Immunopathology of MS and monitoring of therapy Review article
Article Sidebar
Published:
Sep 30, 2018
Keywords:
B cells, T cells, lymphocytes, NK cells, multiple sclerosis, immunomodulating therapies
Main Article Content
Abstract
Multiple sclerosis is an autoimmune disease whose pathogenesis is not completely understood. The immunomodulatory therapies have significantly contributed to both the change in the course of the disease and prognosis, as well as to the basic knowledge of the pathological process in the course of MS. This paper describes some known and new facts about the autoimmune process in MS in the context of immunomodulatory therapy, focusing mainly on the role of T and B lymphocytes.
Article Details
Issue
Section
Articles
Copyright © by Medical Education. All rights reserved.
References
1. Corboy J.R., Weinshenker B.G., Wingerchuk D.M.: Comment on 2018 American Academy of Neurology guidelines on disease-modifying therapies in MS. Neurology 2018; 90: 1106-1112.
2. Yadav S.K., Mindur J.E., Ito K., Dhib-Jalbut S.: Advances in the immunopathogenesis of multiple sclerosis. Curr. Opin. Neurol. 2015; 28(3): 206-219.
3. Sawcer S., Hellenthal G., Pirinen M. et al; International Multiple Sclerosis Genetics Consortium; Wellcome Trust Case Control Consortium 2: Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 2011; 476(7359): 214-219.
4. Dendrou C.A., Fugger L., Friese M.A.: Immunopathology of multiple sclerosis. Nat. Rev. Immunol. 2015; 15: 545-558.
5. Kurkowska-Jastrzębska I., Swiątkiewicz M., Zaremba M. et al.: Neurodegeneration and inflammation in hippocampus in experimental autoimmune encephalomyelitis induced in rats by one – time administration of encephalitogenic T cells. Neuroscience 2013; 248: 690-698.
6. Bjartmar C., Kinkel R.P., Kidd G. et al.: Axonal loss in normal-appearing white matter in a patient with acute MS. Neurology 2001; 57(7): 1248-1252.
7. Kornek B., Storch M.K., Weissert R. et al.: Multiple sclerosis and chronic autoimmune encephalomyelitis: a comparative quantitative study of axonal injury in active, inactive, and remyelinated lesions. Am. J. Pathol. 2000; 157(1): 267-276.
8. Peterson J.W., Bö L., Mörk S. et al.: Transected neurites, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions. Ann. Neurol. 2001; 50(3): 389-400.
9. Miller D.H., Barkhof F., Frank J.A. et al.: Measurement of atrophy in multiple sclerosis: pathological basis, methodological aspects and clinical relevance. Brain 2002; 125(Pt8): 1676-1695.
10. Wekerle H.: Lessons from multiple sclerosis: models, concepts, observations. Ann. Rheum. Dis. 2008; 67 Supl. 3: iii56-60.
11. Hafler D.A., Compston A., Sawcer S. et al.; International Multiple Sclerosis Genetics Consortium: Risk alleles for multiple sclerosis identified by a genomewide study. N. Engl. J. Med. 2007; 357(9): 851-862.
12. Ransohoff R.M., Engelhardt B.: The anatomical and cellular basis of immune surveillance in the central nervous system. Nat. Rev. Immunol. 2012; 12(9): 623-635.
13. Hauser S.L., Bhan A.K., Gilles F. et al.: Immunohistochemical analysis of the cellular infiltrate in multiple sclerosis lesions. Ann. Neurol. 1986; 19(6): 578-587.
14. van Oosten B.W., Lai M., Hodgkinson S. et al.: Treatment of multiple sclerosis with the monoclonal anti-CD4 antibody cM-T412: results of a randomized, double-blind, placebo-controlled, MR-monitored phase II trial. Neurology 1997; 49(2): 351-357.
15. Friese M.A., Fugger L.: Autoreactive CD8+ T cells in multiple sclerosis: a new target for therapy? Brain 2008; 128: 1747-1763.
