Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. X:X | DOI: 10.5507/bp.2026.014

Intrathecal synthesis of antiviral IgG antibodies in multiple sclerosis

Karin Licha1, 2, 3, Pavlina Kusnierova1, 2, 3, 4, Kamila Zondra Revendova4, 5, Vojtech Thon1, 6, David Zeman1, 2, 3, 5
1 Institute of Laboratory Medicine, Faculty of Medicine, University of Ostrava, Syllabova 19, 70300 Ostrava, Czech Republic
2 Institute of Laboratory Medicine, University Hospital Ostrava, 17. listopadu 1790, 70852 Ostrava, Czech Republic
3 LAB4LIFE Ostrava FNOU, Syllabova 19, 70300 Ostrava, Czech Republic
4 Centre for Clinical Neuroscience, Faculty of Medicine, University of Ostrava, Syllabova 19, 70300 Ostrava, Czech Republic
5 Department of Neurology, University Hospital Ostrava, 17. listopadu 1790, 70852 Ostrava, Czech Republic
6 RECETOX, Faculty of Science, Masaryk University, Brno, Kamenice 753/5, 62500 Brno, Czech Republic

The Measles-Rubella-Zoster (MRZ) reaction is a test for the intrathecal synthesis of IgG antibodies against measles, rubella and varicella zoster viruses. Since the 1990s, it has been used as an adjunctive test to support the diagnosis of multiple sclerosis (MS), although it has no formal role in current McDonald diagnostic criteria and its clinical relevance remains debated. While early studies considered a single elevated antibody index (M, R or Z) as a positive result, the practice today requires at least two elevated antibody indices (M+R, M+Z, or R+Z), referred to as a polyspecific MRZ reaction (MRZ-2). MRZ-2 is the most specific laboratory marker for MS, with reported specificity exceeding 90%. However, sensitivity varies widely across studies, ranging from approximately 30% to over 70%. In the Czech adult MS population, MRZ-2 sensitivity was recently reported at 32%, markedly lower than the 67% pooled sensitivity reported in a meta-analysis of predominantly German cohorts. Broadening the panel of anti-viral antibodies (MRZ+) has been proposed to improve sensitivity, with parvovirus B19 and mumps virus being the most promising candidates. Further studies are required to determine whether an extended panel can increase sensitivity while maintaining high diagnostic specificity.

Keywords: cerebrospinal fluid, multiple sclerosis, MRZ reaction, mumps virus, parvovirus B19

Received: April 7, 2026; Revised: May 20, 2026; Accepted: May 20, 2026; Prepublished online: June 22, 2026 

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References

  1. Felgenhauer K, Schädlich HJ, Nekic M, Ackermann R. Cerebrospinal fluid virus antibodies. A diagnostic indicator for multiple sclerosis? J Neurol Sci 1985;71:291-9. doi: 10.1016/0022-510x(85)90067-x Go to original source... Go to PubMed...
  2. Reiber H, Lange P. Quantification of virus-specific antibodies in cerebrospinal fluid and serum: sensitive and specific detection of antibody synthesis in brain. Clin Chem 1991;37/7:1153-60. Go to original source...
  3. Goldmann H, Witmer R. Antikörper im Kammerwasser. Ophthalmologica 1954;127(4-5):323-30. doi: 10.1159/000301976 Go to original source... Go to PubMed...
  4. Adams JM, Imagawa DT. Measles antibodies in multiple sclerosis. Proc Soc Exp Biol Med 1962;111:562-6. doi: 10.3181/00379727-111-27855 Go to original source... Go to PubMed...
  5. Felgenhauer K, Reiber H. The diagnostic significance of antibody specificity indices in multiple sclerosis and herpes virus induced diseases of the central nervous system. Clin Investig 1992;70:28-37. doi: 10.1007/BF00422934 Go to original source... Go to PubMed...
  6. Andersson M, Alvarez-Cermeño J, Bernardi G, Cogato I, Fredman P, Frederiksen J, Fredrikson S, Gallo P, Grimaldi LM, Grønning M, Keir G, Lamers K, Link H, Magalhães A, Massaro AR, Öhman S, Reiber H, Rönnbäck L, Schluep M, Schuller E, Sindic CJM, Thompson EJ, Trojano M, Wurster U. Cerebrospinal fluid in the diagnosis of multiple sclerosis: a consensus report. J Neurol Neurosurg Psychiatry 1994;57(8):897-902. doi: 10.1136/jnnp.57.8.897 Go to original source... Go to PubMed...
  7. Freedman MS, Thompson EJ, Deisenhammer F, Giovannoni G, Grimsley G, Keir G, Öhman S, Racke MK, Sharief M, Sindic CJM, Sellebjerg F, Tourtellotte WW. Recommended standard of cerebrospinal fluid analysis in the diagnosis of multiple sclerosis. Arch Neurol 2005;62(6):865-70. doi: 10.1001/archneur.62.6.865 Go to original source...
