{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T17:40:27Z","timestamp":1791308427506,"version":"4.3.1"},"reference-count":34,"publisher":"Springer Science and Business Media LLC","issue":"10","license":[{"start":{"date-parts":[[2020,8,6]],"date-time":"2020-08-06T00:00:00Z","timestamp":1596672000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.springer.com\/tdm"},{"start":{"date-parts":[[2020,8,6]],"date-time":"2020-08-06T00:00:00Z","timestamp":1596672000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.springer.com\/tdm"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Drugs Aging"],"published-print":{"date-parts":[[2020,10]]},"DOI":"10.1007\/s40266-020-00789-4","type":"journal-article","created":{"date-parts":[[2020,8,6]],"date-time":"2020-08-06T01:02:14Z","timestamp":1596675734000},"page":"739-746","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Age-Related Lymphocyte Output During Disease-Modifying Therapies for Multiple Sclerosis"],"prefix":"10.1007","volume":"37","author":[{"given":"Simone","family":"Paghera","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Sottini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa","family":"Previcini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruggero","family":"Capra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2075-8391","authenticated-orcid":false,"given":"Luisa","family":"Imberti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,8,6]]},"reference":[{"key":"789_CR1","doi-asserted-by":"publisher","first-page":"487","DOI":"10.1038\/s41591-019-0381-y","volume":"25","author":"A Alpert","year":"2019","unstructured":"Alpert A, Pickman Y, Leipold M, Rosenberg-Hasson Y, Ji X, Gaujoux R, et al. A clinically meaningful metric of immune age derived from high-dimensional longitudinal monitoring. Nat Med. 2019;25:487\u201395.","journal-title":"Nat Med."},{"key":"789_CR2","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1016\/j.exger.2017.10.024","volume":"105","author":"G Pawelec","year":"2018","unstructured":"Pawelec G. Age and immunity: what is \u201cimmunosenescence\u201d? Exp Gerontol. 2018;105:4\u20139.","journal-title":"Exp Gerontol."},{"key":"789_CR3","doi-asserted-by":"publisher","first-page":"717","DOI":"10.1177\/1352458516634871","volume":"22","author":"SA Sanai","year":"2016","unstructured":"Sanai SA, Saini V, Benedict RH, Zivadinov R, Teter BE, Ramanathan M, et al. Aging and multiple sclerosis. Mult Scler. 2016;22:717\u201325.","journal-title":"Mult Scler."},{"key":"789_CR4","doi-asserted-by":"publisher","first-page":"350","DOI":"10.1016\/j.smim.2012.04.001","volume":"24","author":"L Haynes","year":"2012","unstructured":"Haynes L, Swain SL. Aged-related shifts in T cell homeostasis lead to intrinsic T cell defects. Semin Immunol. 2012;24:350\u20135.","journal-title":"Semin Immunol."},{"key":"789_CR5","doi-asserted-by":"publisher","first-page":"432","DOI":"10.4049\/jimmunol.171.1.432","volume":"171","author":"A Hug","year":"2003","unstructured":"Hug A, Korporal M, Schr\u00f6der I, Haas J, Glatz K, Storch-Hagenlocher B, et al. Thymic export function and T cell homeostasis in patients with relapsing remitting multiple sclerosis. J Immunol. 2003;171:432\u20137.","journal-title":"J Immunol."},{"key":"789_CR6","doi-asserted-by":"publisher","first-page":"784","DOI":"10.1212\/WNL.0b013e3182a2ce0e","volume":"81","author":"B Balint","year":"2013","unstructured":"Balint B, Haas J, Schwarz A, Jarius S, F\u00fcrwentsches A, Engelhardt K, et al. T-cell homeostasis in pediatric multiple sclerosis: old cells in young patients. Neurology. 2013;81:784\u201392.","journal-title":"Neurology."},{"key":"789_CR7","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1002\/acn3.295","volume":"3","author":"A Lossius","year":"2016","unstructured":"Lossius A, Johansen JN, Vartdal F, Holm\u00f8y T. High-throughput sequencing of immune repertoires in multiple sclerosis. Ann Clin Transl Neurol. 2016;3:295\u2013306.","journal-title":"Ann Clin Transl Neurol."},{"key":"789_CR8","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1016\/j.it.2009.04.005","volume":"30","author":"MP Cancro","year":"2009","unstructured":"Cancro MP, Hao Y, Scholz JL, Riley RL, Frasca D, Dunn-Walters DK, et al. B cells and aging: molecules and mechanisms. Trends Immunol. 2009;30:313\u20138.","journal-title":"Trends Immunol."