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Despite this shared clinical phenotype, a unifying mechanism for the breakdown of B cell tolerance across monogenic forms of CVID has not been established. Here, we demonstrate that patients with loss-of-function\n                  <jats:italic>NFKB1<\/jats:italic>\n                  variants, like those with\n                  <jats:italic>CTLA4<\/jats:italic>\n                  variants and APDS, exhibit dysregulated CD4\n                  <jats:sup>+<\/jats:sup>\n                  T cell expansion, accumulation of transitional B cells, and a relative lack of follicular B cells. In patients with monogenic CVID and clinical autoimmunity, we observed a relative expansion of transitional and activated na\u00efve (aN: CD21\n                  <jats:sup>lo<\/jats:sup>\n                  CD11c\n                  <jats:sup>hi<\/jats:sup>\n                  ) B cells in peripheral blood accompanied by a marked increase in the frequency of VH4-34 expressing autoreactive 9G4\n                  <jats:sup>+<\/jats:sup>\n                  B cells, which expanded between T2 and T3a transitional B cell stages. Single-cell transcriptomic and B cell receptor analysis further revealed a marked expansion of activated T1\/2, T3 and extrafollicular activated na\u00efve and double negative (DN: IgD\n                  <jats:sup>-<\/jats:sup>\n                  CD27\n                  <jats:sup>-<\/jats:sup>\n                  ) B cell subsets in APDS patients. Notably, one B cell subset appeared exclusively in the APDS disease state, characterized by high oxidative phosphorylation in transitional B cells, specifically. In APDS patients, we also observed a clonal expansion of specific extrafollicular class-switched DN B cells, which were clonally derived from activated transitional B cells. DN B cells were also identified in APDS lung tissue, consistent with the contribution of activated, extrafollicularly-derived B cells to tissue inflammation. Together, these findings suggest that in many patients with CVID and autoimmune features, premature activation of autoreactive transitional T2 and T3a B cells induces the survival and expansion, rather than the tolerization and elimination, of self-reactive B cells. This process leads to extrafollicular expansion of autoreactive B cells capable of tissue infiltration.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>One Sentence Summary<\/jats:title>\n                  <jats:p>Loss of transitional B cell tolerance and extrafollicular expansion of autoreactive B cells drive autoimmunity in monogenic causes of CVID.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.06.07.658167","type":"posted-content","created":{"date-parts":[[2025,6,11]],"date-time":"2025-06-11T19:25:10Z","timestamp":1749669910000},"source":"Crossref","is-referenced-by-count":4,"title":["Loss of B cell tolerance at the T2\/T3a B cell transition is a convergent pathogenic mechanism in common variable immunodeficiency"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7080-2293","authenticated-orcid":false,"given":"Kirsty","family":"Hillier","sequence":"first","affiliation":[{"name":"Ragon Institute of MGH, MIT and Harvard; Cambridge, MA, USA"},{"name":"Department of Pediatrics, Division of Pediatric Hematology-Oncology, Hassenfeld Children\u2019s Hospital at NYU Langone Health, NYU Grossman School of Medicine; New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3253-9575","authenticated-orcid":false,"given":"Grace","family":"Yuen","sequence":"additional","affiliation":[{"name":"Ragon Institute of MGH, MIT and Harvard; Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anson","family":"Hui","sequence":"additional","affiliation":[{"name":"Ragon Institute of MGH, MIT and Harvard; Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5748-9343","authenticated-orcid":false,"given":"Suparna","family":"Kumar","sequence":"additional","affiliation":[{"name":"Ragon Institute of MGH, MIT and Harvard; Cambridge, MA, USA"},{"name":"Graduate Program in Immunology and Microbial Pathogenesis, Weill Cornell Graduate School of Medical Sciences; 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