Neutralizing type I IFN antibodies trigger an IFN-like response in endothelial cells.
Neutralizing Abs to type I IFNs are of therapeutic significance, i.e., are currently evaluated for the treatment of autoimmune diseases with pathogenic IFN-alpha production such as for systemic lupus erythematosus. Unexpectedly, we observed that several neutralizing Abs reportedly known to counteract IFN-alpha or IFN-beta activity triggered an "IFN-like" response in quiescent primary human endothelial cells leading to activation of the transcription factor IFN-stimulated gene factor 3 and the expression of IFN-responsive genes. Furthermore, these Abs were found to enhance rather than inhibit type I IFN signals, and the effect was also detectable for distinct other cell types such as PBMCs. The stimulatory capacity of anti-IFN-alpha/beta Abs was mediated by the constitutive autocrine production of "subthreshold" IFN levels, involved the type I IFNR and was dependent on the Fc Ab domain, as Fab or F(ab')(2) fragments potently inhibited IFN activity. We thus propose that a combined effect of IFN recognition by the Ab paratope and the concomitant engagement of the Fc domain may trigger an IFN signal via the respective type I IFNR, which accounts for the observed IFN-like response to the neutralizing Abs. With respect to clinical applications, the finding may be of importance for the design of recombinant Abs vs Fab or F(ab')(2) fragments to efficiently counteract IFN activity without undesirable activating effects.
Moll
Herwig Peter
HP
Department of Surgery Research Laboratories, Medical University of Vienna, Vienna General Hospital, Vienna, Austria.
Freudenthaler
Harald
H
Zommer
Anna
A
Buchberger
Elisabeth
E
Brostjan
Christine
C
D000906:Antibodies / Q000276:immunology* / Q000378:metabolism; D018929:Cell Culture Techniques; D042783:Endothelial Cells / Q000276:immunology* / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000276:immunology* / Q000378:metabolism; D007370:Interferon Type I / Q000276:immunology* / Q000378:metabolism*; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit / Q000378:metabolism; D053633:Receptor, Interferon alpha-beta / Q000276:immunology / Q000378:metabolism*
D000906:Antibodies; C507964:IFNAR1 protein, human; C494227:IRF9 protein, human; D007140:Immunoglobulin Fab Fragments; D007370:Interferon Type I; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D053633:Receptor, Interferon alpha-beta