  8. Deisenhammer F, Hegen H, Arrambide G, Banwell B, Coetzee T, Gnanapavan S, Montalban X, Tumani H, Willrich MA, Freedman MS. Positive cerebrospinal fluid in the 2024 McDonald criteria for multiple sclerosis. eBioMedicine 2025;105905. doi: 10.1016/j.ebiom.2025.105905 Go to original source... Go to PubMed...
  9. Montalban X, Lebrun-Frénay C, Oh J, Arrambide G, Moccia M, Amata MP, Amezcua L, Banwell B, Bar-Or A, Barkhof F, Butzkueven H, Ciccarelli O, Chataway J, Cohen JA, Comi G, Correale J, Deisenhammer F, Filippi M, Fiol J, Freedman MS, Fujihara K, Granziera C, Green AJ, Hartung HP, Hellwig K, Kappos L, Kimbrough D, Killestein J, Lublin F, Marignier R, Marrie RA, Miller A, Otero-Romero S, Ontaneda D, Ramanathan S, Reich D, Rocca MA, Rovira A, Saidha S, Salter A, Sastre-Garriga J, Saylor D, Solomon AJ, Sormani MP, Stankoff B, Tintore M, Tremlett H, Van der Walt A, Viswanathan S, Wiendl H, Wildemann B, Yamout B, Zaratin P, Calabresi PA, Coetzee T, Thompson AJ. Diagnosis of multiple sclerosis: 2024 revisions of the McDonald criteria. Lancet Neurol 2025;24(10):850-65. doi: 10.1016/S1444-4422(25)00270-4 Go to original source...
  10. Tumani H, Petereit HF, Gerritzen A, Gross CC, Huss A, Isenmann S, Jesse S, Khalil M, Lewczuk P, Lewerenz J, Leypoldt F, Melzer N, Meuth SG, Otto M, Ruprecht K, Sindern E, Spreer A, Stangel M, Strik H, Uhr M, Vogelsgang J, Wandinger KP, Weber T, Wick M, Wildemann B, Wiltfang J, Woitalla D, Zerr I, Zimmermann T. S1 guidelines "lumbar puncture and cerebrospinal fluid analysis" (abridged and translated version). Neurol Res Practice 2020;2:8. doi: 10.1186/s42466-020-0051-z Go to original source... Go to PubMed...
  11. Wick M (Ed.) Methodenkatalog. 4. Auflage. 2020. [cited 2026 March 1]. Available from: www.dgln.de/methodenkatalog
  12. Reiber H. Flow rate of cerebrospinal fluid (CSF) - a concept common to normal blood-CSF barrier function and to dysfunction in neurological diseases. J Neurol Sci 1994;122(2):189-203. doi: 10.1016/0022-510x(94)90298-4 Go to original source...
  13. Auer M, Hegen H, Zeileis A, Deisenhammer F. Quantitation of intrathecal immunoglobulin synthesis - a new empirical formula. Eur J Neurol 2016;23(4):713-21. doi: 10.1111/ene-12924 Go to original source... Go to PubMed...
  14. Hegen H, Andreasson U, Archelos-Garcia JJ, Bachmaier G, Blennow K, Bsteh G, Hubeek I, Khalil M, Kuhle J, Kuiperij HB, Lycke J, Rosenstein I, Teunissen CE, Verbeek MM, Willemsen M, Zetterberg H, Walde J, Deisenhammer F. The relationship between CSF/serum immunoglobulin and albumin ratio across laboratories: a retrospective, multi-center study. Fluids Barriers CNS 2026;23:8. doi: 10.1186/s12987-025-00747-5 Go to original source...
  15. Klapper PE, Laing I, Longson M. Rapid non-invasive diagnosis of herpes encephalitis. Lancet 1981:2(8247):607-9. doi: 10.1016/s0140-6736(81)02744-6 Go to original source...
  16. Arnadottir T, Reunanen M, Salmi A. Intrathecal synthesis of virus antibodies in multiple sclerosis patients. Infect Immun 1982;38(2):399-407. doi: 10.1128/iai.38.2.399-407.1982 Go to original source... Go to PubMed...
  17. Ali R, Trier NH, Houen G, Frederiksen JL. Epstein-Barr nuclear antigen 1 antibody-based indices are increased in patients with multiple sclerosis. Mult Scler Rel Disord 2024;92:106173. doi: 10.1016/j.msard.2024.106173 Go to original source...
  18. Reiber H, Ungefehr S, Jacobi C. The intrathecal, polyspecific and oligoclonal immune response in multiple sclerosis. Mult Scler 1998;4(3):111-17. doi: 10.1177/135245859800400304 Go to original source... Go to PubMed...
  19. Conrad AJ, Chiang EY, Andeen LE, Avolio C, Walker SM, Baumhefner RW, Mirzayan R, Tourtellotte WW. Quantitation of intrathecal measles virus IgG antibody synthesis rate: Subacute sclerosing panencephalitis and multiple sclerosis. J Neuroimmunol 1994;54(1-2):99-108. doi: 10.1016/0165-5728(94)90236-4 Go to original source... Go to PubMed...
