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This choice also governs the selection and survival of autoreactive B cells, influencing their potential to enter the memory compartment. During the first 2\u20133\u2009days following antigen encounter, initially activated B cells integrate activating signals from T cells, Toll\u2010like receptors (TLRs), and cytokines, alongside inhibitory signals mediated by inhibitory receptors. This integration modulates the intensity of signaling, particularly of the PI3K\/AKT\/mTOR pathway, which plays a central role in guiding developmental decisions. These early signaling events determine whether B cells undergo GC maturation or differentiate rapidly into antibody\u2010secreting cells (ASCs) via the EF pathway. Dysregulation of these signaling pathways\u2014whether through excessive activation or defective regulatory mechanisms\u2014can disrupt the balance between GC and EF fates, predisposing individuals to autoimmunity. Accordingly, aberrant PI3K\/AKT\/mTOR signaling has been implicated in the defective selection of autoreactive B cells, increasing the risk of autoimmune disease. This review focuses on the signaling events in newly activated B cells, with an emphasis on the induction and regulation of the PI3K\/AKT\/mTOR pathway. It also highlights gaps in our understanding of how alternative B cell fates are regulated. Both the physiological context and the implications of inborn errors of immunity (IEIs) and complex autoimmune conditions will be discussed in this regard.<\/jats:p>","DOI":"10.1111\/imr.70004","type":"journal-article","created":{"date-parts":[[2025,2,7]],"date-time":"2025-02-07T04:58:51Z","timestamp":1738904331000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Signaling Activation and Modulation in Extrafollicular B Cell Responses"],"prefix":"10.1111","volume":"330","author":[{"given":"Julian","family":"Staniek","sequence":"first","affiliation":[{"name":"Department of Rheumatology and Clinical Immunology, Faculty of Medicine, University Medical Center Freiburg University of Freiburg  Freiburg Germany"},{"name":"Faculty of Medicine, Center for Chronic Immunodeficiency, University Medical Center Freiburg University of Freiburg  Freiburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5153-6089","authenticated-orcid":false,"given":"Marta","family":"Rizzi","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Clinical Immunology, Faculty of Medicine, University Medical Center Freiburg University of Freiburg  Freiburg Germany"},{"name":"Faculty of Medicine, Center for Chronic Immunodeficiency, University Medical Center Freiburg University of Freiburg  Freiburg Germany"},{"name":"Division of Clinical and Experimental Immunology, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology Medical University of Vienna  Vienna Austria"},{"name":"CIBSS\u2014Centre for Integrative Biological Signalling Studies University of Freiburg  Freiburg 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