Research Article: ER intrabody-mediated inhibition of interferon α secretion by mouse macrophages and dendritic cells

Date Published: April 16, 2019

Publisher: Public Library of Science

Author(s): Konrad Büssow, Philipp Themann, Sabine Luu, Paul Pentrowski, Claudia Harting, Mira Majewski, Veith Vollmer, Mario Köster, Martina Grashoff, Rainer Zawatzky, Joop Van den Heuvel, Andrea Kröger, Thomas Böldicke, Rafael Aldabe.


Interferon α (IFNα) counteracts viral infections by activating various IFNα-stimulated genes (ISGs). These genes encode proteins that block viral transport into the host cell and inhibit viral replication, gene transcription and translation. Due to the existence of 14 different, highly homologous isoforms of mouse IFNα, an IFNα knockout mouse has not yet been established by genetic knockout strategies. An scFv intrabody for holding back IFNα isoforms in the endoplasmic reticulum (ER) and thus counteracting IFNα secretion is reported. The intrabody was constructed from the variable domains of the anti-mouse IFNα rat monoclonal antibody 4EA1 recognizing the 5 isoforms IFNα1, IFNα2, IFNα4, IFNα5, IFNα6.

Partial Text

Interferons (IFNs) are divided into three multigene families (type I, II and III). The type I interferon family comprises the highest number of members: IFNαs, IFNβ, IFNε, IFNƬ, IFNκ, IFNω, IFNδ and IFNξ respectively [1]. Type I IFNs play a major role in the immune response during acute viral and bacterial infections but also take part in induction of tumor cell death and inhibition of angiogenesis [2–4]. They play a pathogenic role in autoimmune diseases and in chronic infections [5, 6].

IFNα activates intracellular anti-viral and anti-bacterial programs and is involved in the development of innate and adaptive immune responses [4]. Furthermore, dysregulation of IFNα responses can contribute to autoimmune diseases and chronic viral infections [5, 6]. IFNαβ has well-documented antiviral effects, and indications for IFNα treatment are chronic viral hepatitis, haematological disorders and solid tumours. Independently of the form (IFNα can be given alone or conjugated to PEG) and administration route, side effects including acute toxicity have been reported [52]. The underlying mechanism of some side effects have been illuminated. For example, Davidson et al. showed that IFNα and β mediate increased mortality in influenza infected mice [53]. They demonstrated that excessive amounts of IFNα and β are secreted by plasmacytoid DCs of influenza infected mice, leading to interaction of the death-inducing receptor DR5 on lung epithelia cells with Trail on inflammatory monocytes, which results in lung tissue damage.