},{"key":"789_CR9","doi-asserted-by":"publisher","first-page":"577","DOI":"10.3389\/fneur.2017.00577","volume":"8","author":"AM Weideman","year":"2017","unstructured":"Weideman AM, Tapia-Maltos MA, Johnson K, Greenwood M, Bielekova B. Meta-analysis of the age-dependent efficacy of multiple sclerosis treatments. Front Neurol. 2017;8:577.","journal-title":"Front Neurol."},{"key":"789_CR10","unstructured":"MSBase Neuro-Immunology Registry (2019). https:\/\/www.msbase.org\/data-and-findings\/patient-demographics. Accessed Nov 2019."},{"key":"789_CR11","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1038\/s41582-019-0183-3","volume":"15","author":"CB Vaughn","year":"2019","unstructured":"Vaughn CB, Jakimovski D, Kavak KS, Ramanathan M, Benedict RHB, Zivadinov R, et al. Epidemiology and treatment of multiple sclerosis in elderly populations. Nat Rev Neurol. 2019;15:329\u201342.","journal-title":"Nat Rev Neurol."},{"key":"789_CR12","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1097\/WCO.0000000000000701","volume":"32","author":"F Schweitzer","year":"2019","unstructured":"Schweitzer F, Laurent S, Fink GR, Barnett MH, Reddel S, Hartung HP, et al. Age and the risks of high-efficacy disease modifying drugs in multiple sclerosis. Curr Opin Neurol. 2019;32:305\u201312.","journal-title":"Curr Opin Neurol."},{"key":"789_CR13","doi-asserted-by":"publisher","first-page":"690","DOI":"10.1038\/25374","volume":"396","author":"DC Douek","year":"1998","unstructured":"Douek DC, McFarland RD, Keiser PH, Gage EA, Massey JM, Haynes BF, et al. Changes in thymic function with age and during the treatment of HIV infection. Nature. 1998;396:690\u20135.","journal-title":"Nature."},{"key":"789_CR14","doi-asserted-by":"publisher","first-page":"2208","DOI":"10.1016\/j.jaci.2018.02.017","volume":"141","author":"E Blanco","year":"2018","unstructured":"Blanco E, P\u00e9rez-Andr\u00e9s M, Arriba-M\u00e9ndez S, Contreras-Sanfeliciano T, Criado I, Pelak O, et al. Age-associated distribution of normal B-cell and plasma cell subsets in peripheral blood. J Allergy Clin Immunol. 2018;141:2208\u201319.","journal-title":"J Allergy Clin Immunol."},{"key":"789_CR15","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1111\/cei.13062","volume":"191","author":"SP Adams","year":"2018","unstructured":"Adams SP, Kricke S, Ralph E, Gilmour N, Gilmour KC. A comparison of TRECs and flow cytometry for naive T cell quantification. Clin Exp Immunol. 2018;191:198\u2013202.","journal-title":"Clin Exp Immunol."},{"key":"789_CR16","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.02084","author":"RHJ Verstegen","year":"2019","unstructured":"Verstegen RHJ, Aui PM, Watson E, De Jong S, Bartol SJW, Bosco JJ, et al. Quantification of T-cell and B-cell replication history in aging, immunodeficiency, and newborn screening. Front Immunol. 2019. https:\/\/doi.org\/10.3389\/fimmu.2019.02084.","journal-title":"Front Immunol."},{"key":"789_CR17","doi-asserted-by":"publisher","first-page":"726","DOI":"10.1177\/1352458514551456","volume":"21","author":"M Chiarini","year":"2015","unstructured":"Chiarini M, Sottini A, Bertoli D, Serana F, Caimi L, Rasia S, et al. Newly produced T and B lymphocytes and T-cell receptor repertoire diversity are reduced in peripheral blood of fingolimod-treated multiple sclerosis patients. Mult Scler. 2015;21:726\u201334.","journal-title":"Mult Scler."},{"key":"789_CR18","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.clim.2012.07.007","volume":"145","author":"C Zanotti","year":"2012","unstructured":"Zanotti C, Chiarini M, Serana F, Sottini A, Garrafa E, Torri F, et al. Peripheral accumulation of newly produced T and B lymphocytes in natalizumab-treated multiple sclerosis patients. Clin Immunol. 2012;145:19\u201326.","journal-title":"Clin Immunol."},{"key":"789_CR19","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneuroim.2020.577282","author":"M Chiarini","year":"2020","unstructured":"Chiarini M, Paghera S, Moratto D, Rossi N, Giacomelli M, Badolato R, et al. Immunologic characterization of a immunosuppressed multiple sclerosis patient that recovered from SARS-CoV-2 infection. J Neuroimmunol. 2020. https:\/\/doi.org\/10.1016\/j.jneuroim.2020.577282.","journal-title":"J Neuroimmunol."