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Chemokine receptors not only define their brain-infiltrating capacity, but also assist in their maturation in germinal centers. How this corresponds to pregnancy, as a naturally occurring modifier of MS, is underexplored. Here, we aimed to study the impact of pregnancy on both ex vivo and in vitro B-cell differentiation in MS. The composition and outgrowth of peripheral B cells were compared between 19 MS pregnant patients and 12 healthy controls during the third trimester of pregnancy (low relapse risk) and postpartum (high relapse risk). Transitional, and not naive mature, B-cell frequencies\u00a0were found to drop in the third trimester, which was most prominent in patients\u00a0who experienced a pre-pregnancy relapse.\u00a0Early after delivery, these frequencies raised again, while memory B -cell frequencies modestly declined. CXCR4 was downregulated and CXCR5, CXCR3 and CCR6 were upregulated on postpartum memory B cells, implying enhanced recruitment into germinal center light zones for interaction with T follicular helper (T<jats:sub>FH<\/jats:sub>) cells. Postpartum memory B cells of MS patients expressed higher levels of CCR6 and preferentially developed into plasma cells under\u00a0T<jats:sub>FH<\/jats:sub>-like\u00a0in vitro\u00a0conditions. These findings imply that memory B- cell differentiation contributes to postpartum relapse risk in MS.<\/jats:p>","DOI":"10.1038\/s41598-021-91655-9","type":"journal-article","created":{"date-parts":[[2021,6,9]],"date-time":"2021-06-09T10:16:45Z","timestamp":1623233805000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Pregnancy-induced effects on memory B-cell development in multiple sclerosis"],"prefix":"10.1038","volume":"11","author":[{"given":"Malou","family":"Janssen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liza","family":"Rijvers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven C.","family":"Koetzier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annet F.","family":"Wierenga-Wolf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie-Jos\u00e9","family":"Melief","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jamie","family":"van Langelaar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tessel F.","family":"Runia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christianne J. M.","family":"de Groot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rinze","family":"Neuteboom","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joost","family":"Smolders","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marvin M.","family":"van Luijn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,6,9]]},"reference":[{"key":"91655_CR1","doi-asserted-by":"publisher","first-page":"1622","DOI":"10.1016\/S0140-6736(18)30481-1","volume":"391","author":"AJ Thompson","year":"2018","unstructured":"Thompson, A. J., Baranzini, S. E., Geurts, J., Hemmer, B. & Ciccarelli, O. Multiple sclerosis. Lancet 391, 1622\u20131636. https:\/\/doi.org\/10.1016\/S0140-6736(18)30481-1 (2018).","journal-title":"Lancet"},{"key":"91655_CR2","doi-asserted-by":"publisher","first-page":"2737","DOI":"10.1172\/jci68775","volume":"123","author":"T Kinnunen","year":"2013","unstructured":"Kinnunen, T. et al. Specific peripheral B cell tolerance defects in patients with multiple sclerosis. J. Clin. Invest. 123, 2737\u20132741. https:\/\/doi.org\/10.1172\/jci68775 (2013).","journal-title":"J. Clin. Invest."},{"key":"91655_CR3","doi-asserted-by":"crossref","unstructured":"Jelcic, I. et al. Memory B cells activate brain-homing, autoreactive CD4(+) T cells in multiple sclerosis. Cell 175, 85\u2013100 e123 (2018).","DOI":"10.1016\/j.cell.2018.08.011"},{"key":"91655_CR4","doi-asserted-by":"publisher","first-page":"452","DOI":"10.1002\/ana.21939","volume":"67","author":"A Bar-Or","year":"2010","unstructured":"Bar-Or, A. et al. Abnormal B-cell cytokine responses a trigger of T-cell-mediated disease in MS?. Ann. Neurol. 67, 452\u2013461 (2010).","journal-title":"Ann. Neurol."},{"key":"91655_CR5","doi-asserted-by":"publisher","first-page":"264","DOI":"10.1002\/ana.25508","volume":"86","author":"J van Langelaar","year":"2019","unstructured":"van Langelaar, J. et al. Induction of brain-infiltrating T-bet-expressing B cells in multiple sclerosis. Ann. Neurol. 86, 264\u2013278 (2019).","journal-title":"Ann. Neurol."},{"key":"91655_CR6","doi-asserted-by":"publisher","first-page":"2066","DOI":"10.1093\/brain\/awy151","volume":"141","author":"J Machado-Santos","year":"2018","unstructured":"Machado-Santos, J. et al. The compartmentalized inflammatory response in the multiple sclerosis brain is composed of tissue-resident CD8+ T lymphocytes and B cells. Brain 141, 2066\u20132082 (2018).","journal-title":"Brain"},{"key":"91655_CR7","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1111\/j.1750-3639.2004.tb00049.x","volume":"14","author":"B Serafini","year":"2004","unstructured":"Serafini, B., Rosicarelli, B., Magliozzi, R., Stigliano, E. & Aloisi, F. Detection of ectopic B-cell follicles with germinal centers in the meninges of patients with secondary progressive multiple sclerosis. Brain Pathol. 14, 164\u2013174. https:\/\/doi.org\/10.1111\/j.1750-3639.2004.tb00049.x (2004).","journal-title":"Brain Pathol."},{"key":"91655_CR8","doi-asserted-by":"publisher","first-page":"461","DOI":"10.1016\/j.celrep.2017.03.060","volume":"19","author":"D Piovesan","year":"2017","unstructured":"Piovesan, D. et al. c-Myb regulates the T-Bet-dependent differentiation program in B cells to coordinate antibody responses. 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All the other authors declare that there is no conflict of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"12126"}}