  20. Jacobi C, Lange P, Reiber H. Quantitation of intrathecal antibodies in cerebrospinal fluid of subacute sclerosing panencephalitis, herpes simplex encephalitis and multiple sclerosis: Discrimination between microorganism-driven and polyspecific immune response. J Neuroimmunol 2007;187(1-2):139-46. doi: 10.1016/j.jneuroim.2007.04.002 Go to original source... Go to PubMed...
  21. Otto C, Hofmann J, Finke C, Zimmermann M, Ruprecht K. The fraction of varicella zoster virus-specific antibodies among all intrathecally-produced antibodies discriminates between patients with varicella zoster virus reactivation and multiple sclerosis. Fluids Barriers CNS 2014;11:3. doi: 10.1186/2045-8118-11-3 Go to original source... Go to PubMed...
  22. Felgenhauer K, Nekic M, Ackermann R. The demonstration of locally synthesized herpes simplex IgG antibodies in CSF by a sepharose 4B linked enzyme immunoassay. J Neuroimmunol 1982;3(2):149-58. doi: 10.1016/0165-5728(82)90048-0 Go to original source... Go to PubMed...
  23. Reiber H. Polyspecific antibodies without persisting antigen in multiple sclerosis, neurolupus and Guillain-Barré syndrome: immune network connectivity in chronic diseases. Arq Neuropsiquiatr 2017;75(8):580-8. doi: 10.1590/0004-282X20170081 Go to original source...
  24. Kyllesbech C, Trier N, Slibinskas R, Ciplys E, Tsakiri A, Frederiksen JL, Houen G. Virus-specific antibody indices may supplement the total IgG index in diagnostics of multiple sclerosis. J Neuroimmunol 2022;367:577868. doi: 10.1016/j.jneuroim.2022.577868 Go to original source... Go to PubMed...
  25. Gåsland H, Trier NH, Kyllesbech C, Draborg AH, Slibinskas R, Ciplys E, Frederiksen JL, Houen G. Antibodies to expanded virus antigen panels show elevated diagnostic sensitivities in multiple sclerosis and optic neuritis. Immunol Letters 2023;254:54-64. doi: 10.1016/j.imlet.2023.02.003 Go to original source... Go to PubMed...
  26. Ku³akowska A, Mroczko B, Mantur M, Lelental N, Tarasiuk J, Kapica-Topczewska K, Schulz U, Lange P, Zimmermann R, Kornhuber J, Lewczuk P. Multiplexing analysis of the polyspecific intrathecal immune response in multiple sclerosis. Methods 2012;56(4):528-31. doi: 10.1016/j.ymeth:2012.03.002 Go to original source...
  27. Huss A, Buttmann M, Brecht I, Weishaupt A, Otto M, Tumani H. Validation of a multiplexing technique to determine the intrathecal, polyspecific antiviral immune response in multiple sclerosis. Exp Rev Mol Diagn 2016;16(12):1353-6. doi: 10.1080/14737159.2016.1249468 Go to original source... Go to PubMed...
  28. Enose-Akahata Y, Wang L, Almsned F, Johnson KR, Mina Y, Ohayon J, Wang XW, Jacobson S. The repertoire of CSF antiviral antibodies in patients with neuroinflammatory diseases. Sci Adv 2023;9(1):eabq6978. doi: 10.1126/sciadv.abq6978 Go to original source...
  29. Dörries R, Ter Meulen V. Detection and identification of virus-specific, oligoclonal IgG in unconcentrated cerebrospinal fluid by immunoblot technique. J Neuroimmunol 1984;7(2-3):77-89. doi: 10.1016/s0165-5728(84)80008-9 Go to original source... Go to PubMed...
  30. Moyle S, Keir G, Thompson EJ. Viral immunoblotting: A sensitive method for detecting viral-specific oligoclonal bands in unconcentrated cerebrospinal fluid. Biosci Rep 1984;4(6):505-10. doi: 10.1007/BF01122226 Go to original source... Go to PubMed...
  31. Kusnierova P, Zeman D, Revendova K, Dlouhy O. Detection of monoclonal free light chains by immunofixation electrophoresis and isoelectric focusing - comparison with the quantitative method of determination. Scand J Clin Lab Invest 2020;80(7):556-561. doi: 10.1080/00365513.20201804608. Go to original source...
  32. Sindic CJ, Monteyne P, Laterre EC. The intrathecal synthesis of virus-specific oligoclonal IgG in multiple sclerosis. J Neuroimmunol 1994;54(1-2):75-80. doi: 10.1016/0165-5728(94)90233-x Go to original source... Go to PubMed...
  33. Frederiksen JL, Sindic CJM. Intrathecal synthesis of virus-specific oligoclonal IgG, and of free kappa and free lambda oligoclonal bands in acute monosymptomatic optic neuritis. Comparison with brain MRI. Mult Scler 1998;4(1):22-6. doi: 10.1177/135245859800400106 Go to original source...
  34. Stich O, Kluge J, Speck J, Rauer S. Oligoclonal restriction of antiviral immunoreaction in oligoclonal band-negative MS patients. Acta Neurol Scand 2015;131(6):381-8. doi: 10.1111/ane.12350 Go to original source... Go to PubMed...