},{"key":"789_CR20","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1016\/j.clim.2010.04.005","volume":"136","author":"A Sottini","year":"2010","unstructured":"Sottini A, Ghidini C, Zanotti C, Chiarini M, Caimi L, Lanfranchi A, et al. Simultaneous quantification of recent thymic T-cell and bone marrow B-cell emigrants in patients with primary immunodeficiency undergone to stem cell transplantation. Clin Immunol. 2010;136:217\u201327.","journal-title":"Clin Immunol."},{"key":"789_CR21","doi-asserted-by":"publisher","first-page":"540","DOI":"10.1007\/s10875-011-9526-6","volume":"31","author":"F Serana","year":"2011","unstructured":"Serana F, Air\u00f2 P, Chiarini M, Zanotti C, Scarsi M, Frassi M, et al. Thymic and bone marrow output in patients with common variable immunodeficiency. J Clin Immunol. 2011;31:540\u20139.","journal-title":"J Clin Immunol."},{"key":"789_CR22","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1038\/nri.2016.125","volume":"17","author":"P Brodin","year":"2017","unstructured":"Brodin P, Davis MM. Human immune system variation. Nat Rev Immunol. 2017;17:21\u20139.","journal-title":"Nat Rev Immunol."},{"key":"789_CR23","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1007\/s40120-019-00162-7","volume":"8","author":"F Sica","year":"2019","unstructured":"Sica F, Centonze D, Buttari F. Fingolimod immune effects beyond its sequestration ability. Neurol Ther. 2019;8:231\u201340.","journal-title":"Neurol Ther."},{"key":"789_CR24","doi-asserted-by":"publisher","first-page":"1473","DOI":"10.1212\/WNL.0000000000001454","volume":"84","author":"M Mattoscio","year":"2015","unstructured":"Mattoscio M, Nicholas R, Sormani MP, Malik O, Lee JS, Waldman AD, et al. Hematopoietic mobilization: potential biomarker of response to natalizumab in multiple sclerosis. Neurology. 2015;84:1473\u201382.","journal-title":"Neurology."},{"key":"789_CR25","doi-asserted-by":"publisher","first-page":"961","DOI":"10.1001\/jamaneurol.2017.0676","volume":"74","author":"D Baker","year":"2017","unstructured":"Baker D, Herrod SS, Alvarez-Gonzalez C, Giovannoni G, Schmierer K. Interpreting lymphocyte reconstitution data from the pivotal phase 3 trials of alemtuzumab. JAMA Neurol. 2017;74:961\u20139.","journal-title":"JAMA Neurol."},{"key":"789_CR26","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1705065114","author":"KJ Kaczorowski","year":"2017","unstructured":"Kaczorowski KJ, Shekhar K, Nkulikiyimfura D, Dekker CL, Maecker H, Davis MM, et al. Continuous immunotypes describe human immune variation and predict diverse responses. Proc Natl Acad Sci USA. 2017. https:\/\/doi.org\/10.1073\/pnas.1705065114.","journal-title":"Proc Natl Acad Sci USA"},{"key":"789_CR27","doi-asserted-by":"publisher","first-page":"579","DOI":"10.1038\/pr.2015.14","volume":"77","author":"N Dar","year":"2015","unstructured":"Dar N, Gothelf D, Korn D, Frisch A, Weizman A, Michaelovsky E, et al. Thymic and bone marrow output in individuals with 22q11.2 deletion syndrome. Pediatr Res. 2015;77:579\u201385.","journal-title":"Pediatr Res."},{"key":"789_CR28","doi-asserted-by":"publisher","first-page":"1521","DOI":"10.1177\/1352458514564589","volume":"21","author":"J Haas","year":"2015","unstructured":"Haas J, Schwarz A, Korporal-Kunke M, Jarius S, Wiendl H, Kieseier BC, et al. Fingolimod does not impair T-cell release from the thymus and beneficially affects Treg function in patients with multiple sclerosis. Mult Scler. 2015;21:1521\u201332.","journal-title":"Mult Scler."},{"key":"789_CR29","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1016\/j.clim.2014.02.001","volume":"151","author":"Y Miyazaki","year":"2014","unstructured":"Miyazaki Y, Niino M, Fukazawa T, Takahashi E, Nonaka T, Amino I, et al. Suppressed pro-inflammatory properties of circulating B cells in patients with multiple sclerosis treated with fingolimod, based on altered proportions of B-cell subpopulations. Clin Immunol. 2014;151:127\u201335.","journal-title":"Clin Immunol."},{"key":"789_CR30","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1242\/dev.130633","volume":"143","author":"MB Schultz","year":"2016","unstructured":"Schultz MB, Sinclair DA. When stem cells grow old: phenotypes and mechanisms of stem cell aging. Development. 2016;143:3\u201314.","journal-title":"Development."},{"key":"789_CR31","doi-asserted-by":"publisher","first-page":"22","DOI":"10.3324\/haematol.2018.211342","volume":"105","author":"E Mejia-Ramirez","year":"2020","unstructured":"Mejia-Ramirez E, Florian MC. Understanding intrinsic hematopoietic stem cell aging. Haematologica. 