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

Madhvi Menon (1) , Hannah Bradford (2) , Liis Haljasmagi (3) , Martti Vanker (3) , Pärt Peterson (3) , Chris Wincup (2) , Rym Abida (2) , Raquel Fernandez Gonzalez (2) , Vincent Bondet (4) , Darragh Duffy (4) , David A. Isenberg (2) , Kai Kisand (3) , Claudia Mauri (2)

1 University of Manchester [Manchester]
2 UCL - University College of London [London]
3 University of Tartu
4 Immunologie Translationnelle - Translational Immunology lab

Systemic lupus erythematosus (SLE) is characterized by increased expression of type I interferon (IFN)-regulated genes in 50%-75% of patients. We report that out of 501 patients with SLE analyzed, 73 (14%) present autoantibodies against IFNα (anti-IFN-Abs). The presence of neutralizing-anti-IFN-Abs in 4.2% of patients inversely correlates with low circulating IFNα 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 normalized 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 IFNα-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 controlling SLE pathogenesis and support the use of IFN-targeting therapies in patients with SLE lacking neutralizing-anti-IFN-Abs.

Keywords: B cells; SLE; autoimmunity

Domains: Immunology

Madhvi Menon, Hannah Bradford, Liis Haljasmagi, Martti Vanker, Pärt Peterson, et al.. Inactive disease in lupus patients is linked to autoantibodies to type-I interferons that normalize blood IFNα and B cell subsets. Cell Reports Medicine, 2023, 4 (1), pp.100894. ⟨10.1101/2021.04.07.21255049⟩. ⟨pasteur-03244412⟩