  35. Skorstad G, Hestvik AL, Torjesen P, Alvik K, Vartdal F, Vandvik B, Holmøy T. GAD65 IgG autoantibodies in stiff person syndrome: clonality, avidity and persistence. Eur J Neurol 2008;15(9):973-80. doi: 10.1111/j.1468-1331.2008.02221.x Go to original source... Go to PubMed...
  36. Monteyne P, Albert F, Weissbrich B, Zardini E, Ciardi M, Cleator GM, Sindic CJM and The European Union Concerted Action on Virus Meningitis and Encephalitis. The detection of intrathecal synthesis of anti-herpes simplex IgG antibodies: Comparison between an antigen-mediated immunoblotting technique and antibody index calculations. J Med Virol 1997;53(4):324-31. doi: 10.1002/(sici)1096-9071(199712)53:43.0.co;2-9 Go to original source...
  37. Fainardi E, Castellazzi M, Tamborino C, Seraceni S, Tola MR, Granieri E, Contini C. Chlamydia pneumoniae-specific intrathecal oligoclonal antibody response is predominantly detected in a subset of multiple sclerosis patients with progressive forms. J Neurovirol 2009;15(5-6):425-33. doi: 10.3109/13550280903475580 Go to original source... Go to PubMed...
  38. Castellazzi M, Contini C, Tamborino C, Fasolo F, Roversi G, Seraceni S, Rizzo R, Baldi E, Tola MR, Bellini T, Granieri E, Fainardi E. Epstein-Barr virus-specific intrathecal oligoclonal IgG production in relapsing-remitting multiple sclerosis is limited to a subset of patients and is composed of low-affinity antibodies. J Neuroinflamm 2014;11:188. doi: 10.1186/s12974-014-0188-1 Go to original source...
  39. Jarius S, Eichhorn P, Franciotta D, Petereit HF, Akman-Demir G, Wick M, Wildemann B. The MRZ reaction as a highly specific marker of multiple sclerosis: re-evaluation and structured review of the literature. J Neurol 2017;164:453-66. doi: 10.1007/s00415-016-8360-4 Go to original source... Go to PubMed...
  40. Ruprecht K, Wildemann B, Jarius S. Low intrathecal antibody production despite high seroprevalence of Epstein-Barr virus in multiple sclerosis: a review of the literature. J Neurol 2018;265(2):239-52. doi: 10.1007/s00415-017-8656-z Go to original source... Go to PubMed...
  41. Bednarova J, Stourac P, Adam P. Relevance of immunological variables in neuroborreliosis and multiple sclerosis. Acta Neurol Scand 2005;112(2):97-102. doi: 10.1111/j.1600-0404.2005.00418.x Go to original source... Go to PubMed...
  42. Robinson-Agramonte M, Reiber H, Cabrera-Gomez JA, Galvizu R. Intrathecal polyspecific immune response to neurotropic viruses in multiple sclerosis: a comparative report from Cuban patients. Acta Neurol Scand 2007;113:312-8. doi 10.1111/j.1600-0404.2006.00735.x Go to original source...
  43. Brettschneider J, Tumani H, Kiechle U, Muche R, Richards G, Lehmensiek V, Ludolph AC, Otto M. IgG antibodies against measles, rubella, and varicella zoster virus predict conversion to multiple sclerosis in clinically isolated syndrome. PLoS ONE 2009;4(11):e7638 Go to original source...
  44. Jarius S, Eichhorn P, Jacobi C, Wildemann B, Wick M, Voltz R. The intrathecal, polyspecific antiviral immune response: Specific for MS or a general marker of CNS autoimmunity? J Neurol Sci 2009;280:98-100. doi: 10.1016/j.jns.2008.08.002 Go to original source... Go to PubMed...
  45. Pohl D, Rostasy K, Jacobi C, Lange P, Nau R, Krone B, Hanefeld F. Intrathecal antibody production against Epstein-Barr and other neurotropic viruses in pediatric and adult onset multiple sclerosis. J Neurol 2010;257:212-16. doi: 10.1007/s00415-009-5296-y Go to original source... Go to PubMed...
  46. Hottenrott T, Dersch R, Berger B, Rauer S, Eckenweiler M, Huzly D, Stich O. The intrathecal, polyspecific antiviral immune response in neurosarcoidosis, acute disseminated encephalomyelitis and autoimmune encephalitis compared to multiple sclerosis in a tertiary hospital cohort. Fluids Barriers CNS 2015;12:27. doi: 10.1186/s12987-015-0024-8 Go to original source... Go to PubMed...
  47. Dias-Carneiro RP, von Glehn F, Moraes AS, Boldrini VO, Damasceno A, Andrade MD, Lima AC, Casanova CS, Tilbery CP, Damasceno BP, Santos LM, Brandão CO. MRZH reaction increases sensitivity for intrathecal IgG synthesis in IgG oligoclonal band negative multiple sclerosis patients. J Neuroimmunol 2016;300:30-5. doi: 10.1016/j.jneuroim.2016.10.001 Go to original source...
