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

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...

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Published in:Cell reports. Medicine 2023-01, Vol.4 (1), p.100894, Article 100894
Main Authors: Bradford, Hannah F, Haljasmägi, Liis, Menon, Madhvi, McDonnell, Thomas C R, Särekannu, Karita, Vanker, Martti, Peterson, Pärt, Wincup, Chris, Abida, Rym, Gonzalez, Raquel Fernandez, Bondet, Vincent, Duffy, Darragh, Isenberg, David A, Kisand, Kai, Mauri, Claudia
Format: Article
Language:English
Subjects:
Autoantibodies
B-Lymphocyte Subsets - metabolism
Humans
Interferon Type I
Interferon-alpha - genetics
Interferon-alpha - therapeutic use
Lupus Erythematosus, Systemic - drug therapy
Lupus Erythematosus, Systemic - genetics
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Summary: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.
ISSN:2666-3791
2666-3791
DOI:10.1016/j.xcrm.2022.100894