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ObjectivesType-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.MethodsWe 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.ResultsNeutralising 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.ConclusionThe 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.

unexplained weight loss and asthenia. His immunosuppressive regimen was associated with low-dose corticosteroid, tacrolimus, and mycophenolate mofetil. Complete blood count revealed a low platelet count of 110 × 10 9 /L and a hemoglobin level of 6 g/dl associated with an elevated mean corpuscular volume of 105 fl, but low reticulocyte counts of 36 × 10 9 /L. Thrombotic microangiopathy (TMA) was suspected because of increased lactate dehydrogenase levels (1250 IU/L) and undetectable haptoglobin associated with schistocytes (2%), suggestive of Intravascular hemolysis. F I G U R E 1 Light microscopy of peripheral blood smear in a patient with severe B12 deficiency. (A) Red blood cell fragments (red arrowhead) together with enlarged red blood cells with an oval shape (oval macrocytosis, black arrowhead) and (B) hypersegmented polymorphonuclear, suggestive of B12 deficiency This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.