  48. Feki S, Gargouri S, Mejdoub S, Dammak M, Hachicha H, Hadiji O, Feki L, Hammami A, Mhiri C, Karray H, Masmoudi H. The intrathecal polyspecific antiviral immune response (MRZ reaction): A potential cerebrospinal fluid marker for multiple sclerosis diagnosis. J Neuroimmunol 2018;321:66-71. doi: 10.1016/j.jneuroim.2018.05.015 Go to original source... Go to PubMed...
  49. Venhoff N, Thiel J, Rizzi M, Venhoff A, Rauer S, Endres D, Hentze C, Staniek J, Huzly D, Voll RE, Salzer U, Hottenrott T. The MRZ-reaction and specific autoantibody detection for differentiation of ANA-positive multiple sclerosis from rheumatic diseases with cerebral involvement. Front Immunol 2019;10:514. doi: 10.3389/fimmu.2019.00514 Go to original source...
  50. Largey F, Jelcic Iv, Sospedra M, Heesen C, Martin R, Jelcic Il. Effects of natalizumab therapy on intrathecal antiviral antibody responses in MS. Neurol Neuroimmunol Neuroinflamm 2019;6.e621. doi: 10.1212/NXI.0000000000000621 Go to original source... Go to PubMed...
  51. Robinson T, Abdelhak A, Bose T, Meinl E, Otto M, Zettl UK, Dersch R, Tumani H, Rauer S, Huss A. Cerebrospinal fluid biomarkers in relation to MRZ reaction status in primary progressive multiple sclerosis. Cells 2020;9:2543. doi: 10.3390/cells9122543 Go to original source... Go to PubMed...
  52. Jarius S, Wilken D, Haas J, Ruprecht K, Komorowski L, Wildemann B. Parvovirus B19 and mumps virus antibodies are major constituents of the intrathecal immune response in European patients with MS and increase the diagnostic sensitivity and discriminatory power of the MRZ reaction. J Neurol 2021;268:3758-65. doi: 10.1007/s00415-021-10471-3 Go to original source...
  53. Schwenkenbecher P, Skripuletz T, Lange P, Dürr M, Konen FF, Möhn N, Ringelstein M, Menge T, Friese MA, Melzer N, Malter MP, Häusler M, Thaler FS, Stangel M, Lewerenz J, Sühs KW, on behalf of the German Network for Research on Autoimmune Encephalitis. Intrathecal antibody production against Epstein-Barr, herpes simplex, and other neurotropic viruses in autoimmune encephalitis. Neurol Neuroimmunol Neuroinflamm 2021;8.e1062. doi: 10.1212/NXL0000000000001062 Go to original source...
  54. Zondra Revendova K, Svub K, Bunganic R, Pelisek O, Volny O, Ganesh A, Bar M, Zeman D, Kusnierova P. A comparison of measles-rubella-zoster reaction, oligoclonal IgG bands, oligoclonal kappa free light chains and kappa index in multiple sclerosis. Mult Scler Rel Disord 2024;105125. doi: 10.1016/j.msard.2023.105125 Go to original source... Go to PubMed...
  55. Neidhart S, Vlad B, Hilty M, Högelin KA, Ziegler M, Berenjeno-Correa E, Reichen I, Stridh P, Jelcic Iv, Khademi M, Kockum I, Sospedra M, Al Nimer F, Martin R, Jelcic Il. HLA associations of intrathecal IgG production against specific viruses in multiple sclerosis. Ann Neurol 2024;95:1112-26. doi: 10.1002/ana.26921 Go to original source... Go to PubMed...
  56. Vlad B, Neidhart S, Hilty M, Högelin KA, Reichen I, Ziegler M, Khademi M, Lutterotti A, Regeniter A, Martin R, Al Nimer F, Jelcic Il. Intrathecal immune reactivity against measles-, rubella- and varicella zoster viruses is associated with cerebrospinal fluid inflammation in multiple sclerosis. Mult Scler 2024;30(13):1598-608. doi 10.1177/13524585241279645 Go to original source... Go to PubMed...
  57. D'Cunha MA, Pandit L, Sudhir A. MRZ-reaction maybe influenced by immunization status and is not exclusive to multiple sclerosis. J Neurol Sci 2025;468:123365. doi: 10.1016/j.jns.2024.123365 Go to original source... Go to PubMed...
  58. Pache F, Otto C, Wilken D, Lietzow T, Steinhagen K, Grage-Griebenow E, Schindler P, Niederschweiberer M, Wildemann B, Jarius S, Ruprecht K. Broad analysis of serum and intrathecal antimicrobial antibodies in multiple sclerosis underscores unique role of Epstein-Barr virus. Neurol Neuroimmunol Neuroinflamm 2025;12:e200332. doi: 10.1212/NXI.0000000000200332 Go to original source...
  59. Rodomonti M, Pache F, Otto C, Schindler P, Eberspächer B, Geran R, Puthenparampil M, Gallo P, Wildemann B, Jarius S, Erdur H, Ruprecht K. Retrospective in silico analysis of routine laboratory data supports a specific association of Epstein-Barr virus and multiple sclerosis. Eur J Neurol 2025:32:e70430. doi: 10.1111/ene.70430 Go to original source... Go to PubMed...
