Purpose Type I IFNs and their autoantibodies are implicated in the pathogenesis of Systemic lupus erythematosus (SLE), but their incidence and importance is still unclear. Neutralizing autoantibodies against IFNα have been previously reported in patients with autoimmune polyendocrinopathy syndrome type I (APS-1), rheumatoid arthritis, thymoma and more recently life-threatening COVID-19 patients. We hypothesized that autoantibodies towards type I IFNs, that develop in some patients with SLE, are neutralizing and may interfere with the course of the disease.

Methods Luciferase immunoprecipitation (LIPS) analysis was used to screen 474 SLE patient and 312 control serum samples for the presence of IFNα binding autoantibodies and determine their subclasses. Type I IFN neutralizing capacity was tested using a reporter cell line. Circulating levels of IFNα were measured with Single Molecule Array (Simoa).

Results 14% of SLE patients were positive for anti-IFNα and 13% were positive for anti-IFNω. The autoantibodies against IFNα were predominantly of IgG1 subclass and neutralized IFNα bioactivity in approximately one half of the positive cases. Once developed, anti-IFNα autoantibodies were present throughout the disease course. IFNα2 and -α8 were targeted first in two informative follow-up cases. The reactivity broadened to other IFNα subtypes and IFNω within several months. Serum levels of IFNα correlated negatively with anti-IFNα neutralizing titers. Patients with high levels of autoantibodies against IFNα had significantly lower levels of circulating IFNα compared to anti-IFNα negative patients. Interestingly, patients with high IFNα neutralizing capacity displayed significantly lower disease activity than patients without these autoantibodies.

Conclusions Based on our results we suggest that autoantibodies that are able to neutralize the circulating levels of all IFNα subtypes may have a beneficial effect to SLE disease course.