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To substantiate this, we investigated lung\u2010resident B cells in bronchoalveolar lavage (BAL) samples from untreated early RA patients and anti\u2013citrullinated protein antibody (ACPA)\u2013positive individuals at risk for developing RA.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Single B cells (n\u00a0=\u00a07,680) were phenotyped and isolated from BAL samples from individuals at risk of RA (n\u00a0=\u00a03) and at RA diagnosis (n\u00a0=\u00a09). The immunoglobulin variable region transcripts were sequenced and selected for expression as monoclonal antibodies (n\u00a0=\u00a0141). Monoclonal ACPAs were tested for reactivity patterns and binding to neutrophils.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Using our single\u2010cell approach, we found significantly increased proportions of B lymphocytes in ACPA+ compared to ACPA\u2013 individuals. Memory and double\u2010negative B cells were prominent in all subgroups. Upon antibody re\u2010expression, 7 highly mutated citrulline\u2010autoreactive clones originating from different memory B cell subsets were identified, both in individuals at risk of RA and early RA patients. Lung IgG variable gene transcripts from ACPA+ individuals carried frequent mutation\u2010induced <jats:italic>N<\/jats:italic>\u2010linked Fab glycosylation sites (<jats:italic>P<\/jats:italic> &lt;\u20090.001), often in the framework 3 of the variable region. Two of the lung ACPAs bound to activated neutrophils, 1 from an individual at risk of RA and 1 from an early RA patient.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>T cell\u2013driven B cell differentiation resulting in local class switching and somatic hypermutation are evident in lungs before as well as in early stages of ACPA+ RA. Our findings add to the notion of lung mucosa being a site for initiation of citrulline autoimmunity preceding seropositive RA.<\/jats:p><jats:p><jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/art42549-toc-0001-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p><\/jats:sec>","DOI":"10.1002\/art.42549","type":"journal-article","created":{"date-parts":[[2023,5,16]],"date-time":"2023-05-16T14:08:33Z","timestamp":1684246113000},"page":"1910-1922","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["Rheumatoid Arthritis\u2013Specific Autoimmunity in the Lung Before and at the Onset of Disease"],"prefix":"10.1002","volume":"75","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2606-8180","authenticated-orcid":false,"given":"Vijay","family":"Joshua","sequence":"first","affiliation":[{"name":"Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet Karolinska University Hospital  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malena","family":"Loberg Haarhaus","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet Karolinska University Hospital  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7669-3777","authenticated-orcid":false,"given":"Aase","family":"Hensvold","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet Karolinska University Hospital  Stockholm 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