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Adv."],"published-print":{"date-parts":[[2026,9,18]]},"abstract":"<jats:p>\n                    Human interferon-\u03b2 (IFN-\u03b2), a type I IFN, is critical for effective innate immunity and is also an approved disease-modifying therapeutic. While genetic variations in several components of the type I IFN system are associated with infectious and immune diseases, consequences of\n                    <jats:italic toggle=\"yes\">IFNB1<\/jats:italic>\n                    variation remain unexplored. Here, we functionally evaluated 70 naturally occurring rare protein-altering\n                    <jats:italic toggle=\"yes\">IFNB1<\/jats:italic>\n                    variants detected in humans globally. Twenty-five percent of all protein variants were found to be substantially less active than the common reference IFN-\u03b2, a phenotype that for many correlated with retention in the ER and poor secretion, or to compromised interaction with IFNAR1\/IFNAR2 cell surface receptors. Notably, three\n                    <jats:italic toggle=\"yes\">IFNB1<\/jats:italic>\n                    variants, including one found to be homozygous in a single individual, encode IFN-\u03b2 proteins with enhanced capacity to engage IFNAR1\/IFNAR2 and which exhibit greater signaling and antiviral potency than common IFN-\u03b2. Our mechanistic survey of natural human IFN-\u03b2 functional diversity provides a framework to explore both disease associations and the optimization of human IFN-\u03b2 in next-generation therapeutics.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.aeh4755","type":"journal-article","created":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T18:04:04Z","timestamp":1789754644000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["Functional diversity of natural human\n                    <i>IFNB1<\/i>\n                    variants in innate immunity"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9422-5646","authenticated-orcid":true,"given":"Samira","family":"Schiefer","sequence":"first","affiliation":[{"name":"Institute of Medical Virology, University of Zurich, 8057 Zurich, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4789-203X","authenticated-orcid":true,"given":"David","family":"Jones","sequence":"additional","affiliation":[{"name":"Institute of Medical Virology, University of Zurich, 8057 Zurich, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9540-7991","authenticated-orcid":true,"given":"Florence","family":"Kwaschik","sequence":"additional","affiliation":[{"name":"Institute of Medical Virology, University of Zurich, 8057 Zurich, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3891-9480","authenticated-orcid":true,"given":"Benjamin G.","family":"Hale","sequence":"additional","affiliation":[{"name":"Institute of Medical Virology, University of Zurich, 8057 Zurich, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2025.06.044"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2019.03.025"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41564-019-0421-x"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2007.05.019"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-021-00659-y"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2667"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.605673"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2020.07.005"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrd2422"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2015294"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10875-021-01068-6"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2020.106903"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)31042-4"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-2600(20)30511-7"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10875-021-01023-5"},{"key":"e_1_3_2_17_2","first-page":"205521732412386","article-title":"Safety and clinical effectiveness of peginterferon beta-1a for relapsing multiple sclerosis in a real-world setting: Final results from the Plegridy Observational Program","volume":"10","author":"Salvetti M.","year":"2024","unstructured":"M. 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