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DIAGNOSTIC AND PROGNOSTIC SIGNIFICANCE OF INTRATHECAL SYNTHESIS OF IMMUNOGLOBULIN FREE LIGHT CHAINS IN MULTIPLE SCLEROSIS

https://doi.org/10.15789/1563-0625-2015-3-235-244

Abstract

Increased intrathecal synthesis and oligoclonal banding of immunoglobulins (Ig) in cerebrospinal fluid (CSF) are major immunological findings in multiple sclerosis. Free light chains are fragments of Ig molecules that are produced in parallel to oligoclonal Ig, and their production reflects total Ig synthesis within central nervous system. Assessment of intrathecal kappaand lambda free light chain production within CNS compartment will help to improve diagnosis and prediction of outcomes in multiple sclerosis. Concentrations of kappa and lambda free light chains and clonality of immunoglobulin pattern synthesis were studied in paired CSF and serum samples of 151 patients, including 92 patients with multiple sclerosis, and 33 patients with clinically isolated syndrome which later was transformed into the definite multiple sclerosis. A control group consisted of 26 patients with other inflammatory diseases of central nervous system. Several Ig parameters have been determined in the patients, i.e., Ig clonality in CSF; concentrations of free light chains (both kappaand lambda-) in CSF; as well as their indexes and ratios. It was established that synthesis of kappa free light chains were significantly elevated in patients with multiple sclerosis. Moreover, the amounts of free light Ig chains in patients with positive oligoclonality test were significantly higher than in cases without intrathecal oligoclonal synthesis. With respect to diagnostic significance, the kappa quotient proved the best available option for diagnosis of multiple sclerosis. Its combination with Ig oligoclonality assays caused a decrease in false-negative diagnostics by 42%. Diagnostic benefit of the kappa quotient could be also confirmed by the data of ROC analysis. Also concentration of lambda free light chains in cerebrospinal fluid showed a negative correlation with conversion terms of clinically isolated syndrome to evident multiple sclerosis. Therefore, the indexes of free Ig light chains enables more precise diagnostics, like as more efficient severity evaluation of multiple sclerosis. 

About the Authors

V. D. Nazarov
First I. Pavlov State Medical University, St. Petersburg
Russian Federation

Laboratory of Autoimmune Diagnostics, Center for Molecular Medicine.

Address for correspondence: Nazarov Vladimir D. First I. Pavlov State Medical University 197022, Russian Federation, St. Petersburg, L. Tolstoy str., 6/8, Bldg 28. Phone: 7 (812) 499-71-94. E-mail: Nazarov19932@mail.ru



S. V. Lapin
First I. Pavlov State Medical University, St. Petersburg
Russian Federation
PhD (Medicine), Chief, Laboratory of Autoimmune Diagnostics, Center for Molecular Medicine


E. A. Surkova
First I. Pavlov State Medical University, St. Petersburg
Russian Federation
PhD (Biology), Senior Research Associate, Laboratory for Diagnostics of Autoimmune Diseases, Center for Molecular Medicine


E. P. Evdoshenko
Municipal Hospital N 31, St. Petersburg
Russian Federation
PhD (Medicine), Neurologist, Chief, St. Petersburg Center of Multiple Sclerosis


G. S. Makshakov
Municipal Hospital N 31, St. Petersburg
Russian Federation
Neurologist, St. Petersburg Center of Multiple Sclerosis


Areg A. Totolian
St. Petersburg Pasteur Institute of Epidemiology and Microbiology
Russian Federation
PhD, MD (Medicine), Professor, Corresponding Member of the Russian Academy of Medical Sciences, Director for Research, St. Petersburg Pasteur Institute of Epidemiology and Microbiology


References

1. Бойко А.Н., Фаворова О.О., Кулакова О.Г., Гусев Е.И. Эпидемиология и этиология рассеянного склероза. В кн.: Рассеянный склероз, ред. Гусев Е.И., Завалишин И.А., Бойко А.Н. М., 2004. С. 7-42. [Boyko A.N., Favorova O.O., Kulakova O.G., Gusev E.I. Epidemiology and etiology of multiple sclerosis. Edited by Gusev E.I., Zavalishin I.A., Boyko A.N.]. Moscow, 2004, pp. 7-42.

2. Лапин С. В., Евдошенко Е. П. Лабораторные методы диагностики рассеянного склероза и других неврологических заболеваний // Справочник заведующего КДЛ, 2011. № 1. C. 22-32. [Lapin S.V., Evdoshenko E.P. Laboratory diagnostic of multiple sclerosis and other neurologic diseases. Spravochnik zaveduyushchego KDL = Handbook of Clinical Diagnostic Laboratory, 2011, no. 1, pp. 22-32. [In Russ.]

