{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T10:25:17Z","timestamp":1777890317356,"version":"3.51.4"},"reference-count":62,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T00:00:00Z","timestamp":1777593600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Maintaining B-cell tolerance \u2013 the elimination of self-reactive B-cells \u2013 is literally a life-long challenge because the B-cell receptor mutates to generate millions of new variants during each immune response in the germinal center (GC) of lymph nodes. B-cell tolerance therefore rests on local mechanisms within GCs, i.e., in the periphery, whereas classical T-cell tolerance mechanisms operate in the thymus (central tolerance) when T-cell diversity is generated during immune development. While T-cell tolerance has been shown to be mediated by kinetic proofreading mechanisms that are capable of distinguishing small affinity differences, we argue here that B-cell tolerance mechanisms in the GC operate at different timescales covering intra- and, inter-cellular signaling in the light zone, and iterative light-dark-zone cycling, where the temporal relationship between BCR and CD40 signaling are key to determining whether a B-cell is positively or negatively selected. This review summarizes how recent research points to a new conceptual paradigm for B-cell tolerance that must involve the analysis of intracellular and intercellular network dynamics. We show how multi-scale dynamical systems modeling will be key to elucidate B-cell selection mechanisms and enable a predictive understanding of how autoimmune pathologies arise.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1799465","type":"journal-article","created":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T05:35:24Z","timestamp":1777613724000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["B-cell peripheral tolerance: think dynamics beyond affinity"],"prefix":"10.3389","volume":"17","author":[{"given":"Patrick Henong","family":"Yuan","sequence":"first","affiliation":[{"name":"Institute for Quantitative and Computational Biosciences, University of California, Los Angeles","place":["Los Angeles, CA, United States"]},{"name":"Biomathematics Graduate Program, University of California, Los Angeles","place":["Los Angeles, CA, United 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