Inactive disease in patients with lupus is linked to autoantibodies to type I interferons that normalize blood IFNa and B cell subsets

Systemic lupus erythematosus (SLE) is characterized by increased expression of type I interferon (IFN)-regu-lated genes in 50%-75% of patients. We report that out of 501 patients with SLE analyzed, 73 (14%) present autoantibodies against IFNa (anti-IFN-Abs). The presence of neutralizing-anti-IFN-Abs in 4.2% of patients inversely correlates with low circulating IFNa protein levels, inhibition of IFN-I downstream gene signatures, and inactive global disease score. Hallmarks of SLE pathogenesis, including increased immature, double -negative plasmablast B cell populations and reduction in regulatory B cell (Breg) frequencies, were normal-ized in patients with neutralizing anti-IFN-Abs compared with other patient groups. Immunoglobulin G (IgG) purified from sera of patients with SLE with neutralizing anti-IFN-Abs impedes CpGC-driven IFNa-dependent differentiation of B cells into immature B cells and plasmablasts, thus recapitulating the neutralizing effect of anti-IFN-Abs on B cell differentiation in vitro. Our findings highlight a role for neutralizing anti-IFN-Abs in con-trolling SLE pathogenesis and support the use of IFN-targeting therapies in patients with SLE lacking neutral-izing-anti-IFN-Abs.

Automated summary

Systemic lupus erythematosus (SLE) patients often exhibit increased expression of type I interferon (IFN)-regulated genes. In our study of 501 SLE patients, we found that 73 (14%) had autoantibodies against IFN-alpha (anti-IFN-Abs). The presence of neutralizing anti-IFN-Abs in 4.2% of patients correlated with low IFN-alpha protein levels, inhibition of IFN-I downstream gene signatures, and inactive disease score. These neutralizing anti-IFN-Abs were found to play a role in controlling SLE pathogenesis, specifically in regulating B cell populations.