{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T16:54:40Z","timestamp":1791219280869,"version":"4.1.0"},"reference-count":44,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2024,12,12]],"date-time":"2024-12-12T00:00:00Z","timestamp":1733961600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antibodies"],"abstract":"<jats:p>Background: The presence of intrathecal total IgG production is a hallmark of cerebrospinal fluid (CSF) characteristics in multiple sclerosis (MS). Herein, we systematically analyze how the intensity (instead of mere presence) of intrathecal total IgG production relates to basic CSF parameters in MS. Methods: We retrospectively assessed clinical routine CSF findings from 390 therapy-na\u00efve relapsing-remitting MS patients diagnosed according to 2017 revised McDonald criteria. The intensity of intrathecal total IgG synthesis according to Reiber\u2019s formula was stratified and correlated to demographics, CSF white cell count (WCC), and diversity of MRZ reaction, defined as a polyspecific intrathecal production of IgG reactive against \u22652 of the 3 viruses; measles (M), rubella (R), and varicella zoster (Z) virus. Results: The higher intensity of intrathecal total IgG production significantly correlated with higher CSF WCC (Spearman\u2019s \u03c1 = 0.433, p &lt; 0.001) and with the increasing presence and diversity of positive MRZ reaction (Spearman\u2019s \u03c1 = 0.600, p &lt; 0.001). Female patients showed higher intensity of intrathecal total IgG production and higher prevalence of positive MRZ reaction than males. Conclusions: The intensity of intrathecal total IgG production correlates with the degree of CSF WCC and diversity of MRZ reaction in MS. As yet unidentified female sex-related factors increase the intensity and diversity of intrathecal IgG production in MS.<\/jats:p>","DOI":"10.3390\/antib13040102","type":"journal-article","created":{"date-parts":[[2024,12,12]],"date-time":"2024-12-12T04:52:49Z","timestamp":1733979169000},"page":"102","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Intensity of Intrathecal Total IgG Synthesis in Multiple Sclerosis Correlates with the Degree of Pleocytosis, Diversity of Intrathecal Antiviral Antibody Specificities, and Female Sex"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-8830-0173","authenticated-orcid":false,"given":"Benjamin","family":"Vlad","sequence":"first","affiliation":[{"name":"Neuroimmunology and Multiple Sclerosis Research Section, Department of Neurology, University Hospital Zurich, 8091 Zurich, Switzerland"},{"name":"Faculty of Medicine, University of Zurich, 8006 Zurich, Switzerland"},{"name":"Department of Neurology, University Hospital Jena, 07749 Jena, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8454-531X","authenticated-orcid":false,"given":"Marc","family":"Hilty","sequence":"additional","affiliation":[{"name":"Neuroimmunology and Multiple Sclerosis Research Section, Department of Neurology, University Hospital Zurich, 8091 Zurich, Switzerland"},{"name":"Faculty of Medicine, University of Zurich, 8006 Zurich, Switzerland"},{"name":"Department of Neurology, Hirslanden Klinik Zurich, 8032 Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephan","family":"Neidhart","sequence":"additional","affiliation":[{"name":"Neuroimmunology and Multiple Sclerosis Research Section, Department of Neurology, University Hospital Zurich, 8091 Zurich, Switzerland"},{"name":"Faculty of Medicine, University of Zurich, 8006 Zurich, Switzerland"},{"name":"Swiss Epilepsy Center (Klinik Lengg), 8008 Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klara","family":"Asplund H\u00f6gelin","sequence":"additional","affiliation":[{"name":"Center for Molecular Medicine, Neuroimmunology Unit, Department of Clinical Neuroscience, Karolinska Institutet, 17177 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Ziegler","sequence":"additional","affiliation":[{"name":"Neuroimmunology and Multiple Sclerosis Research Section, Department of Neurology, University Hospital Zurich, 8091 Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohsen","family":"Khademi","sequence":"additional","affiliation":[{"name":"Center for Molecular Medicine, Neuroimmunology Unit, Department of Clinical Neuroscience, Karolinska Institutet, 17177 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Lutterotti","sequence":"additional","affiliation":[{"name":"Neuroimmunology and Multiple Sclerosis Research Section, Department of Neurology, University Hospital Zurich, 8091 Zurich, Switzerland"},{"name":"Faculty of Medicine, University of Zurich, 8006 Zurich, Switzerland"},{"name":"Department of Neurology, Hirslanden Klinik Zurich, 8032 Zurich, Switzerland"},{"name":"Clinical Research Priority Program MS (CRPP) PrecisionMS, University of Zurich, 8006 Zurich, Switzerland"},{"name":"Neuroimmunology Outpatient Clinic, Center for Multiple Sclerosis, Neurocenter Bellevue, 8001 Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6639-3594","authenticated-orcid":false,"given":"Axel","family":"Regeniter","sequence":"additional","affiliation":[{"name":"Infectious Disease Serology and Immunology, Medica Medizinische Laboratorien Dr. F. Kaeppeli AG, 8032 Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roland","family":"Martin","sequence":"additional","affiliation":[{"name":"Neuroimmunology and Multiple Sclerosis Research Section, Department of Neurology, University Hospital Zurich, 8091 Zurich, Switzerland"},{"name":"Faculty of Medicine, University of Zurich, 8006 Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Faiez","family":"Al Nimer","sequence":"additional","affiliation":[{"name":"Center for Molecular Medicine, Neuroimmunology Unit, Department of Clinical Neuroscience, Karolinska Institutet, 17177 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3090-7319","authenticated-orcid":false,"given":"Ilijas","family":"Jelcic","sequence":"additional","affiliation":[{"name":"Neuroimmunology and Multiple Sclerosis Research Section, Department of Neurology, University Hospital Zurich, 8091 Zurich, Switzerland"},{"name":"Faculty of Medicine, University of Zurich, 8006 Zurich, Switzerland"},{"name":"Department of Neurology, Hirslanden Klinik Zurich, 8032 Zurich, Switzerland"},{"name":"Clinical Research Priority Program MS (CRPP) PrecisionMS, University of Zurich, 8006 Zurich, Switzerland"},{"name":"Neuroimmunology Outpatient Clinic, Center for Multiple Sclerosis, Neurocenter Bellevue, 8001 Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1159\/000235944","article-title":"The discovery of oligoclonal bands: A 50-year anniversary","volume":"62","author":"Holmoy","year":"2009","journal-title":"Eur. Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1007\/BF00422934","article-title":"The diagnostic significance of antibody specificity indices in multiple sclerosis and herpes virus induced diseases of the nervous system","volume":"70","author":"Felgenhauer","year":"1992","journal-title":"Clin. Investig."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1007\/s00415-016-8360-4","article-title":"The MRZ reaction as a highly specific marker of multiple sclerosis: Re-evaluation and structured review of the literature","volume":"264","author":"Jarius","year":"2017","journal-title":"J. Neurol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"632","DOI":"10.1093\/brain\/awu405","article-title":"Genetic variants are major determinants of CSF antibody levels in multiple sclerosis","volume":"138","author":"Goris","year":"2015","journal-title":"Brain"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Castellazzi, M., Ferri, C., Alfiero, S., Lombardo, I., Laudisi, M., Tecilla, G., Boni, M., Pizzicotti, S., Fainardi, E., and Bellini, T. (2021). Sex-Related Differences in Cerebrospinal Fluid Plasma-Derived Proteins of Neurological Patients. Diagnostics, 11.","DOI":"10.3390\/diagnostics11050884"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1112","DOI":"10.1002\/ana.26921","article-title":"HLA Associations of Intrathecal IgG Production against Specific Viruses in Multiple Sclerosis","volume":"95","author":"Neidhart","year":"2024","journal-title":"Ann. Neurol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1598","DOI":"10.1177\/13524585241279645","article-title":"Intrathecal immune reactivity against Measles-, Rubella-, and Varicella Zoster viruses is associated with cerebrospinal fluid inflammation in multiple sclerosis","volume":"30","author":"Vlad","year":"2024","journal-title":"Mult. Scler."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1136\/jnnp-2012-304695","article-title":"Cerebrospinal fluid oligoclonal bands in multiple sclerosis and clinically isolated syndromes: A meta-analysis of prevalence, prognosis and effect of latitude","volume":"84","author":"Dobson","year":"2013","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1001\/jamaneurol.2019.0905","article-title":"Association of Intrathecal Immunoglobulin G Synthesis with Disability Worsening in Multiple Sclerosis","volume":"76","author":"Gasperi","year":"2019","journal-title":"JAMA Neurol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Angeloni, B., Bigi, R., Bellucci, G., Mechelli, R., Ballerini, C., Romano, C., Morena, E., Pellicciari, G., Reni\u00e8, R., and Rinaldi, V. (2021). A Case of Double Standard: Sex Differences in Multiple Sclerosis Risk Factors. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22073696"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"397","DOI":"10.3109\/00365517709091498","article-title":"Principles of albumin and IgG analyses in neurological disorders. III. Evaluation of IgG synthesis within the central nervous system in multiple sclerosis","volume":"37","author":"Link","year":"1977","journal-title":"Scand. J. Clin. Lab. Invest."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/0022-510X(94)90298-4","article-title":"Flow rate of cerebrospinal fluid (CSF)\u2014A concept common to normal blood-CSF barrier function and to dysfunction in neurological diseases","volume":"122","author":"Reiber","year":"1994","journal-title":"J. Neurol. Sci."