16. Jacobsen M., Cepok S., Quak E. et al.: Oligoclonal expansion of memory CD8+ T cells in cerebrospinal fluid from multiple sclerosis patients. Brain 2002; 125: 538-550.
17. Link J., Lorentzen A.R., Kockum I. et al.: Two HLA class I genes independently associated with multiple sclerosis. J. Neuroimmunol. 2010; 226(1-2): 172-176.
18. Melzer N., Meuth S.G., Wiendl H.: CD8+ T cells and neuronal damage: direct and collateral mechanisms of cytotoxicity and impaired electrical excitability. FASEB J. 2009; 23: 3659-3673.
19. Panitch H.S., Hirsch R.L., Schindler J., Johnson K.P.: Treatment of multiple sclerosis with gamma interferon: exacerbations associated with activation of the immune system. Neurology 1987; 37(7): 1097-1102.
20. Wuest S.C., Edwan J.H., Martin J.F. et al.: A role for interleukin-2 trans-presentation in dendritic cell-mediated T cell activation in humans, as revealed by daclizumab therapy. Nat. Med. 2011; 17: 604-609.
21. EMA urgently reviewing multiple sclerosis medicine Zinbryta following cases of inflammatory brain disorders [online].
22. Maimone D., Gregory S., Arnason B.G., Reder A.T.: Cytokine levels in the cerebrospinal fluid and serum of patients with multiple sclerosis. J. Neuroimmunol. 1991; 32(1): 67-74.
23. Hofman F.M., Hinton D.R., Johnson K., Merrill J.E.: Tumour necrosis factor identified in multiple sclerosis brain. J. Exp. Med. 1989; 170: 607-612.
24. The Lenercept Multiple Sclerosis Study Group and The University of British Columbia MS/MRI Analysis Group; TNF neutralization in MS: results of a randomized, placebo-controlled multicenter study. Neurology 1999; 53(3): 457-465.
25. Gu C., Wu L., Li, X.: IL-17 family: cytokines, receptors and signaling. Cytokine 2013; 64: 477-485.
26. Havrdová E., Belova A., Goloborodko A. et al.: Activity of secukinumab, an anti-IL-17A antibody, on brain lesions in RRMS: results from a randomized, proof-of-concept study. J. Neurol. 2016; 263(7): 1287-1295.
27. Simmons S.B., Pierson E.R., Lee S.Y., Goverman J.M.: Modeling the heterogeneity of multiple sclerosis in animals. Trends Immunol. 2013; 34(8): 410-422.
28. Van Kaer L., Wu L., Parekh V.V.: Natural killer T cells in multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis. Immunology 2015; 146(1): 1-10.
29. Gross C.C., Schulte-Mecklenbeck A., Wiendl H. et al.: Regulatory Functions of Natural Killer Cells in Multiple Sclerosis. Front Immunol. 2016; 7: 606.
30. De Jager P.L., Rossin E., Pyne S. et al.: Cytometric profiling in multiple sclerosis uncovers patient population structure and a reduction of CD8 low cells. Brain 2008; 131: 1701-1711.
31. Takahashi K., Miyake S., Kondo T. et al.: Natural killer type 2 bias in remission of multiple sclerosis. J. Clin. Invest. 2001; 107: R23-R29.
32. Anolik J.H., Campbell D., Felgar R.E. et al.: The relationship of FcgammaRIIIa genotype to degree of B cell depletion by rituximab in the treatment of systemic lupus erythematosus. Arthritis Rheum. 2003; 48: 455-459.
33. Hu Y., Turner M.J., Shields J. et al.: Investigation of the mechanism of action of alemtuzumab in a human CD52 transgenic mouse model. Immunology 2009; 128: 260-270.
34. Salvetti M., Giovannoni G., Aloisi F.: Epstein-Barr virus and multiple sclerosis. Curr. Opin. Neurol. 2009; 22(3): 201-206.
35. Howell O.W., Reeves C.A., Nicholas R. et al.: Meningeal inflammation is widespread and linked to cortical pathology in multiple sclerosis. Brain 2011; 134(Pt 9): 2755-2771.
