Autoantibodies targeting type I interferons: Prevalence, mechanisms of induction, and association with viral disease susceptibility

Abstract

AbstractThe type I IFN (IFN‐I) system is essential to limit severe viral disease in humans. Thus, IFN‐I deficiencies are associated with serious life‐threatening infections. Remarkably, some rare individuals with chronic autoimmune diseases develop neutralizing autoantibodies (autoAbs) against IFN‐Is thereby compromising their own innate antiviral defenses. Furthermore, the prevalence of anti‐IFN‐I autoAbs in apparently healthy individuals increases with age, such that ∼4% of those over 70 years old are affected. Here, I review the literature on factors that may predispose individuals to develop anti‐IFN‐I autoAbs, such as reduced self‐tolerance caused by defects in the genes AIRE, NFKB2, and FOXP3 (among others), or by generally impaired thymus function, including thymic involution in the elderly. In addition, I discuss the hypothesis that predisposed individuals develop anti‐IFN‐I autoAbs following “autoimmunization” with IFN‐Is generated during some acute viral infections, systemic inflammatory events, or chronic IFN‐I exposure. Finally, I highlight the enhanced susceptibility that individuals with anti‐IFN‐I autoAbs appear to have towards viral diseases such as severe COVID‐19, influenza, or herpes (e.g., varicella‐zoster virus, herpes simplex virus, cytomegalovirus), as well as adverse reactions to live‐attenuated vaccines. Understanding the mechanisms underlying development and consequences of anti‐IFN‐I autoAbs will be key to implementing effective prophylactic and therapeutic measures.