Diagnostic significance of intrathecally synthesized immunoglobulins against neurotropic viruses (MRZ-reaction) in diagnosis of multiple sclerosis

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Abstract

Multiple sclerosis is chronic demyelinating disease of the central nervous system with autoimmune inflammation and accretive neurodegeneration. One of the characteristics of autoimmune inflammation in multiple sclerosis is a polyspecific intrathecal humoral immune response against neurotropic viruses (Measles, Rubella and varicella Zoster) called MRZ-reaction. This immune response is based on polyclonal activation of mature B lymphocytes in the central nervous system and intrathecal synthesis of antibodies to anamnestic antigens unrelated to viral replication in the central nervous system as well as serum antibody release. Immunoglobulins produced against neurotropic viruses are an integral part of the oligoclonal antibody pool in the cerebrospinal fluid. Because immunoglobulins can penetrate the blood brain barrier, not only serum and cerebrospinal fluid specific antibody indices are calculated, but also blood-brain barrier antibody permeability (Qalbumin, QIgG) are taken into account to assess their intrathecal synthesis. The aim of the study was to assess the informative value of the intrathecal antibodies against neurotropic viruses (MRZ-reaction) in multiple sclerosis. There were enrolled 60 patients divided into 2 groups: group 1 — 35 patients diagnosed with multiple sclerosis, group 2 — 25 patients with inflammatory and non-inflammatory disоrders of the central nervous system. Paired cerebrospinal fluid and serum samples were collected from all patients to measure level of oligoclonal IgG, immunoglobulin free kappa and lambda light chains, IgG index and specific antibodies indices, followed by assessing magnitude of MRZ-reaction. We found that the MRZ-reaction was the most specific test to diagnose multiple sclerosis. Intrathecally produced antibodies against neurotropic viruses were detected in 3 of 35 multiple sclerosis patients with lacking oligoclonal IgG antibodies. In addition, a relationship between MRZ-reaction and degree of EDSS disability was found in MS patients: peak EDSS score was reported in patients with intrathecally synthesized antibodies against 3 viral agents, whereas the minimum EDSS score — among MRZ-negative patients. Thus, assessing MRZ-reaction seems rational for confirming MS diagnosis in case of other negative laboratory tests (oligoclonal immunoglobulins and free kappa/lambda light chains in cerebrospinal fluid) allowing to improves diagnostic accuracy and evaluation of MS severity.

About the authors

A. N. Moshnikova

Pavlov First St. Petersburg State Medical University

Author for correspondence.
Email: moshnikova-anna@mail.ru

Anna N. Moshnikova, Junior Researcher, Autoimmune Diseases Diagnostics Laboratory, Scientific and Methodological Center for Molecular Medicine

197022, St. Petersburg, L. Tolstoy str., 6/8.

Phone: +7 (812) 499-71-94 (office).

Russian Federation

V. K. Maksimchuk

Pavlov First St. Petersburg State Medical University

Email: guravkon@mail.ru

6th Year Student

St. Petersburg

Russian Federation

S. V. Lapin

Pavlov First St. Petersburg State Medical University

Email: svlapin@mail.ru

PhD (Medicine), Head of the Autoimmune Diseases Diagnostics Laboratory, Scientific and Methodological Center for Molecular Medicine

St. Petersburg

Russian Federation

V. D. Nazarov

Pavlov First St. Petersburg State Medical University

Email: nazarov19932@mail.ru

Junior Researcher, Autoimmune Diseases Diagnostics Laboratory, Scientific and Methodological Center for Molecular Medicine

St. Petersburg

Russian Federation

E. A. Surkova

Pavlov First St. Petersburg State Medical University

Email: easurkova@mail.ru

PhD (Biology), Senior Researcher, Autoimmune Diseases Diagnostics Laboratory, Scientific and Methodological Center for Molecular Medicine

St. Petersburg

Russian Federation

S. A. Novikov

Pavlov First St. Petersburg State Medical University

Email: fake@neicon.ru

PhD, MD (Medicine), Professor of the Department of Ophthalmology

St. Petersburg

Russian Federation

G. S. Makshakov

City Center for Multiple Sclerosis and Autoimmune Diseases Treatment, St. Petersburg

Email: g.makshakov@centrems.com
ORCID iD: 0000-0001-6831-0441

Neurologist, City Center for Multiple Sclerosis and Autoimmune Diseases Treatment