36. Magliozzi R., Howell O., Vora A. et al.: Meningeal B-cell follicles in secondary progressive multiple sclerosis associate with early onset of disease and severe cortical pathology. Brain 2007; 130(Pt 4): 1089-1104.
37. Castillo-Trivino T., Braithwaite D., Bacchetti P., Waubant E.: Rituximab in relapsing and progressive forms of multiple sclerosis: a systematic review. PLoS ONE 2013; 8: e66308.
38. Naismith R.T., Piccio L., Lyons J.A. et al.: Rituximab add-on therapy for breakthrough relapsing multiple sclerosis: a 52-week phase II trial. Neurology 2010; 74: 1860-1867.
39. Hauser S.L., Waubant E., Arnold D.L. et al.; HERMES Trial Group: B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N. Engl. J. Med. 2008; 358: 676-688.
40. Schuh E., Berer K., Mulazzani M. et al.: Features of human CD3+CD20+ T cells. J. Immunol. 2016; 197: 1111-1117.
41. Palanichamy A., Jahn S., Nickles D. et al.: Rituximab efficiently depletes increased CD20-expressing T cells in multiple sclerosis patients. J. Immunol. 2014; 193: 580-586.
42. Rissanen E., Tuisku J., Rokka J. et al.: In vivo detection of diffuse inflammationin secondary progressive multiple sclerosis using PET imaging and the radioligand 11C-PK11195. J. Nucl. Med. 2014; 55: 939-944.
43. Zrzavy T., Hametner S., Wimmer I. et al.: Loss of ‘homeostatic’ microglia and patterns of their activation in active multiple sclerosis. Brain 2017; 140: 1900-1913.
44. Correale J., Gaitán M.I., Ysrraelit M.C., Fiol M.P.: Progressive multiple sclerosis: from pathogenic mechanisms to treatment. Brain 2017; 140: 527-546.
45. Montalban X., Hauser S.L., Kappos L. et al.; ORATORIO Clinical Investigators: Ocrelizumab versus Placebo in Primary Progressive Multiple Sclerosis. N. Engl. J. Med. 2017; 376(3): 209-220.
46. Rothhammer V., Kenison J.E., Tjon E. et al.: Sphingosine 1-phosphate receptor modulation suppresses pathogenic astrocyte activation and chronic progressive CNS inflammation. Proc. Natl. Acad. Sci. USA 2017; 114: 2012-2017.
47. Kappos L., Bar-Or A., Cree B.A.C. et al.; EXPAND Clinical Investigators: Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double- blind, randomised, phase 3 study. Lancet 2018; 391(10127): 1263-1273.
48. Tourbah A., Lebrun-Frenay C., Edan G. et al.; MS-SPI study group: MD1003 (high-dose biotin) for the treatment of progressive multiple sclerosis: A randomised, double-blind, placebo-controlled study. Mult. Scler. 2016; 22: 1719-1731.
49. Hegen H., Bsteh G., Berger T.: “No evidence of disease activity” – is it an appropriate surrogate in multiple sclerosis? Eur. J. Neurol. 2018. DOI: 10.1111/ene.13669.
50. Rotstein D.L., Healy B.C., Malik M.T. et al.: Evaluation of no evidence of disease activity in a 7-year longitudinal multiple sclerosis cohort. JAMA Neurol. 2015; 72: 152-158.
51. Joseph F.G., Hirst C.L., Pickersgill T.P. et al.: CSF oligoclonal band status informs prognosis in multiple sclerosis: a case control study of 100 patients. J. Neurol. Neurosurg. Psychiatry 2009; 80: 292-296.
52. Harrer A., Tumani H., Niendorf S. et al.: Cerebrospinal fluid parameters of B cell-related activity in patients with active disease during natalizumab therapy. Mult. Scler. 2013; 19: 1209-1212.
53. Bankoti J., Apeltsin L., Hauser S.L. et al.: In multiple sclerosis, oligoclonal bands connect to peripheral B-cell responses. Ann. Neurol. 2014; 75(2): 266-276.
