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Currently, the mechanisms driving flares remain incompletely understood. Type I interferon (IFN) signalling is strongly implicated in SLE pathogenesis and promotes expansion of age-associated B cells in murine lupus, which are phenotypically similar to double negative 2 (DN2) B cells in humans. We investigated how IFN exposure influences B cell activation and differentiation in SLE, and whether type I IFN promotes DN2 differentiation in human na\u00efve B cells in vitro.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A cytometry by time of flight panel was developed to identify B cell subsets, markers associated with B cell activation and IFN-stimulated proteins (ISPs), with a composite ISP score used as a surrogate for IFN exposure. Peripheral blood mononuclear cells from 18 healthy controls (HCs), 25 quiescent patients and 41 recently flaring patients with SLE were analysed. HC na\u00efve B cells were stimulated under conditions that promote or inhibit DN2 differentiation with and without IFNs.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>All B cell subsets exhibited higher ISP levels in flaring than quiescent disease. DN2 cells were more abundant in flaring patients and correlated with the ISP score. ISP scores strongly correlated with markers associated with B cell activation even after controlling for disease status. In vitro, IFN\u03b1 and IFN\u03b2 promoted DN2 differentiation in HC B cells. In patients treated with the type I IFN receptor-blocking therapy anifrolumab, DN2 frequency and ISP scores significantly decreased.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Type I IFN promotes human B cell activation and DN2 differentiation, supporting IFN blockade as a strategy to reduce pathogenic B cells and prevent SLE flares.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/lupus-2026-002042","type":"journal-article","created":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T07:30:30Z","timestamp":1782718230000},"page":"e002042","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["Type I interferons enhance B cell activation and promote differentiation of double negative 2 cells in SLE"],"prefix":"10.1136","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-3045-7657","authenticated-orcid":false,"given":"Zoha","family":"Faheem","sequence":"first","affiliation":[{"name":"Schroeder Arthritis Institute, University Health Network, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giselle M","family":"Boukhaled","sequence":"additional","affiliation":[{"name":"Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-0054-4496","authenticated-orcid":false,"given":"Carol","family":"Nassar","sequence":"additional","affiliation":[{"name":"Schroeder Arthritis Institute, University Health Network, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kieran","family":"Manion","sequence":"additional","affiliation":[{"name":"Schroeder Arthritis Institute, University 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