},{"key":"ref_13","first-page":"99","article-title":"Cerebrospinal fluid\u2013physiology, analysis and interpretation of protein patterns for diagnosis of neurological diseases","volume":"4","author":"Reiber","year":"1998","journal-title":"Mult. Scler."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1136\/jnnp.57.8.897","article-title":"Cerebrospinal fluid in the diagnosis of multiple sclerosis: A consensus report","volume":"57","author":"Andersson","year":"1994","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1001\/archneur.62.6.865","article-title":"Recommended standard of cerebrospinal fluid analysis in the diagnosis of multiple sclerosis: A consensus statement","volume":"62","author":"Freedman","year":"2005","journal-title":"Arch. Neurol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1269","DOI":"10.1093\/brain\/113.5.1269","article-title":"A study of immunoglobulin G in the cerebrospinal fluid of 1007 patients with suspected neurological disease using isoelectric focusing and the Log IgG-Index. A comparison and diagnostic applications","volume":"113","author":"McLean","year":"1990","journal-title":"Brain"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1177\/135245859800400304","article-title":"The intrathecal, polyspecific and oligoclonal immune response in multiple sclerosis","volume":"4","author":"Reiber","year":"1998","journal-title":"Mult. Scler."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1016\/S1474-4422(17)30470-2","article-title":"Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria","volume":"17","author":"Thompson","year":"2018","journal-title":"Lancet Neurol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1186\/s42466-020-0051-z","article-title":"S1 guidelines \u201clumbar puncture and cerebrospinal fluid analysis\u201d (abridged and translated version)","volume":"2","author":"Tumani","year":"2020","journal-title":"Neurol. Res. Pract."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Vlad, B., Reichen, I., Neidhart, S., Hilty, M., Lekaditi, D., Heuer, C., Eisele, A., Ziegler, M., Reindl, M., and Lutterotti, A. (2023). Basic CSF parameters and MRZ reaction help in differentiating MOG antibody-associated autoimmune disease versus multiple sclerosis. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1237149"},{"key":"ref_21","first-page":"74","article-title":"Reporting Cerebrospinal Fluid Data: Knowledge Base and Interpretation Software","volume":"15","author":"Reiber","year":"2004","journal-title":"Clin. Chem. Lab. Med."},{"key":"ref_22","first-page":"241","article-title":"Intrathecal antibody synthesis to virus antigens in multiple sclerosis","volume":"52","author":"Salmi","year":"1983","journal-title":"Clin. Exp. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1111\/j.1749-6632.1965.tb20235.x","article-title":"Problems of Experimental Trials of Therapy in Multiple Sclerosis: Report by the Panel on the Evaluation of Experimental Trials of Therapy in Multiple Sclerosis","volume":"122","author":"Schumacher","year":"1965","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1007\/BF00313680","article-title":"On the diagnostic value of different CSF investigations in multiple sclerosis","volume":"231","author":"Lauer","year":"1984","journal-title":"J. Neurol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1002\/ana.410130302","article-title":"New diagnostic criteria for multiple sclerosis: Guidelines for research protocols","volume":"13","author":"Poser","year":"1983","journal-title":"Ann. Neurol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1016\/0022-510X(70)90156-5","article-title":"On cerebrospinal fluid immunoglobulin-G (IgG) quotients in multiple sclerosis and other diseases. A review and a new formula to estimate the amount of IgG synthesized per day by the central nervous system","volume":"10","author":"Tourtellotte","year":"1970","journal-title":"J. Neurol. Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/0022-510X(85)90067-X","article-title":"Cerebrospinal fluid virus antibodies. A diagnostic indicator for multiple sclerosis?","volume":"71","author":"Felgenhauer","year":"1985","journal-title":"J. Neurol. Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1016\/0009-8981(87)90250-6","article-title":"Protein transfer at the blood cerebrospinal fluid barrier and the quantitation of the humoral immune response within the central nervous system","volume":"163","author":"Reiber","year":"1987","journal-title":"Clin. Chim. Acta"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1153","DOI":"10.1093\/clinchem\/37.7.1153","article-title":"Quantification of virus-specific antibodies in cerebrospinal fluid and serum: Sensitive and specific detection of antibody synthesis in brain","volume":"37","author":"Reiber","year":"1991","journal-title":"Clin. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1002\/ana.1032","article-title":"Recommended diagnostic criteria for multiple sclerosis: Guidelines from the International Panel on the diagnosis of multiple sclerosis","volume":"50","author":"McDonald","year":"2001","journal-title":"Ann. Neurol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.cca.2019.08.016","article-title":"Association of cerebrospinal fluid kappa free light chains with the intrathecal polyspecific antiviral immune response in multiple sclerosis","volume":"498","author":"Huss","year":"2019","journal-title":"Clin. Chim. Acta"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"577287","DOI":"10.1016\/j.jneuroim.2020.577287","article-title":"Free light chain kappa and the polyspecific immune response in MS and CIS\u2014Application of the hyperbolic reference range for most reliable data interpretation","volume":"346","author":"Susse","year":"2020","journal-title":"J. Neuroimmunol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1038\/nrneurol.2013.41","article-title":"The utility of cerebrospinal fluid analysis in patients with multiple sclerosis","volume":"9","author":"Stangel","year":"2013","journal-title":"Nat. Rev. Neurol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1186\/s12974-017-0929-z","article-title":"Pattern II and pattern III MS are entities distinct from pattern I MS: Evidence from cerebrospinal fluid analysis","volume":"14","author":"Jarius","year":"2017","journal-title":"J. Neuroinflamm."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.cell.2018.08.011","article-title":"Memory B Cells Activate Brain-Homing, Autoreactive CD4+ T Cells in Multiple Sclerosis","volume":"175","author":"Jelcic","year":"2018","journal-title":"Cell"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1093\/trstmh\/tru167","article-title":"Sex-based differences in immune function and responses to vaccination","volume":"109","author":"Klein","year":"2015","journal-title":"Trans. R. Soc. Trop. Med. Hyg."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1007\/s10753-013-9775-z","article-title":"Lower serum levels of Th2-related chemokine CCL22 in women patients with multiple sclerosis: A comparison between patients and healthy women","volume":"37","author":"Jafarzadeh","year":"2014","journal-title":"Inflammation"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Berek, K., Bauer, A., Rudzki, D., Auer, M., Barket, R., Zinganell, A., Lerch, M., Hofer, L., Grams, A., and Poskaite, P. (2023). Immune profiling in multiple sclerosis: A single-center study of 65 cytokines, chemokines, and related molecules in cerebrospinal fluid and serum. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1200146"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Winschel, I., Willing, A., Engler, J.B., Walkenhorst, M., Meurs, N., Binkle-Ladisch, L., Woo, M.S., Pfeffer, L.K., Sonner, J.K., and Borgmeyer, U. (2024). Sex- and species-specific contribution of CD99 to T cell costimulation during multiple sclerosis. Biol. Sex. Differ., 15.","DOI":"10.1186\/s13293-024-00618-y"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.jneuroim.2013.05.004","article-title":"Gender differences in circulating levels of neutrophil extracellular traps in serum of multiple sclerosis patients","volume":"261","author":"Tillack","year":"2013","journal-title":"J. Neuroimmunol."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Castellazzi, M., Ferri, C., Tecilla, G., Huss, A., Crociani, P., Desina, G., Barbella, G., Piola, A., Permunian, S., and Senel, M. (2022). The Sexual Dimorphism in Cerebrospinal Fluid Protein Content Does Not Affect Intrathecal IgG Synthesis in Multiple Sclerosis. J. Pers. Med., 12.","DOI":"10.3390\/jpm12060977"},{"key":"ref_42","unstructured":"Montalban, X. (2024, January 18\u201320). 2024 revisions of the McDonald criteria 2024. Proceedings of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) Congress, Copenhagen, Denmark."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1177\/13524585221134213","article-title":"Cerebrospinal fluid kappa free light chains for the diagnosis of multiple sclerosis: A systematic review and meta-analysis","volume":"29","author":"Hegen","year":"2023","journal-title":"Mult. Scler."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1177\/13524585221134217","article-title":"Cerebrospinal fluid kappa free light chains for the diagnosis of multiple sclerosis: A consensus statement","volume":"29","author":"Hegen","year":"2023","journal-title":"Mult. Scler."}],"container-title":["Antibodies"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4468\/13\/4\/102\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:53:26Z","timestamp":1760115206000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4468\/13\/4\/102"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,12]]},"references-count":44,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["antib13040102"],"URL":"https:\/\/doi.org\/10.3390\/antib13040102","relation":{},"ISSN":["2073-4468"],"issn-type":[{"value":"2073-4468","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,12]]}}}