St. Petersburg

Russian Federation

I. Yu. Krutetskaya

A.M. Granov Russian Research Center for Radiology and Surgical Technologies

Email: mpsamoylovich@gmail.com

PhD (Biology), Senior Researcher, Laboratory of Hybridoma Technology

St. Petersburg

Russian Federation

V. S. Krasnov

Pavlov First St. Petersburg State Medical University

Email: krasnov_volod@mail.ru

Associate Professor, Department of Neurology

St. Petersburg

Russian Federation

Ya. B. Kushnir

Pavlov First St. Petersburg State Medical University

Email: kushnir.yana2014@yandex.ru

Neurologist, Neurology Clinic No. 1

St. Petersburg

Russian Federation

N. A. Neofidov

Pavlov First St. Petersburg State Medical University; City Center for Multiple Sclerosis and Autoimmune Diseases Treatment, St. Petersburg

Email: n.neofidov@centrems.com
ORCID iD: 0000-0001-9043-9823

PhD Student, Department of Neurology; Neurologist

St. Petersburg

Russian Federation

N. A. Totolian

Pavlov First St. Petersburg State Medical University

Email: ntotolyan@mail.ru

PhD, MD (Medicine), Professor of the Department of Neurology

St. Petersburg

Russian Federation

A. A. Skoromets

Pavlov First St. Petersburg State Medical University

Email: askoromets@gmail.com

RAS Full Member, PhD, MD (Medicine), Professor, Head of the Department of Neurology

St. Petersburg

Russian Federation

E. P. Evdoshenko

Pavlov First St. Petersburg State Medical University; City Center for Multiple Sclerosis and Autoimmune Diseases Treatment, St. Petersburg

Email: e.evdoshenko@centrems.com
ORCID iD: 0000-0002-8006-237X

PhD (Medicine), Neurologist, Head of the City Center for Multiple Sclerosis and Autoimmune Diseases Treatment; Doctoral Student, Department of Neurology

St. Petersburg

Russian Federation

Areg A. Totolian

Pavlov First St. Petersburg State Medical University; St. Petersburg Pasteur Institute

Email: totolian@spbraaci.ru

RAS Full Member, PhD, MD (Medicine), Professor, Head of the Department of Immunology; Director, St. Petersburg Pasteur Institute

