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Their physical location guided the nomenclature: outside, or at the edges of B cell follicles and near T cell zones of secondary lymphoid organs, thus distinct from the follicular situated germinal centers (GCs). Because EFs are often induced transiently and to both T\u2010dependent and T\u2010independent antigens, and because they generate IgM and class\u2010switched antibodies often with no or little signs of somatic hypermutations, they were thought to be less impactful than GC\u2010derived antibodies. However, highly protective antibodies are generated by these EFs rapidly after acute infections and their induction often correlates with pathogen clearance, while in autoimmunity EF\u2010derived antibodies have been implicated as pathogenic drivers of disease. Moreover, subsets of memory B cells, including some CD11c+ \u201catypical\u201d B cells\/ABCs are generated independently of GC. Their diverse appearance and impact have initiated an ongoing debate about whether all \u201cnon\u2010GC responses\u201d are necessarily EF responses. The current debate is reflected also in the articles compiled for this issue of Immunological Reviews considering EF responses. Here, I briefly summarize the steps leading to B cell activation and EF and GC formation, providing context for the contributed reviews that span a breadth of topics from descriptions of non\u2010GC responses in jawed non\u2010mammalian vertebrates as possible orthologues of mammalian EF to the molecular and metabolic requirements and CD4 T cell helper quality of EF, tissue\u2010specific B cell responses, and discussions on the origins and classifications of \u201catypical\u201d memory B cells in mice and man.<\/jats:p>","DOI":"10.1111\/imr.70066","type":"journal-article","created":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T05:26:01Z","timestamp":1762320361000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Extrafollicular B Cell Responses\u2014Is One Tent Big Enough?"],"prefix":"10.1111","volume":"336","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2891-4483","authenticated-orcid":false,"given":"Nicole","family":"Baumgarth","sequence":"first","affiliation":[{"name":"W. Harry Feinstone Department of Molecular Microbiology &amp; Immunology, Lyme and Tickborne Diseases Research and Education Institute, Bloomberg School of Public Health and Department of Molecular and Comparative Pathobiology, School of Medicine Johns Hopkins University  Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,11,4]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-042718-041238"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2020.11.006"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1034\/j.1600-065X.2003.00058.x"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1201730"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20111696"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-023-01721-9"},{"key":"e_1_2_7_8_1","article-title":"A Roadmap to Defining \u2018Extrafollicular B Cell Responses\u2019","volume":"22","author":"Eisenbarth S. 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