54. Kuhle J., Nourbakhsh B., Grant D. et al.: Serum neurofilament is associated with progression of brain atrophy and disability in early MS. Neurology 2017; 88: 826-831.
55. Kuhle J., Barro C., Disanto G. et al.: Serum neurofilament light chain in early relapsing remitting MS is increased and correlates with CSF levels and with MRI measures of disease severity. Mult. Scler. 2016; 22(12): 1550-1559.
56. Kuhle J., Disanto G., Lorscheider J. et al.: Fingolimod and CSF neurofilament light chain levels in relapsing-remitting multiple sclerosis. Neurology 2015; 84(16): 1639-1643.
57. Mellergård J., Tisell A., Blystad I. et al.: Cerebrospinal fluid levels of neurofilament and tau correlate with brain atrophy in natalizumab-treated multiple sclerosis. Eur. J. Neurol. 2017; 24(1): 112-121.
58. Novakova L., Axelsson M., Khademi M. et al.: Cerebrospinal fluid biomarkers as a measure of disease activity and treatment efficacy in relapsing-remitting multiple sclerosis. J. Neurochem. 2017; 141(2): 296-304.
59. Gandhi R., Healy B., Gholipour T. et al.: Circulating microRNAs as biomarkers for disease staging in multiple sclerosis. Ann. Neurol. 2013; 73: 729-740.
60. Ottoboni L., Keenan B.T., Tamayo P. et al.: An RNA profile identifies two subsets of multiple sclerosis patients differing in disease activity. Sci. Transl. Med. 2012; 4: 153ra131.
61. Housley W.J., Pitt D., Hafler D.A.: Biomarkers in multiple sclerosis. Clin. Immunol. 2015; 161(1): 51-58.
2. Yadav S.K., Mindur J.E., Ito K., Dhib-Jalbut S.: Advances in the immunopathogenesis of multiple sclerosis. Curr. Opin. Neurol. 2015; 28(3): 206-219.
3. Sawcer S., Hellenthal G., Pirinen M. et al; International Multiple Sclerosis Genetics Consortium; Wellcome Trust Case Control Consortium 2: Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 2011; 476(7359): 214-219.
4. Dendrou C.A., Fugger L., Friese M.A.: Immunopathology of multiple sclerosis. Nat. Rev. Immunol. 2015; 15: 545-558.
5. Kurkowska-Jastrzębska I., Swiątkiewicz M., Zaremba M. et al.: Neurodegeneration and inflammation in hippocampus in experimental autoimmune encephalomyelitis induced in rats by one – time administration of encephalitogenic T cells. Neuroscience 2013; 248: 690-698.
6. Bjartmar C., Kinkel R.P., Kidd G. et al.: Axonal loss in normal-appearing white matter in a patient with acute MS. Neurology 2001; 57(7): 1248-1252.
7. Kornek B., Storch M.K., Weissert R. et al.: Multiple sclerosis and chronic autoimmune encephalomyelitis: a comparative quantitative study of axonal injury in active, inactive, and remyelinated lesions. Am. J. Pathol. 2000; 157(1): 267-276.
8. Peterson J.W., Bö L., Mörk S. et al.: Transected neurites, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions. Ann. Neurol. 2001; 50(3): 389-400.
9. Miller D.H., Barkhof F., Frank J.A. et al.: Measurement of atrophy in multiple sclerosis: pathological basis, methodological aspects and clinical relevance. Brain 2002; 125(Pt8): 1676-1695.
10. Wekerle H.: Lessons from multiple sclerosis: models, concepts, observations. Ann. Rheum. Dis. 2008; 67 Supl. 3: iii56-60.
11. Hafler D.A., Compston A., Sawcer S. et al.; International Multiple Sclerosis Genetics Consortium: Risk alleles for multiple sclerosis identified by a genomewide study. N. Engl. J. Med. 2007; 357(9): 851-862.