St. Petersburg

Russian Federation

References

  1. Евдошенко Е.П., Маслянский А.Л., Заславский Л.Г., Скоромец А.А., Зюзгин И.С., Рябыкина О.Е., Тотолян Н.А., Зуева Е.Е., Лапин С.В., Тотолян А.А. Возможности анти-В-клеточной терапии при рассеянном склерозе // Медицинская иммунология. 2009. Т. 11, № 1. С. 63–70. doi: 10.15789/1563-0625-2009-1-63-70
  2. Маслянский А.Л., Евдошенко Е.П., Заславский Л.Г., Скоромец А.А., Зюзгин И.С., Рябыкина О.Е., Тотолян Н.А., Лапин С.В., Станкевич Ю.А., Тотолян А.А. Роль В-лимфоцитов в патогенезе рассеянного склероза и новые возможности терапии // Молекулярная медицина. 2010. № 2. С. 22–27.
  3. Назаров В.Д., Лапин С.В., Суркова Е.А., Евдошенко Е.П., Макшаков Г.С. Диагностическая информативность показателей интратекального синтеза свободных легких цепей иммуноглобулинов при рассеянном склерозе // Медицинская иммунология. 2015. Т. 17, № 3. С. 235–244. doi: 10.15789/1563-0625-2015-3-235-244
  4. Тотолян Н.А., Георгеос Ф., Смирнов А.Ю. Методические особенности определения иммунологических показателей в цереброспинальной жидкости // Лабораторное дело. 1990. № 7. С. 57–60.
  5. Тотолян Н.А., Готовчиков А.А., Лапин С.В., Максимов И.В., Кодзаева А.Ю., Прахова Л.Н., Ильвес А.Г., Скоромец А.П., Скоромец А.А. Интратекальный синтез иммуноглобулинов в диагностике и дифференциальной диагностике рассеянного склероза // Журнал неврологии и психиатрии имени С.С. Корсакова. 2012. Т. 112, № 9. С. 73–86.
  6. Тотолян Н.А., Грязева И.В., Климович В.Б., Тотолян А.А. Интратекальный синтез свободных легких цепей иммуноглобулинов и его связь с другими иммунными нарушениями у больных рассеянным склерозом // Иммунология. 1994. № 1. C. 54–57.
  7. Тотолян Н.А., Грязева И.В., Климович В.Б., Тотолян А.А. Свободные легкие цепи иммуноглобулинов в биологических жидкостях больных рассеянным склерозом // Журнал неврологии и психиатрии им. С.С. Корсакова. 1997. № 5. С. 34–38.
  8. Тотолян Н.А., Скоромец А.А., Барбас И.М., Трофимова Т.Н. Актуальные практические вопросы диагностики рассеянного склероза // Ученые записки СПбГМУ им. академика И.П. Павлова. 2000. Т. 7, № 3. С. 37–48.
  9. Bonnan M. Does disease-irrelevant intrathecal synthesis in multiple sclerosis make sense in the light of tertiary lymphoid organs? Front. Neurol., 2014, no. 5. doi: 10.3389/fneur.2014.00027
  10. Brecht I., Weissbrich B., Braun J., Toyka K., Weishaupt A., Buttmann M. Intrathecal, polyspecific antiviral immune response in oligoclonal band negative multiple sclerosis. PLoS One, 2012, vol. 7, no. 7: e40431. doi: 10.1371/journal.pone.0040431
  11. Brettschneider J., Tumani H., Kiechle U., Muche R., Richards G., Lehmensiek V., Ludolph A.C., Otto M. IgG antibodies against measles, rubella, and varicella zoster virus predict conversion to multiple sclerosis in clinically isolated syndrome. PLoS One, 2009, vol. 4, no. 11: 7638. doi: 10.1371/journal.pone.0007638
  12. Conrad A.J., Chiang E.Y., Andeen L.E., Avolio C., Walker S.M., Baumhefner R.W., Mirzayan R., Tourtellotte W.W. Quantitation of intrathecal measles virus IgG antibody synthesis rate: subacute sclerosing panencephalitis and multiple sclerosis. J. Neuroimmunol., 1994, vol. 54, no. 1–2, pp. 99–108. doi: 10.1016/0165-5728(94)90236-4
  13. Evdoshenko E., Maslyanskiy A., Lapin S., Zaslavsky L., Dobson R., Skoromets A., Bar-Or A. Dynamics of B-Cell Populations in CSF and Blood in Patients Treated with a Combination of Rituximab and Mitoxantrone. ISRN Neurology, 2013, 8 p. doi: 10.1155/2013/748127
  14. Felgenhauer K., Reiber H. The diagnostic significance of antibody specificity indices in multiple sclerosis and herpes virus induced diseases of the nervous system. Clin. Investig., 1992, vol. 70, no. 1, pp. 28–37. doi: 10.1007/bf00422934
  15. Graef I.T., Henze T., Reiber H. Polyspecific immune reaction in the central nervous system in autoimmune diseases with CNS involvement. Z. Arztl. Fortbild., 1994, vol. 88, pp. 587–591. doi: 10.1186/s12987-015-0024-8
  16. Hela-Felicitas P., Reske D. Expansion of antibody reactivity in the cerebrospinal fluid of multiple sclerosis patients — follow-up and clinical implications. Cerebrospinal. Fluid Res., 2005, vol. 2, pp. 3–10. doi: 10.1186/1743-8454-2-3
  17. 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, no. 12: 27. doi: 10.1186/s12987-015-0024-8
