Objectives Type-I interferons (IFNs-I) have potent antiviral effects. IFNs-I are also overproduced in patients with systemic lupus erythematosus (SLE). Autoantibodies (AAbs) neutralising IFN-α, IFN-β and/or IFN-ω subtypes are strong determinants of hypoxemic COVID-19 pneumonia, but their impact on inflammation remains unknown.
Methods We retrospectively analysed a monocentric longitudinal cohort of 609 patients with SLE. Serum AAbs against IFN-α were quantified by ELISA and functionally assessed by abolishment of Madin-Darby bovine kidney cell protection by IFN-α2 against vesicular stomatitis virus challenge. Serum-neutralising activity against IFN-α2, IFN-β and IFN-ω was also determined with a reporter luciferase activity assay. SARS-CoV-2 antibody responses were measured against wild-type spike antigen, while serum-neutralising activity was assessed against the SARS-CoV-2 historical strain and variants of concerns.
Results Neutralising and non-neutralising anti-IFN-α antibodies are present at a frequency of 3.3% and 8.4%, respectively, in individuals with SLE. AAbs neutralising IFN-α, unlike non-neutralising AAbs, are associated with reduced IFN-α serum levels and a reduced likelihood to develop active disease. However, they predispose patients to an increased risk of herpes zoster and severe COVID-19 pneumonia. Severe COVID-19 pneumonia in patients with SLE is mostly associated with combined neutralisation of different IFNs-I. Finally, anti-IFN-α AAbs do not interfere with COVID-19 vaccine humoral immunogenicity.
Conclusion The production of non-neutralising and neutralising anti-IFN-I antibodies in SLE is likely to be a consequence of SLE-associated high IFN-I serum levels, with a beneficial effect on disease activity, yet a greater viral risk. This finding reinforces the recommendations for vaccination against SARS-CoV-2 in SLE.
- lupus erythematosus, systemic
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Data are available upon reasonable request.
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AM, PB and KD are joint first authors.
ZA and GG are joint last authors.
Handling editor Josef S Smolen
AM, PB and KD contributed equally.
ZA and GG contributed equally.
Contributors AM, PBr, KD, PBa, SM-M, CM, RL, JLC, FR, ZA and GG contributed to the conception and design of the study; AM, PBr, KD, PBa, CC, RL, QM, AAM, SMM, CM, FA, JH, FCA, DS, NZ, AG, TLV, LB, QA, MP, MH, FC, MM, PGD, FR and ZA were involved in the acquisition of data; AM, PBr, KD, PBa, CC, RL, PQ, QM, AAM, SMM, CM, FA, DS, HY, PC, PGD, JLC, FR, ZA and GG contributed to the analysis and interpretation of data. All authors contributed to drafting and/or revising the manuscript. AM acts as guarantor for the overall content of the study.
Funding The study was supported by the Recherche Hospitalo-Universitaire RHU-COVIFERON project under the program 'Investissement d’Avenir' launched by the French Government and implemented by the Agence Nationale de la Recherche (ANR) with the reference ANR-21-RHUS-08 and by the EU Horizon 101057100 UNDINE project (JLC and GG). The Laboratory of Human Genetics of Infectious Diseases is supported by the Howard Hughes Medical Institute, the Rockefeller University, the St. Giles Foundation, the National Institutes of Health (NIH) (R01AI088364 and R01AI163029), the National Center for Advancing Translational Sciences (NCATS), the NIH Clinical and Translational Science Award (CTSA) program (UL1 TR001866), a Fast Grant from Emergent Ventures, Mercatus Center at George Mason University, the Yale Center for Mendelian Genomics and the GSP Coordinating Center funded by the National Human Genome Research Institute (NHGRI) (UM1HG006504 and U24HG008956), the Yale High-Performance Computing Center (S10OD018521), the Fisher Center for Alzheimer’s Research Foundation, the Meyer Foundation, the French National Research Agency (ANR) under the 'Investments for the Future' program (ANR-10-IAHU-01), the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID), the French Foundation for Medical Research (FRM) (EQU201903007798), the FRM and ANR GENCOVID project, the ANRS-COV05, ANR GENVIR (ANR-20-CE93-003) and ANR AABIFNCOV (ANR-20-CO11-0001) projects, the European Union’s Horizon 2020 research and innovation program under grant agreement on. 824110 (EASI-genomics), the Square Foundation, Grandir—Fonds de solidarité pour l’enfance, the Fondation du Souffle, the SCOR Corporate Foundation for Science, Institut National de la Santé et de la Recherche Médicale (INSERM), The French Ministry of Higher Education, Research, and Innovation (MESRI-COVID-19) and the University of Paris. PBa was supported by the French Foundation for Medical Research (FRM, EA20170638020) and by the MD-PhD program of the Imagine Institute (with the support of Fondation Bettencourt-Schueller). PBr was supported by the Regional Health care Agency of Île-de-France (bourse année recherche de l’Agence Régional de Sante) and the Villa M grant (with the support of Groupe Pasteur Mutualité Hospitalier).
Competing interests AM has received grant/research support from Sobi; participated in advisory board related to lupus for AstraZeneca; received payment for expert testimony for GSK; received support for attending meetings and/or travel from AstraZeneca and GSK; received consulting fees, speaking fees and honoraria from AstraZeneca and GSK. FC has received grant/research support from AstraZeneca; participated in advisory board related to lupus for AstraZeneca, GSK, Celgene and Principabio; received speaking fees and honoraria from AstraZeneca and GSK. ZA has received grant/research support from GSK, AstraZeneca, Roche, Novartis, Amgen; participated in advisory board related to lupus for GSK, AstraZeneca, Kezar, Amgen, Otsuka; received consulting fees, speaking fees and honoraria from AstraZeneca and GSK.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
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