Neutralizing Type I Interferon Antibodies trigger an Interferon-Like Response in Endothelial Cells1

Neutralizing antibodies to type I interferons are of therapeutic significance i.e. are currently evaluated for the treatment of autoimmune diseases with pathogenic IFN-α production such as for systemic lupus erythematosus. Unexpectedly, we observed that several neutralizing antibodies reportedly known to counteract IFN-α or -β activity triggered an “IFN-like” response in quiescent primary human endothelial cells leading to activation of the transcription factor ISGF3 and the expression of interferon-responsive genes. Furthermore, these antibodies were found to enhance rather than inhibit type I interferon signals, and the effect was also detectable for distinct other cell types such as PBMCs. The stimulatory capacity of anti-IFN-α/β antibodies was mediated by the constitutive autocrine production of sub-threshold IFN levels, involved the type I IFN receptor and was dependent on the Fc antibody domain, as Fab or F(ab’) 2 fragments potently inhibited IFN activity. We thus propose that a combined effect of IFN recognition by the antibody paratope and the concomitant engagement of the Fc domain may trigger an interferon signal via the respective type I IFN receptor which accounts for the observed “IFN-like” response to the neutralizing antibodies. With respect to clinical applications, the finding may be of importance for the design of recombinant antibodies versus Fab or F(ab’) 2 fragments to efficiently counteract IFN activity without undesirable activating effects.