Longitudinal Analysis Over Decades Reveals the Development and Immune Implications of Type I Interferon Autoantibodies in an Aging Population

Pre-existing autoantibodies (autoAbs) neutralizing type I interferons (IFN-Is: IFNα, IFNβ, IFNω) have recently been described as significant contributors to the severity of viral infectious diseases. Here, we explore the development and consequences of anti-IFN-I autoAbs at high-resolution using retrospective samples and data from 1876 well-treated individuals >65 years of age enrolled in the Swiss HIV Cohort Study, a nationwide, longitudinal cohort with up to 35 years of follow-up. Approximately 1.9% of individuals developed anti-IFN-I autoAbs, with a median onset age of ∼63 years (range 45-80). Once developed, anti-IFN-I autoAbs persisted for life, and generally increased in titer over years. Most individuals developed distinct neutralizing and non-neutralizing anti-IFN-I autoAb repertoires at discrete times that selectively targeted various combinations of IFNα, IFNβ, and IFNω. Longitudinal analyses further revealed that emergence of neutralizing anti-IFNα autoAbs correlated with reduced IFN-stimulated gene (ISG) levels, indicating impairment of innate immunity. Patient data review suggested that prior recorded viral infections and autoimmune history influence the likelihood of mounting anti-IFN-I autoAbs. Indeed, systematic measurements in biobanked samples revealed significant enrichment of pre-existing autoreactivity against clinically relevant autoantigens in individuals who later developed anti-IFN-I autoAbs. In this context, we describe lifelong neutralizing anti-IFNα autoAbs (and impaired innate immunity), that manifested in an individual following IFNα therapy, and who was retrospectively found to have had pre-existing autoreactivity to β2-glycoprotein-I before IFNα treatment. Our decades-spanning longitudinal analyses illuminate the development and immune implications of anti-IFN-I autoAbs in an aging population, and support a ‘two-hit’ hypothesis whereby loss of self-tolerance prior to immune-triggering with endogenous or exogenous IFN-I may pose a risk for developing late-onset, lifelong IFN-I functional deficiency. ### Competing Interest Statement IAA received the Swiss Fellowship Gilead research grant and participated in advisory boards from Astra Zeneca and Moderna. EB received travel grants and payments for participation in advisory boards from Gilead Sciences, MSD, ViiV Healthcare, Pfizer, Abbvie, Astra Zeneca, Moderna and Ely Lilly. AR received support for advisory boards and/or travel grants from MSD, Gilead Sciences, Pfizer and Moderna. HFG received unrestricted research grants from Gilead Sciences; fees for data and safety monitoring board membership from Merck; consulting/advisory board membership fees from Gilead Sciences, Merck, Johnson and Johnson, Janssen, GSK, Novartis and ViiV Healthcare; and grants from the Swiss National Science Foundation, the Bill and Melinda Gates Foundation, the Yvonne Jacob Foundation, Gilead Sciences, ViiV Healthcare and the National Institutes of Health. All the reported grants and remuneration were provided outside the context of this work. All other authors did not report any disclosures. ### Funding Statement Financial support for this study was provided by the Swiss National Science Foundation (SNF; grants 31003A\_182464 and 310030\_214957 to BGH), the Novartis Foundation for Medical-Biological Research (grant 23A069 to BGH), and the Promedica Foundation (to IAA). The study was also co-financed within the framework of the Swiss HIV Cohort Study (SHCS), supported by the SNF (33CS30_201369 to HFG), by the small nested SHCS project 898 (to BGH and IAA). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study has been approved by the ethics committees of all participating SHCS institutions (Kantonale Ethikkommission Bern, Ethikkommission des Kantons St. Gallen, Comite Departemental d'Ethique des Specialites Medicales et de Medicine Communataire et de Premier Recours, Kantonale Ethikkommission Zurich, Repubblica et Cantone Ticino-Comitato Ethico Cantonale, Commission Cantonale d'Etique de la Recherche sur l'Etre Humain, Ethikkommission beider Basel), and written informed consent has been obtained from all participants. The personnel who conducted the work with patient samples had no information on patient demographics at the time of analysis, and all data have subsequently been analyzed anonymously. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present work are contained in the manuscript