Autoantibodies Neutralizing Type III Interferons Are Uncommon in Patients with Severe Coronavirus Disease 2019 Pneumonia
Martti Vanker, Karita Särekannu, Arnaud Fekkar, Sofie E. Jørgensen, Liis Haljasmägi, Anne Kallaste, Kalle Kisand, Kalle Kisand, Margus Lember, Pärt Peterson, Madhvi Menon, Tracy Hussell, Sean Knight, James Oscar Moore-Stanley, CIRCO, COVID Human Genetic Effort, Paul Bastard, Shen‐Ying Zhang, Trine H. Mogensen, Quentin Philippot, Qian Zhang, Anne Puel, Jean-Laurent Casanova, Kai Kisand, Kai Kisand
Abstract
Autoantibodies (AABs) neutralizing type I interferons (IFN) underlie about 15% of cases of critical coronavirus disease 2019 (COVID-19) pneumonia. The impact of autoimmunity toward type III IFNs remains unexplored. We included samples from 1,002 patients with COVID-19 (50% with severe disease) and 1,489 SARS-CoV-2-naive individuals. We studied the prevalence and neutralizing capacity of AABs toward IFNλ and IFNα. Luciferase-based immunoprecipitation method was applied using pooled IFNα (subtypes 1, 2, 8, and 21) or pooled IFNλ1–IFNλ3 as antigens, followed by reporter cell-based neutralization assay. In the SARS-CoV-2-naive cohort, IFNλ AABs were more common (8.5%) than those targeting IFNα2 (2.9%) and were related with older age. In the COVID-19 cohort the presence of autoreactivity to IFNλ did not associate with severe disease [odds ratio (OR) 0.84; 95% confidence interval (CI) 0.40–1.73], unlike to IFNα (OR 4.88; 95% CI 2.40–11.06; P < 0.001). Most IFNλ AAB-positive COVID-19 samples (67%) did not neutralize any of the 3 IFNλ subtypes. Pan-IFNλ neutralization occurred in 5 patients (0.50%), who all suffered from severe COVID-19 pneumonia, and 4 of them neutralized IFNα2 in addition to IFNλ. Overall, AABs to type III IFNs are rarely neutralizing, and do not seem to predispose to severe COVID-19 pneumonia on their own.