  18. 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, vol. 187, no. 1–2, pp. 139–146. doi: 10.1016/j.jneuroim.2007.04.002
  19. Jarius S., Eichhorn P., Franciotta D., Petereit H.F., 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, vol. 264, no. 3, pp. 453–466. doi: 10.1007/s00415-016-8360-4
  20. 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, vol. 280, no. 1–2, pp. 98–100. doi: 10.1371/journal.pone.0028094
  21. Jarius S., Franciotta D., Bergamaschi R., Rauer S., Wandinger K.P., Petereit H.F., Maurer M., Tumani H., Vincent A., Eichhorn P., Wildemann B., Wick M., Voltz R. Polyspecific, antiviral immune response distinguishes multiple sclerosis and neuromyelitis optica. J. Neurol. Neurosurg. Psychiatry, 2008, vol. 79, pp. 1134–1136. doi: 10.1136/jnnp.2007.133330
  22. Kurtzke J.F. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology, 1983, vol. 33, no. 11, pp. 1444–1452. doi: 10.1212/WNL.33.11.1444
  23. Krumbholz M., Theil D., Cepok S., Hemmer B., Kivisäkk P., Ransohoff R.M., Hofbauer M., Farina C., Derfuss T., Hartle C., Newcombe J., Hohlfeld R., Meinl E. Chemokines in multiple sclerosis: CXCL12 and CXCL13 up-regulation is differentially linked to CNS immune cell recruitment. Brain, 2006, vol. 129, pt. 1, pp. 200–211. doi: 10.1093/brain/awh680
  24. Quentin C.D., Reiber H. Fuchs heterochromic cyclitis: rubella virus antibodies and genome in aqueous humor. Am. J. Ophthalmol., 2004, vol. 138, no. 1, pp. 46–54. doi: 10.1016/j.ajo.2004.02.055
  25. Ragheb S., Li Y., Simon K., Vanhaerents S., Galimberti D., De Riz M., Lisak R. Multiple sclerosis: BAFF and CXCL13 in cerebrospinal fluid. Mult. Scler., 2011, vol. 17, no. 7, pp. 819–829. doi: 10.1177%2F1352458511398887
  26. Reiber H. Knowledge-base for interpretation of cerebrospinal fluid data patterns: essentials in neurology and psychiatry. Arq. Neuropsiquiatr., 2016, vol. 74, no. 6, pp. 501–512. doi: 10.1590/0004-282x20160066
  27. Reiber H. Polyspecific antibodies without persisting antigen in multiple sclerosis, neurolupus and Guillain-Barre syndrome: immune network connectivity in chronic diseases. Arq. Neuro-Psiquiatr., 2017, vol. 75, no. 8, pp. 580–588. doi: 10.1590/0004-282X20170081
  28. 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, vol. 278, pp. 247–254. doi: 10.1016/j.jneuroim.2014.11.013
  29. 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, vol. 37, no. 7, pp. 1153–1160.
  30. Reiber H., Ungefehr S., Jacobi C. The intrathecal, polyspecific and oligoclonal immune response in multiple sclerosis. Mult. Scler., 1998, vol. 4, no. 3, pp. 111–117. doi: 10.1177%2F135245859800400304
  31. Robinson-Agramonte M., Reiber H., Cabrera-Gomez J., Galvizu R. Intrathecal polyspecific immune response to neurotropic viruses in multiple sclerosis: a comparative report from Cuban patients. Acta Neurol. Scand., 2007, vol. 115, no. 5, pp. 312–318. doi: 10.1111/j.1600-0404.2006.00755.x
  32. Sindic C.J., Monteyne P., Laterre E.C. The intrathecal synthesis of virus-specific oligoclonal IgG in multiple sclerosis. J. Neuroimmunol., 1994, vol. 54, pp. 75–80. doi: 10.1016/0165-5728(94)90233-X
  33. Stich O., Kluge J., Speck J., Rauer S. Oligoclonal restriction of antiviral immunoreaction in oligoclonal band-negative MS patients. Acta Neurol. Scand., 2015, vol. 131, pp. 381–388. doi: 10.1111/ane.12350
  34. Thompson A.J., Banwell B. L., Barkhof F., Carroll W.M., Coetzee T., Comi G., Correale J., Fazekas F., Filippi M., Freedman M.S., Fujihara K., Galetta S.L., Hartung H.P., Kappos L., Lublin F.D., Ann M.R., Miller A.E., Miller D.H., Montalban X., Mowry E.M., Sorensen P. S., Tintor M., Traboulsee A.L., Trojano M., Uitdehaag B.M.J., Vukusic S., Waubant E., Weinshenker B.G., Reingold S.C., Cohen J.A. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol., 2018, vol. 17, no. 2, pp. 162–173. doi: 10.1016/S1474-4422(17)30470-2

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Copyright (c) 2019 Moshnikova A.N., Maksimchuk V.K., Lapin S.V., Nazarov V.D., Surkova E.A., Novikov S.A., Makshakov G.S., Krutetskaya I.Y., Krasnov V.S., Kushnir Y.B., Neofidov N.A., Totolian N.A., Skoromets A.A., Evdoshenko E.P., Totolian A.A.

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