2020;105:22\u201337.","journal-title":"Haematologica."},{"key":"789_CR32","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1111\/imm.12244","volume":"142","author":"PL Johnson","year":"2014","unstructured":"Johnson PL, Goronzy JJ, Antia R. A population biological approach to understanding the maintenance and loss of the T-cell repertoire during aging. Immunology. 2014;142:167\u201375.","journal-title":"Immunology."},{"key":"789_CR33","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1111\/j.1474-9726.2008.00443.x","volume":"8","author":"KL Gibson","year":"2009","unstructured":"Gibson KL, Wu YC, Barnett Y, Duggan O, Vaughan R, Kondeatis E, et al. B-cell diversity decreases in old age and is correlated with poor health status. Aging Cell. 2009;8:18\u201325.","journal-title":"Aging Cell."},{"key":"789_CR34","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1016\/S2468-2667(18)30091-4","volume":"3","author":"P Hanlon","year":"2018","unstructured":"Hanlon P, Nicholl BI, Jani BD, Lee D, McQueenie R, Mair FS. Frailty and pre-frailty in middle-aged and older adults and its association with multimorbidity and mortality: a prospective analysis of 493.737 UK Biobank participants. Lancet Public Health. 2018;3:323\u201332.","journal-title":"Lancet Public Health."}],"container-title":["Drugs & Aging"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s40266-020-00789-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s40266-020-00789-4\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s40266-020-00789-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,8,5]],"date-time":"2021-08-05T23:12:43Z","timestamp":1628205163000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s40266-020-00789-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,8,6]]},"references-count":34,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2020,10]]}},"alternative-id":["789"],"URL":"https:\/\/doi.org\/10.1007\/s40266-020-00789-4","relation":{},"ISSN":["1170-229X","1179-1969"],"issn-type":[{"value":"1170-229X","type":"print"},{"value":"1179-1969","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,8,6]]},"assertion":[{"value":"6 August 2020","order":1,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The study has not been supported by specific funding.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Funding"}},{"value":"SP, AS, and VP have no conflicts of interest to disclose. RC has received lecture fees and\/or travel grants from Biogen, Celgene, Genzyme-Sanofi, Novartis, and TEVA. LI has received speaker honoraria from Biogen, Genzyme-Sanofi, Merck-Serono, and Novartis, has participated in a scientific advisory board for Biogen and received research funding from FISM (Fondazione Italiana Sclerosi Multipla) and research support from Genzyme-Sanofi.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"Samples were collected after approval by the Ethics Committee of Brescia (n. 113\/2006; n. 24401; EMR200136-555; 12-13-2011; and NP2263) and was conducted according to the Declaration of Helsinki recommendations and its later amendments. Written informed consent was obtained from all patients.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}},{"value":"Not applicable.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate"}},{"value":"Not applicable.","order":6,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to publication"}},{"value":"The datasets generated and analyzed during the current study are not publicly available due to ethical and law restrictions but are available from the corresponding author on reasonable request.","order":7,"name":"Ethics","group":{"name":"EthicsHeading","label":"Availability of data and material"}},{"value":"Not applicable.","order":8,"name":"Ethics","group":{"name":"EthicsHeading","label":"Code availability"}},{"value":"LI conceived the study and wrote the first version of the manuscript. RC made substantial contributions to the acquisition of patients\u2019 informed consents, samples, and clinical data. SP, AS, and VP performed laboratory tests. SP performed statistical analysis. All authors revised critically for important intellectual content. All authors read and approved the final manuscript.","order":9,"name":"Ethics","group":{"name":"EthicsHeading","label":"Authors\u2019 contributions"}}]}}