  60. Reiber H, Teut M, Pohl D, Rostasy KM, Hanefeld F. Paediatric and adult multiple sclerosis: age-related differences and time course of the neuroimmunological response in cerebrospinal fluid. Mult Scler 2009;15(12):1466-80. doi: 10.1177/1352458509348418 Go to original source...
  61. Petereit HF, Reske D. Expansion of antibody reactivity in the cerebrospinal fluid of multiple sclerosis patients - follow-up and clinical implications. Cerebrospinal Fluid Res 2005;2:3. doi: 10.1186/1743-8454-2-3 Go to original source... Go to PubMed...
  62. Süße M, Reiber H, Grothe M, Petersmann A, Nauck M, Dressel A, Hannich MJ. Free light chain kappa and the polyspecific immune response in MS and CIS - Application of the hyperbolic reference range for most reliable data interpretation. J Neuroimmunol 2020;346:577287. doi: 10.1016/j.jneuroim.2020.577287 Go to original source... Go to PubMed...
  63. Kauth F, Chen S, Wendel EM, Reindl M, Heußinger N, Rostasy K. The presence of MRZ reactions improves the prediction of multiple sclerosis in children with optic neuritis. Children 2025;12:497. doi: 10.3390/children12040497 Go to original source...
  64. Chen S, Bertolini A, Koukou G, Wendel EM, Thiels C, Baumann M, Lechner C, Blaschek A, Della Marina A, Classen G, Stüve B, Kauffmann B, Kapanci T, Mayer B, Otto M, Rostásy K. Frequency of an intrathecal IgM synthesis and MRZ reaction in children with MS. Eur J Paed Neurol 2024;50:51-6. doi: 10.1016/j.ejpn.2024.04.005 Go to original source... Go to PubMed...
  65. Hottenrott T, Dersch R, Berger B, Rauer S, Huzly D, Stich O. The MRZ reaction in primary progressive multiple sclerosis. Fluids Barriers CNS 2017;14:2. doi: 10.1186/s12987-016-0049-7 Go to original source...
  66. Konen FF, Hannich MJ, Schwenkenbecher P, Grothe M, Gag K, Jendretzky KF, Gingele S, Sühs KW, Witte T, Skripuletz T, Süße M. Diagnostic cerebrospinal fluid biomarker in early and late onset multiple sclerosis. Biomedicines 2022;10:1629. doi: 10.3390/biomedicines10071629 Go to original source... Go to PubMed...
  67. Steinegger L, Kana V, Nierobisch N, Elshahabi A, Weller M, Herwerth M, Roth P. Distinct clinical, imaging, and cerebrospinal fluid profiles in people with late-onset multiple sclerosis. Mult Scler Rel Disord 2025;97:106399. doi: 10,1016/j.msard.106399 Go to original source...
  68. Vlad B, Hilty M, Neidhart S, Högelin KA, Ziegler M, Khademi M, Lutterotti A, Regeniter A, Martin R, Al Nimer F, Jelcic Il. Intensity of intrathecal total IgG synthesis in multiple sclerosis correlates with the degree of pleocytosis, diversity of intrathecal antiviral antibody specificities, and female sex. Antibodies 2024;13:102. doi: 10.3390/antib13040102 Go to original source... Go to PubMed...
  69. Davidkin I, Jokinen S, Broman M, Leinikki P, Peltola H. Persistence of measles, mumps, and rubella antibodies in an MMR-vaccinated cohort: a 20-year follow-up. J Infect Dis 2008;197(7):950-6. doi: 10.1086/528993 Go to original source... Go to PubMed...
  70. Li W, Sguigna P, Rupareliya C, Subramanian S, Salahuddin H, Husari KS, Moore W, Johnson M, Magadan A, Grose C, Nijhawan AE, Shang T. Detection of varicella zoster virus reactivation in cerebrospinal fluid in ischemic stroke or transient ischemic attack. J Am Heart Assoc 2025;14:e039489. doi: 10.1161/JAHA.124.039489 Go to original source... Go to PubMed...
  71. Sternberger Mariæ L, Dakoviæ Rode O, Vi¹koviæ K, Heæimoviæ H, Lamba¹a S, Lepur D. Atypical adult-onset subacute sclerosing panencephalitis. Acta Clin Croat 2020;59:543-8. doi: 10.20571/acc.2020.59.00.21 Go to original source...
  72. Wurster U, Bachhuber F, Tumani H. Nachweis und Bedeutung von oligoklonalen Banden. In: Zettl UK, Tumani H, Süßmuth SD (Eds.) Klinische Liquordiagnostik. 3rd Edition.Walter de Gruyter, Berlin 2025, pp. 309-361. ISBN 978-3-11-022193-0.
  73. Graef IT, Henze T, Reiber H. Polyspezifische Immunreaktion im ZNS bei Autoimmunerkrankungen mit ZNS-Beteiligung. Z Ärztl Fortbild 1994;88:587-91.