3. Тотолян Н.А., Грязева И.В., Климович В.Б., Скоромец А.А. Содержание свободных легких цепей иммуноглобулинов в ликворе и значение его определения для дифференциальной диагностики рассеянного склероза // Журнал неврологии и психиатрии им. С.С. Корсакова, 1994, № 94. C. 49-53. [Totolian N.A., Griazeva I.V., Klimovich V.B., Skoromets A.A. The content of free light-chain immunoglobulins in the cerebrospinal fluid and the importance of its determination for the differential diagnosis of multiple sclerosis. Zhurnal nevrologii i psikhiatrii im. S.S. Korsakova = S.S. Korsakov Journal of Neurology and Psychiatry, 1994, no. 94, pp. 49-53. [In Russ.]

4. 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. [Totolian N.A., Griazeva I.V., Klimovich V.B., Totolian A.A. Intrathecal synthesis of free light chains of immunoglobulins and its connection with other immunological aberration in patients with multiple sclerosis. Immunologiya = Immunology, 1994, no. 1, pp. 54-57. [In Russ.]

5. 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. C. 34-38. [Totolian N.A., Griazeva I.V., Klimovich V.B., Totolian A.A. Free light-chain immunoglobulins in the biological fluids of patients with multiple sclerosis. Zhurnal nevrologii i psikhiatrii im. S.S. Korsakova = S.S. Korsakov Journal of Neurology and Psychiatry, 1997, Vol. 97, pp. 34-38. [In Russ.]

6. Тотолян Н.А., Скоромец А.А., Барбас И.М., Трофимова Т.Н., Тотолян А.А. Актуальные практические вопросы диагностики рассеянного склероза // Ученые записки, 2000. Т. 7, № 3. C. 37-48. [Totolian N.A., Skoromets A.A., Barbas I.M., Trophimova T.N., Totolian A.A. Current practical questions of diagnosis of multiple sclerosis. Uchenye zapiski= Scientific Notes, 2007, Vol. 3, pp. 37-48. [In Russ.]

7. Тотолян Н.А., Готовчиков А.А., Лапин С.В., Максимов И.В., Кодзаева А.Ю., Прахова Л.Н., Ильвес А.Г., Скоромец А.П., Тотолян А.А., Скоромец А.А. Интратекальный синтез иммуноглобулинов в диагностике и дифференциальной диагностике рассеянного склероза // Журнал неврологии и психиатрии им. С.С. Корсакова, 2012. Т. 112. C. 73-86. [Totolian N.A., Gotovchikov A.A., Lapin S.V., Maksimov I.V., Kodzaeva A.Yu., Prakhova L.N., Il’ves A.G, Skoromets A.P., Totolian A.A., Skoromets A.A . Intrathecal immunoglobulin production in the diagnosis and differential diagnosis of multiple sclerosis. Zhurnal nevrologii i psikhiatrii im. S.S. Korsakova = S.S. Korsakov Journal of Neurology and Psychiatry, 2012, Vol. 112, pp. 73-86. [In Russ.]

8. A.P.D. Henderson, M.H. Barnett, J.D.E. Parratt, and J.W. Prineas. Multiple sclerosis: distribution of inflammatory cells in newly forming lesions. Annals of Neurology, 2009, Vol. 66, no. 6, pp. 739-753.

9. Anderson M., Alverez-Cermeno J., Bernardi G. CSF in the diagnosis of MS: a consensus report. J. Neurol. Neurosurg. Psychiatry, 1994, Vol. 57, pp. 897-902.

10. Arneth B., Birklein F. High sensitivity of free lambda and free kappa light chains for detection of intrathecal immunoglobulin synthesis in cerebrospinal fluid. Acta Neurol. Scand., 2009, Vol. 119, pp. 39-44.

11. Brian G.M. Durie, Robert Kyle, Andrew Belch, William Bensinger, Joan Blade, Mario Boccadoro. J. Anthony Child, Raymond Comenzo Myeloma management guidelines. A consensus report from the scientific advisors of the international myeloma foundation. Hematology Journal, 2003, Vol. 4, pp. 379-398.

12. Clinical Neuroimmunology: Multiple Sclerosis and Related Disorders. Edited by Syed A. Rizvi, Patricia K. Coyle. Current Clinical Neurology, 2011.

13. Dobson R., Ramagopalan S., Davis A. Cerebrospinal fluid oligoclonal bands in multiple sclerosis and clinically isolated syndromes: a meta-analysis of prevalence, prognosis and effect of latitude. J. Neurol. Neurosurg. Psychiatry, 2013, Vol. 84, pp. 909-914.

