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We focused on IgA, which is the second-most prevalent isotype in serum and, along with IgG, is deposited in glomeruli in individuals with lupus nephritis. We show that individuals with SLE have serum IgA autoantibodies against most nuclear antigens, correlating with IgG against the same antigen. We investigated whether IgA autoantibodies against a major SLE autoantigen, Smith ribonucleoprotein (Sm\/RNP), played a role in IC activation of pDCs. We found that pDCs expressed the IgA-specific Fc receptor, Fc\u03b1R, and IgA1 autoantibodies synergized with IgG in RNA-containing ICs to generate robust primary blood pDC IFN-\u03b1 responses in vitro. pDC responses to these ICs required both Fc\u03b1R and Fc\u03b3RIIa, showing synergy between these Fc receptors. Sm\/RNP IC binding to and internalization by pDCs were greater when ICs contained both IgA1 and IgG. Circulating pDCs from individuals with SLE had higher binding of IgA1-containing ICs and higher expression of Fc\u03b1R than pDCs from healthy control individuals. Although pDC Fc\u03b1R expression correlated with the blood IFN-stimulated gene signature in SLE, Toll-like receptor 7 agonists, but not IFN-\u03b1, up-regulated pDC Fc\u03b1R expression in vitro. Together, we show a mechanism by which IgA1 autoantibodies contribute to SLE pathogenesis.<\/jats:p>","DOI":"10.1126\/scitranslmed.adl3848","type":"journal-article","created":{"date-parts":[[2024,7,3]],"date-time":"2024-07-03T13:59:54Z","timestamp":1720015194000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":19,"title":["Lupus IgA1 autoantibodies synergize with IgG to enhance plasmacytoid dendritic cell responses to RNA-containing immune complexes"],"prefix":"10.1126","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2260-9813","authenticated-orcid":true,"given":"Hayley R.","family":"Waterman","sequence":"first","affiliation":[{"name":"Molecular and Cell Biology Program, University of Washington, Seattle, WA 98195, USA."},{"name":"Center for Fundamental Immunology, Benaroya Research Institute, Seattle, WA 98101, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5200-0040","authenticated-orcid":true,"given":"Matthew J.","family":"Dufort","sequence":"additional","affiliation":[{"name":"Center for Systems Immunology, Benaroya Research Institute, Seattle, WA 98101, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6572-4291","authenticated-orcid":true,"given":"Sylvia E.","family":"Posso","sequence":"additional","affiliation":[{"name":"Center for Translational Immunology, Benaroya Research Institute, Seattle, WA 98101, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2136-3543","authenticated-orcid":true,"given":"Minjian","family":"Ni","sequence":"additional","affiliation":[{"name":"Center for Fundamental Immunology, Benaroya Research Institute, Seattle, WA 98101, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4616-736X","authenticated-orcid":true,"given":"Lucy Z.","family":"Li","sequence":"additional","affiliation":[{"name":"Molecular and Cell Biology Program, University of Washington, Seattle, WA 98195, USA."},{"name":"Center for Fundamental Immunology, Benaroya Research Institute, Seattle, WA 98101, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8872-9450","authenticated-orcid":true,"given":"Chengsong","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Immunology, Microarray and Immune Phenotyping Core Facility, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4068-4358","authenticated-orcid":true,"given":"Prithvi","family":"Raj","sequence":"additional","affiliation":[{"name":"Department of Immunology, Microarray and Immune Phenotyping Core Facility, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2368-4957","authenticated-orcid":true,"given":"Kelly D.","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98195, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9005-1885","authenticated-orcid":true,"given":"Jane H.","family":"Buckner","sequence":"additional","affiliation":[{"name":"Center for Translational Immunology, Benaroya Research Institute, Seattle, WA 98101, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5864-5299","authenticated-orcid":true,"given":"Jessica A.","family":"Hamerman","sequence":"additional","affiliation":[{"name":"Molecular and Cell Biology Program, University of Washington, Seattle, WA 98195, USA."},{"name":"Center for Fundamental Immunology, Benaroya Research Institute, Seattle, WA 98101, USA."},{"name":"Department of Immunology, University of Washington, Seattle, WA 98195, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.3390\/antib5010002"},{"key":"e_1_3_2_3_2","first-page":"e30330","article-title":"An overview of systemic lupus erythematosus (SLE) pathogenesis, classification, and management","volume":"14","author":"Ameer M. 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