  74. Hottenrott T, Dersch R, Berger B, Rauer S, Eckenweiler M, Huzly D, Stich O. The intrathecal, polyspecific antiviral immune response in neurosarcoidosis, acute disseminated encephalomyelitis and autoimmune encephalitis compared to multiple sclerosis in a tertiary hospital cohort. Fluids Barriers CNS 2015;12:27. doi: 10.1186/s12987-015-0024-8 Go to original source... Go to PubMed...
  75. Hottenrott T, Dersch R, Berger B, Endres D, Huzly D, Thiel J, Rauer S, Stich O, Salzer U, Venhoff N. The MRZ reaction helps to distinguish rheumatologic disorders with central nervous involvement from multiple sclerosis. BMC Neurology 2018;18:14. doi: 10.1186/s12883-018-1018-3 Go to original source... Go to PubMed...
  76. Moshnikova AN, Lapin SV, Nazarov VD, Krasnov VS, Dovidenko KS, Surkova EA, Savostyanova VN. [The diagnostic significance of intrathecal synthesis of antibodies against measles, rubella, and varicella zoster viruses in the differential diagnosis of demyelinating diseases of the central nervous system.] Ann Clin Exp Neurol 2020;14(2):15-22. doi: 10.25692/ACEN.2020.2.2 Go to original source...
  77. Vlad B, Neidhart S, Hilty M, Ziegler M, Jelcic Il. Differentiating neurosarcoidosis from multiple sclerosis using combined analysis of basic CSF parameters and MRZ reaction. Front Neurol 2023;14:1135392. doi: 10.3389/fneur.2023.1135392 Go to original source... Go to PubMed...
  78. Vlad B, Reichen I, Neidhart S, Hilty M, Lekaditi D, Heuer C, Eisele A, Ziegler M, Reindl M, Lutterotti A, Regeniter A, Jelcic Il. Basic CSF parameters and MRZ reaction help in differentiating MOG antibody-associated autoimmune disease versus multiple sclerosis. Front Immunol 2023;14:1237149. doi: 10.3389/fimmu.20231237149 Go to original source...
  79. Hottenrott T, Schorb E, Fritsch K, Dersch R, Berger B, Huzly D, Rauer S, van Elst LT, Endres D, Stich O. The MRZ reaction and a quantitative intrathecal IgG synthesis may be helpful to differentiate between primary central nervous system lymphoma and multiple sclerosis. J Neurol 2018;265:1106-14. doi: 10.1007/s00415-018-8779-x Go to original source... Go to PubMed...
  80. Brauchle F, Rapp D, Senel M, Huss A, Dreyhaupt J, Klose V, Süße M, Stürner KH, Leypoldt F, Tumani H, Lewerenz J. Clinical associations and characteristics of the polyspecific intrathecal immune response in elderly patients with non-multiple sclerosis chronic autoimmune-inflammatory neurological diseases - a retrospective cross-sectional study. Front Neurol 2023;14:11903015. doi: 10.3389/fneur.2023.1193015 Go to original source...
  81. Rosche B, Laurent S, Conradi S, Hofmann J, Ruprecht K, Harms L. Measles IgG antibody index correlates with T2 lesion load on MRI in patients with early multiple sclerosis. PLoS ONE 2012;7(1):e28094. doi: 10.1371/journal.pone.0028094 Go to original source... Go to PubMed...
  82. Huss A, Mojib-Yezdani F, Bachhuber F, Fangerau T, Lewerenz J, Otto M, Tumani H, Senel M. Association of cerebrospinal fluid kappa free light chains with the intrathecal polyspecific antiviral immune response in multiple sclerosis. Clin Chim Acta 2019;498:148-53. doi: 10.1016/j.cca.2019.08.016 Go to original source... Go to PubMed...
  83. Auf dem Brinke K, Thust NB, Simou A, Lattau SSJ, Lange P, Hansen N, Wallbach M, Fitzner D. Intrathecal kappa free light chains in relation to IgM synthesis and MRZH reaction in a mixed neurological cohort. J Neurochem 2026;170(2):e70383. doi: 10.1111/jnc.70383 Go to original source...
  84. Brecht I, Weissbrich B, Braun J, Toyka KV, Weishaupt A, Buttmann M. Intrathecal, polyspecific antiviral immune response in oligoclonal band negative multiple sclerosis. PLoS ONE 2012;7(7):e40431. doi: 10.1371/journal.pone.0040431 Go to original source... Go to PubMed...
  85. Jarius S, Eichhorn P, Wildemann B, Wick B. Usefulness of antibody index assessment in cerebrospinal fluid from patients negative for total-IgG oligoclonal bands. Fluids Barriers CNS 2012;9(1):14. doi: 10.1186/2045-8118-9-14 Go to original source...
  86. Roström B, Link H, Laurenzi MA, Kam-Hansen S, Norrby E, Wahren B. Viral antibody activity of oligoclonal and polyclonal immunoglobulins synthesized within the central nervous system in multiple sclerosis. Ann Neurol 1981;9(6):569-74. doi: 10.1002/ana.410090610 Go to original source... Go to PubMed...
