFNs were first discovered in a woman with disseminated shingles and were described by Ion Gresser from 1981 to 1984. They have since been found in patients with diverse conditions and are even used as a diagnostic criterion in patients with autoimmune polyendocrinopathy syndrome type 1 (APS-1). However, their apparent lack of association with viral diseases, including shingles, led to wide acceptance of the conclusion that they had no pathological consequences. This perception began to change in 2020, when they were found to underlie about 15% of cases of critical COVID-19 pneumonia. They have since been shown to underlie other severe viral diseases, including 5%, 20%, and 40% of cases of critical influenza pneumonia, critical MERS pneumonia, and West Nile virus encephalitis, respectively. They also seem to be associated with shingles in various settings. These auto-Abs are present in all age groups of the general population, but their frequency increases with age to reach at least 5% in the elderly. We estimate that at least 100 million people worldwide carry auto-Abs neutralizing type I IFNs. Here, we briefly review the history of the study of these auto-Abs, focusing particularly on their known causes and consequences.

Keywords: COVID-19; aging; autoimmunity; type I interferons; viral infections.

Figure 1:. Causes and consequences of auto-Abs neutralizing type I IFNs. Thymic defects of epithelial cells (e.g. APS-1) or thymocytes (e.g. IPEX) can lead to the production of auto-Abs against type I IFNs by type I IFN-specific B cells and plasmocytes. These defects can be inherited (e.g. APS-1, IPEX) or acquired (e.g. thymoma). Upon viral infection, when type I IFNs are produced by infected cells in the tissues as well as by newly recruited plasmacytoid dendritic cells, their activity is blocked by neutralizing auto-Abs, leading to higher viral replication and severe disease.

Ab: antibody. TEC: thymic epithelial cells. IFNs: interferons. NFKB: Nuclear factor kappa-light-chain-enhancer of activated B cells. AIRE: Autoimmune regulator. NIK: NF-kappa-B-inducing kinase. RAG: Recombination-activating gene. FOXP3: forkhead box P3. IKAROS Family Zinc Finger 2. RELB Proto-Oncogene, NF-KB Subunit. IKBKG : inhibitor of nuclear factor kappa-B kinase subunit gamma. Created with BioRender.com.