12. Ransohoff R.M., Engelhardt B.: The anatomical and cellular basis of immune surveillance in the central nervous system. Nat. Rev. Immunol. 2012; 12(9): 623-635.
13. Hauser S.L., Bhan A.K., Gilles F. et al.: Immunohistochemical analysis of the cellular infiltrate in multiple sclerosis lesions. Ann. Neurol. 1986; 19(6): 578-587.
14. van Oosten B.W., Lai M., Hodgkinson S. et al.: Treatment of multiple sclerosis with the monoclonal anti-CD4 antibody cM-T412: results of a randomized, double-blind, placebo-controlled, MR-monitored phase II trial. Neurology 1997; 49(2): 351-357.
15. Friese M.A., Fugger L.: Autoreactive CD8+ T cells in multiple sclerosis: a new target for therapy? Brain 2008; 128: 1747-1763.
16. Jacobsen M., Cepok S., Quak E. et al.: Oligoclonal expansion of memory CD8+ T cells in cerebrospinal fluid from multiple sclerosis patients. Brain 2002; 125: 538-550.
17. Link J., Lorentzen A.R., Kockum I. et al.: Two HLA class I genes independently associated with multiple sclerosis. J. Neuroimmunol. 2010; 226(1-2): 172-176.
18. Melzer N., Meuth S.G., Wiendl H.: CD8+ T cells and neuronal damage: direct and collateral mechanisms of cytotoxicity and impaired electrical excitability. FASEB J. 2009; 23: 3659-3673.
19. Panitch H.S., Hirsch R.L., Schindler J., Johnson K.P.: Treatment of multiple sclerosis with gamma interferon: exacerbations associated with activation of the immune system. Neurology 1987; 37(7): 1097-1102.
20. Wuest S.C., Edwan J.H., Martin J.F. et al.: A role for interleukin-2 trans-presentation in dendritic cell-mediated T cell activation in humans, as revealed by daclizumab therapy. Nat. Med. 2011; 17: 604-609.
21. EMA urgently reviewing multiple sclerosis medicine Zinbryta following cases of inflammatory brain disorders [online].
22. Maimone D., Gregory S., Arnason B.G., Reder A.T.: Cytokine levels in the cerebrospinal fluid and serum of patients with multiple sclerosis. J. Neuroimmunol. 1991; 32(1): 67-74.
23. Hofman F.M., Hinton D.R., Johnson K., Merrill J.E.: Tumour necrosis factor identified in multiple sclerosis brain. J. Exp. Med. 1989; 170: 607-612.
24. The Lenercept Multiple Sclerosis Study Group and The University of British Columbia MS/MRI Analysis Group; TNF neutralization in MS: results of a randomized, placebo-controlled multicenter study. Neurology 1999; 53(3): 457-465.
25. Gu C., Wu L., Li, X.: IL-17 family: cytokines, receptors and signaling. Cytokine 2013; 64: 477-485.
26. Havrdová E., Belova A., Goloborodko A. et al.: Activity of secukinumab, an anti-IL-17A antibody, on brain lesions in RRMS: results from a randomized, proof-of-concept study. J. Neurol. 2016; 263(7): 1287-1295.
27. Simmons S.B., Pierson E.R., Lee S.Y., Goverman J.M.: Modeling the heterogeneity of multiple sclerosis in animals. Trends Immunol. 2013; 34(8): 410-422.
28. Van Kaer L., Wu L., Parekh V.V.: Natural killer T cells in multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis. Immunology 2015; 146(1): 1-10.
29. Gross C.C., Schulte-Mecklenbeck A., Wiendl H. et al.: Regulatory Functions of Natural Killer Cells in Multiple Sclerosis. Front Immunol. 2016; 7: 606.
30. De Jager P.L., Rossin E., Pyne S. et al.: Cytometric profiling in multiple sclerosis uncovers patient population structure and a reduction of CD8 low cells. Brain 2008; 131: 1701-1711.
31. Takahashi K., Miyake S., Kondo T. et al.: Natural killer type 2 bias in remission of multiple sclerosis. J. Clin. Invest. 2001; 107: R23-R29.