14. Dobson R., Topping J., Davis A., Thompson E., Giovannoni G. Cerebrospinal fluid and urinary biomarkers in multiple sclerosis. Acta Neurol. Scand., 2013, Vol. 128, pp. 321-327.

15. Duranti F., Pieri M., Centonze D., Buttari F., Bernardini S., Dessi M. Determination of κFLC and κ Index in cerebrospinal fluid: a valid alternative to assess intrathecal immunoglobulin synthesis. J. Neuroimmunol., 2013, Vol. 263.

16. Makbule S., Hayrettin T., Florian L., Stefan P., Rehaneh M., Markus O., Johannes B. Cerebrospinal Fluid Immunoglobulin Kappa Light Chain in Clinically Isolated Syndrome and Multiple Sclerosis. PLoS One., 2014, Vol. 9, p. 4.

17. Fischer C., Arneth B., Koehler J., Lotz J., Lackner K.J. Kappa free light chains in cerebrospinal fluid as markers of intrathecal immunoglobulin synthesis. Clin Chem., 2004, Vol. 50, pp. 1809-1813.

18. Gottenberg J.E., Aucouturier F., Goetz J., Sordet C., Jahn I., Busson M., Cayuela J.M., Sibilia J., Mariette X. Serum immunoglobulin free light chain assessment in rheumatoid arthritis and primary Sjogren›s syndrome. Ann. Rheum. Dis., 2007, Vol. 66, pp. 23-27.

19. Petzold A. Intrathecal oligoclonal IgG synthesis in multiple sclerosis. J. Neuroimmunol., 2013, p. 262.

20. Polman C.H., Reingold S.C., Banwell B., Clanet M., Cohen J.A., Filippi M., Fujihara K., Havrdova E., Hutchinson M., Kappos L., Lublin F.D., Montalban X., O›Connor P., Sandberg-Wollheim M., Thompson A.J., Waubant E., Weinshenker B., Wolinsky. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. J.S. Ann. Neurol., 2011, Vol. 69, pp. 292-302.

21. Polman C.H., Reingold S.C., Edan G., Filippi M., Hartung H.P., Kappos L., Lublin F.D., Metz L.M., McFarland H.F., O›Connor P.W., Sandberg-Wollheim M., Thompson A.J., Weinshenker B.G., Wolinsky J.S. Diagnostic criteria for multiple sclerosis: 2005 revisions to the «McDonald Criteria». Ann Neurol, 2005, Vol. 58, no. 6, pp. 840-846.

22. Rinker J.R., Trinkaus K., Cross A.H. Elevated CSF free kappa light chains correlate with disability prognosis in multiple sclerosis. Neurology, 2006, Vol. 67, pp. 1288-1290.

23. Bradwell A.R., Carr-Smith H.D., Mead G.P. Highly sensitive, automated immunoassay for immunoglobulin free light chains in serum and urine. Clin. Chem., 2001, Vol. 47, pp. 673-680.

24. Stefan Presslauer, Dejan Milosavljevic, Wolfgang Huebl, Silvia Parigger, Gabriele Schneider-Koch, Thomas Bruecke. Kappa Free Light Chains: Diagnostic and Prognostic Relevance in MS and CIS. PLoS One, 2014, Vol. 9.

25. Tintoré M., Rovira A., Río J., Tur C., Pelayo R., Nos C., Téllez N., Perkal H., Comabella M., Sastre-Garriga J., Montalban X. Do oligoclonal bands add information to MRI in first attacks of multiple sclerosis? Neurology, 2008, Vol. 70, pp.1079-1083.

26. Totolian N.A., Griazeva I.V., Totolian A.A., Klimovich V.B. Intrathecal free light chains of immunoglobulins in parainfectious conditions: comparison with multiple sclerosis. 14th Congress ECTRIMS, 9-12 Sep. 1998, Stockholm, Sweden, Poster 2113.

27. Villar L.M., Espino M., Costa-Frossard L., Muriel A, Jimenez J. High levels of cerebrospinal fluid free kappa chains predict conversion to multiple sclerosis. Clin. Chim. Acta, 2012, Vol. 413, pp. 1813-1816. 28. Wildemann B., Oschmann P., Reiber H. Laboratory diagnosis in neurology. Stuttgart: ThiemeVerlag, 2010, pp. 452-456.


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For citations:


Nazarov V.D., Lapin S.V., Surkova E.A., Evdoshenko E.P., Makshakov G.S., Totolian A. DIAGNOSTIC AND PROGNOSTIC SIGNIFICANCE OF INTRATHECAL SYNTHESIS OF IMMUNOGLOBULIN FREE LIGHT CHAINS IN MULTIPLE SCLEROSIS. Medical Immunology (Russia). 2015;17(3):235-244. (In Russ.) https://doi.org/10.15789/1563-0625-2015-3-235-244

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