{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T06:01:17Z","timestamp":1792130477073,"version":"4.4.0"},"posted":{"date-parts":[[2026,5,18]]},"group-title":"Allergy and Immunology","reference-count":44,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T00:00:00Z","timestamp":1779062400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,18]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease driven by uncensored B and T cell autoreactivity. Understanding this pathogenic process has been hampered by lack of studies of secondary lymphoid organs in human SLE. Using minimally invasive lymph node fine needle aspirates (LN-FNAs), we profiled tissue-resident immune cells from 59 SLE patients and 34 healthy controls through high-dimensional 43-color flow cytometry, antigen-specific tetramer probing, and sc-RNA sequencing with paired VH\/VL repertoire analysis. Our findings reveal hyperactive lymph node immunity in SLE characterized by spontaneous germinal center (GC) activation, plasma cell accumulation enriched in mature CD19\n                  <jats:sup>-<\/jats:sup>\n                  and CD138\n                  <jats:sup>+<\/jats:sup>\n                  antibody-secreting cells, and increased frequencies of both GC-T\n                  <jats:sub>FH<\/jats:sub>\n                  and PD-1\n                  <jats:sup>+<\/jats:sup>\n                  CXCR5\n                  <jats:sup>-<\/jats:sup>\n                  T extra-follicular helper cells. SLE lymph nodes harbored large oligoclonal B cell families with altered isotype usage, dominated by IgG1 and IgG4. Critically, self-reactive 9G4\n                  <jats:sup>+<\/jats:sup>\n                  and Ro60\n                  <jats:sup>+<\/jats:sup>\n                  B cells showed defective tolerance checkpoint control, accumulating in activated na\u00efve, GC, and plasma cell compartments with distinctive PD-1\n                  <jats:sup>+<\/jats:sup>\n                  Tox\n                  <jats:sup>+<\/jats:sup>\n                  expression absent in viral-specific responses. Single-cell repertoire analysis revealed VH\n                  <jats:sub>4-34<\/jats:sub>\n                  clones in SLE B\n                  <jats:sub>GC<\/jats:sub>\n                  and B\n                  <jats:sub>PC<\/jats:sub>\n                  , that in contrast to HD, had not experienced clonal redemption. Instead, SLE VH\n                  <jats:sub>4-34<\/jats:sub>\n                  clones displayed low somatic hypermutation and preserved the AVY hydrophobic patch associated with autoreactivity. Monoclonal antibody testing confirmed that unmutated AVY\n                  <jats:sup>+<\/jats:sup>\n                  VH\n                  <jats:sub>4-34<\/jats:sub>\n                  clones retained polyreactivity against na\u00efve B cells, apoptotic cells, and multiple self-antigens. Together, these results define \u201cclonal damnation\u201d as a key mechanism in SLE whereby autoreactive VH\n                  <jats:sub>4-34<\/jats:sub>\n                  clones of pathogenic potential escape tolerance checkpoints, expand in germinal centers, and differentiate into tissue plasma cells while preserving germline-encoded self-reactivity. Combined, our study defines critical mechanisms of tolerance breakdown in lupus pathogenesis.\n                <\/jats:p>","DOI":"10.64898\/2026.05.18.26353148","type":"posted-content","created":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T22:00:19Z","timestamp":1779141619000},"source":"Crossref","is-referenced-by-count":1,"title":["Defective B cell tolerance in SLE lymph nodes underpins VH\n                  <sub>4-34<\/sub>\n                  \u201cclonal damnation\u201d and PD-1\u207aTOX\u207a autoreactive B cells expansion"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0487-1914","authenticated-orcid":false,"given":"Caterina E.","family":"Faliti","sequence":"first","affiliation":[{"name":"Department of Medicine, Division of Rheumatology, Lowance Center for Human Immunology, Emory University, Atlanta, GA, USA"},{"name":"Emory Autoimmunity Center of Excellence, Emory University, Atlanta, GA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Midushi","family":"Ghimire","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Rheumatology, Lowance Center for Human Immunology, Emory University, Atlanta, GA, USA"},{"name":"Emory Autoimmunity Center of Excellence, Emory University, Atlanta, GA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5902-4603","authenticated-orcid":false,"given":"Melissa","family":"Garcia-Vega","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Rheumatology, Lowance Center for Human Immunology, Emory University, Atlanta, GA, USA"},{"name":"Emory Autoimmunity Center of Excellence, Emory University, Atlanta, GA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel C.","family":"Watermeier","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine, Emory University, Atlanta, GA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda","family":"Callahan","sequence":"additional","affiliation":[{"name":"Department of Microbiology, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, AL 35294, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Burke","sequence":"additional","affiliation":[{"name":"Department of Microbiology, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, AL 35294, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivia","family":"Posadas","sequence":"additional","affiliation":[{"name":"Division of Viral Products, Center for Biologics Evaluation and Research (CBER), Food and Drug Administration, Silver Spring, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashish K.","family":"Mishra","sequence":"additional","affiliation":[{"name":"Division of Viral Products, Center for Biologics Evaluation and Research (CBER), Food and Drug Administration, Silver Spring, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0593-7965","authenticated-orcid":false,"given":"Surender","family":"Khurana","sequence":"additional","affiliation":[{"name":"Division of Viral Products, Center for Biologics Evaluation and Research (CBER), Food and Drug Administration, Silver Spring, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2622-5032","authenticated-orcid":false,"given":"Victor","family":"Greiff","sequence":"additional","affiliation":[{"name":"Department of Immunology, University of Oslo, Oslo University Hospital, Oslo, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7716-8504","authenticated-orcid":false,"given":"Chris D.","family":"Scharer","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4940-5354","authenticated-orcid":false,"given":"John M.","family":"Lindner","sequence":"additional","affiliation":[{"name":"BioMed X Institute, Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6522-0053","authenticated-orcid":false,"given":"R. 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