{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T20:17:23Z","timestamp":1789244243934,"version":"build-2803163510"},"posted":{"date-parts":[[2023,9,12]]},"group-title":"Immunology","reference-count":76,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,4,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Autoantibodies to nuclear antigens are hallmarks of the autoimmune disease systemic lupus erythematosus (SLE) where they contribute to pathogenesis. However, there remains a gap in our knowledge regarding how different isotypes of autoantibodies contribute to disease, including the production of the critical type I interferon (IFN) cytokines by plasmacytoid dendritic cells (pDCs) in response to immune complexes (ICs). We focused on IgA, which is the second most prevalent isotype in serum, and along with IgG is deposited in glomeruli in lupus nephritis. Here, we show that individuals with SLE have IgA autoantibodies against most nuclear antigens, correlating with IgG against the same antigen. We investigated whether IgA autoantibodies against a major SLE autoantigen, Smith ribonucleoproteins (Sm\/RNPs), play a role in IC activation of pDCs. We found that pDCs express the IgA-specific Fc receptor, Fc\u03b1R, and there was a striking ability of IgA1 autoantibodies to synergize with IgG in RNA-containing ICs to generate robust pDC IFN\u03b1 responses. pDC responses to these ICs required both Fc\u03b1R and Fc\u03b3RIIa, showing a potent synergy between these Fc receptors. Sm\/RNP IC binding to and internalization by pDCs were greater when ICs contained both IgA1 and IgG. pDCs from individuals with SLE had higher binding of IgA1-containing ICs and higher expression of Fc\u03b1R than pDCs from healthy control individuals. Whereas pDC Fc\u03b1R expression correlated with blood ISG signature in SLE, TLR7 agonists, but not IFN\u03b1, upregulated pDC Fc\u03b1R expression in vitro. Together, we show a new mechanism by which IgA1 autoantibodies contribute to SLE pathogenesis.<\/jats:p>\n                <jats:sec>\n                  <jats:title>One Sentence Summary<\/jats:title>\n                  <jats:p>IgA1 autoantibodies synergize with IgG in RNA-containing immune complexes to generate robust pDC IFN\u03b1 responses in a Fc\u03b1R receptor dependent manner.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2023.09.07.556743","type":"posted-content","created":{"date-parts":[[2023,9,12]],"date-time":"2023-09-12T08:45:13Z","timestamp":1694508313000},"source":"Crossref","is-referenced-by-count":3,"title":["Lupus IgA1 autoantibodies synergize with IgG to enhance pDC responses to RNA-containing immune complexes"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2260-9813","authenticated-orcid":false,"given":"Hayley R.","family":"Waterman","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew J.","family":"Dufort","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylvia E.","family":"Posso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minjian","family":"Ni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucy Z.","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengsong","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prithvi","family":"Raj","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly D.","family":"Smith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9005-1885","authenticated-orcid":false,"given":"Jane H.","family":"Buckner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5864-5299","authenticated-orcid":false,"given":"Jessica A.","family":"Hamerman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2024040807451056000_2023.09.07.556743v3.1","doi-asserted-by":"crossref","unstructured":"B. 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