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Given these successes, it is evident that B cells are central orchestrators in the processes leading to the signs and symptoms hallmarking many human autoimmune diseases. The pathways provoking the generation of such autoreactive B cells or mechanisms preventing their induction in health are, however, poorly explored. Nevertheless, such information is crucial for the development of preventative\/curative interventions aiming to permanently deplete\u2010 or prohibit the emergence of autoreactive B cells. Hence, this review will focus on how B cell tolerance might be breached, and which checkpoints are at play preventing the arousal of autoreactive B cells in human. Especially antigen presentation by follicular dendritic cells, somatic hypermutation, and cross\u2010reactivity to the microbiome\/environment could operate as actors playing pivotal roles in the induction of B cell\u2010mediated humoral autoimmunity. Moreover, we highlight the human autoimmune disease rheumatoid arthritis as a prototype where autoreactive B cells combine several mechanisms to overcome peripheral B cell checkpoints.<\/jats:p>","DOI":"10.1002\/eji.202048820","type":"journal-article","created":{"date-parts":[[2020,11,5]],"date-time":"2020-11-05T19:12:44Z","timestamp":1604603564000},"page":"1885-1894","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Checkpoints controlling the induction of B cell mediated autoimmunity in human autoimmune diseases"],"prefix":"10.1002","volume":"50","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4424-4256","authenticated-orcid":false,"given":"S.","family":"Reijm","sequence":"first","affiliation":[{"name":"Department of Rheumatology Leiden University Medical Center  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5749-8087","authenticated-orcid":false,"given":"T.","family":"Kissel","sequence":"additional","affiliation":[{"name":"Department of Rheumatology Leiden University Medical Center  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9618-6414","authenticated-orcid":false,"given":"R.E.M.","family":"Toes","sequence":"additional","affiliation":[{"name":"Department of Rheumatology Leiden University Medical Center  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,12,2]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/keh446"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa032534"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(17)30070-3"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.00622"},{"key":"e_1_2_6_6_1","first-page":"2012","article-title":"B Cell in Autoimmune Diseases","author":"Hampe C. 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