  87. Virtanen JO, Wohler J, Fenton K, Reich DS, Jacobson S. Oligoclonal bands in multiple sclerosis reactive against two herpesviruses and association with magnetic resonance imaging findings. Mult Scler 2014;20(1):27-43. doi: 10.1177/1352458513490545 Go to original source... Go to PubMed...
  88. Franciotta D, Zardini E, Bergamaschi R, Grimaldi LM, Andreoni L, Cosi V. Analysis of Chlamydia pneumoniae-specific oligoclonal bands in multiple sclerosis and other neurologic diseases. Acta Neurol Scand 2005;112(4):238-41. doi: 10.1111/j.1600-0404.2005.00407x Go to original source...
  89. Martin C, Enbom M, Söderström M, Fredrikson S, Dahl H, Lycke J, Bergström T, Linde A. Absence of seven human herpesviruses, including HHV-6, by polymerase chain reaction in CSF and blood from patients with multiple sclerosis and optic neuritis. Acta Neurol Scand 1997;95(5):280-3. doi:10.1111/j.1600-0404.1997.tb00210.x Go to original source... Go to PubMed...
  90. Godec MS, Asher DM, Murray RS, Shin ML, Greenham LW, Gibbs CJ, Gajdusek C. Absence of measles, mumps, and rubella viral genomic sequences from multiple sclerosis brain tissue by polymerase chain reaction. Ann Neurol 1992;32(3):401-4. doi:10.1002/ana.410320317 Go to original source...
  91. Bigdeli A, Ghaderi-Zefrehei M, Lesch BJ, Behmanesh M, Arab SS. Bioinformatics analysis of myelin-microbe interactions suggests multiple types of molecular mimicry in the pathogenesis of multiple sclerosis. PLoS ONE 2024;19(12):e0308817. doi: 10.1371/journal.pone.0308817 Go to original source... Go to PubMed...
  92. Thomas G, Rael L, Shimonkevitz R, Melamed I, Bar-Or D. Autoantibody reaction to myelin basic protein by plasma parvovirus B19 IgG in MS patients. Protein Pept Lett 2006;13(2):109-11. doi: 10.2174/092986606775101715 Go to original source... Go to PubMed...
  93. von Büdingen HC, Kuo TC, Sirota M, van Belle CJ, Apeltsin L, Glanville J, Cree BA, Gourraud PA, Schwartzburg A, Huerta G, Telman D, Sundar PD, Casey T, Cox DR, Hauser SL. B cell exchange across the blood-brain barrier in multiple sclerosis. J Clin Invest 2012;122(12):4533-43. doi: 10.1172/JCI63842 Go to original source...
  94. Tomescu-Baciu A, Johansen JN, Holmøy T, Greiff V, Stensland M, de Souza GA, Vartdal F, Lossius A. Persistence of intrathecal oligoclonal B cells and IgG in multiple sclerosis. J Neuroimmunol 2019;333:576966. doi: 10.1016/j.jneuroim.2019.576966 Go to original source... Go to PubMed...
  95. Reiber H, Kruse-Sauter H, Quentin CD. Antibody patterns vary arbitrarily between cerebrospinal fluid and aqueous humor of the individual multiple sclerosis patient: Specificity-independent pathological B cell function. J Neuroimmunol 2015;278:247-54. doi: 10.1016/j.jneuroim.2014.11.013 Go to original source... Go to PubMed...
  96. Skorstad G, Vandvik B, Vartdal F, Holmøy T. MS and clinically isolated syndromes: Shared specificity but diverging clonal patterns of virus-specific IgG antibodies produced in vivo and by CSF B cells in vitro. Eur J Neurol 2009;16(10):1124-9. doi: 10.1111/j.1468-1331.2009.02657.x Go to original source... Go to PubMed...
  97. Maruyama M, Lam KP, Rajewsky K. Memory B-cell persistence is independent of persisting immunizing antigen. Nature 2000;407(6804):636-42. doi:10.1038/35036600 Go to original source...
  98. Tomescu-Baciu A, Vartdal F, Holmøy T, Vedeler CA, Lossius A. G1m1 predominance of intrathecal virus-specific antibodies in multiple sclerosis. Ann Clin Transl Neurol 2018;5(10):1303-9. doi: 10.1002/acn3.642 Go to original source... Go to PubMed...
  99. Høglund RA, Bremel RD, Homan EJ, Torsetnes SB, Lossius A, Holmøy T. CD4+ T cells in the blood of MS patients respond to predicted epitopes from B cell receptors found in spinal fluid. Front Immunol 2020;11:598. doi: 10.3389/fimmu.2020.00598 Go to original source... Go to PubMed...
  100. Ahlgren C, Odén A, Haghighi S, Andersen O, Bergström T, Lycke J. The effect of live, attenuated measles vaccine and measles infection on measles antibody levels in serum and CSF of patients with multiple sclerosis or clinically isolated syndrome. J Neuroimmunol 2011;235:98-103. doi: 10.1016/j.jneuroim.2011.04.002 Go to original source...

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