32. Anolik J.H., Campbell D., Felgar R.E. et al.: The relationship of FcgammaRIIIa genotype to degree of B cell depletion by rituximab in the treatment of systemic lupus erythematosus. Arthritis Rheum. 2003; 48: 455-459.
33. Hu Y., Turner M.J., Shields J. et al.: Investigation of the mechanism of action of alemtuzumab in a human CD52 transgenic mouse model. Immunology 2009; 128: 260-270.
34. Salvetti M., Giovannoni G., Aloisi F.: Epstein-Barr virus and multiple sclerosis. Curr. Opin. Neurol. 2009; 22(3): 201-206.
35. Howell O.W., Reeves C.A., Nicholas R. et al.: Meningeal inflammation is widespread and linked to cortical pathology in multiple sclerosis. Brain 2011; 134(Pt 9): 2755-2771.
36. Magliozzi R., Howell O., Vora A. et al.: Meningeal B-cell follicles in secondary progressive multiple sclerosis associate with early onset of disease and severe cortical pathology. Brain 2007; 130(Pt 4): 1089-1104.
37. Castillo-Trivino T., Braithwaite D., Bacchetti P., Waubant E.: Rituximab in relapsing and progressive forms of multiple sclerosis: a systematic review. PLoS ONE 2013; 8: e66308.
38. Naismith R.T., Piccio L., Lyons J.A. et al.: Rituximab add-on therapy for breakthrough relapsing multiple sclerosis: a 52-week phase II trial. Neurology 2010; 74: 1860-1867.
39. Hauser S.L., Waubant E., Arnold D.L. et al.; HERMES Trial Group: B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N. Engl. J. Med. 2008; 358: 676-688.
40. Schuh E., Berer K., Mulazzani M. et al.: Features of human CD3+CD20+ T cells. J. Immunol. 2016; 197: 1111-1117.
41. Palanichamy A., Jahn S., Nickles D. et al.: Rituximab efficiently depletes increased CD20-expressing T cells in multiple sclerosis patients. J. Immunol. 2014; 193: 580-586.
42. Rissanen E., Tuisku J., Rokka J. et al.: In vivo detection of diffuse inflammationin secondary progressive multiple sclerosis using PET imaging and the radioligand 11C-PK11195. J. Nucl. Med. 2014; 55: 939-944.
43. Zrzavy T., Hametner S., Wimmer I. et al.: Loss of ‘homeostatic’ microglia and patterns of their activation in active multiple sclerosis. Brain 2017; 140: 1900-1913.
44. Correale J., Gaitán M.I., Ysrraelit M.C., Fiol M.P.: Progressive multiple sclerosis: from pathogenic mechanisms to treatment. Brain 2017; 140: 527-546.
45. Montalban X., Hauser S.L., Kappos L. et al.; ORATORIO Clinical Investigators: Ocrelizumab versus Placebo in Primary Progressive Multiple Sclerosis. N. Engl. J. Med. 2017; 376(3): 209-220.
46. Rothhammer V., Kenison J.E., Tjon E. et al.: Sphingosine 1-phosphate receptor modulation suppresses pathogenic astrocyte activation and chronic progressive CNS inflammation. Proc. Natl. Acad. Sci. USA 2017; 114: 2012-2017.
47. Kappos L., Bar-Or A., Cree B.A.C. et al.; EXPAND Clinical Investigators: Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double- blind, randomised, phase 3 study. Lancet 2018; 391(10127): 1263-1273.
48. Tourbah A., Lebrun-Frenay C., Edan G. et al.; MS-SPI study group: MD1003 (high-dose biotin) for the treatment of progressive multiple sclerosis: A randomised, double-blind, placebo-controlled study. Mult. Scler. 2016; 22: 1719-1731.
49. Hegen H., Bsteh G., Berger T.: “No evidence of disease activity” – is it an appropriate surrogate in multiple sclerosis? Eur. J. Neurol. 2018. DOI: 10.1111/ene.13669.
50. Rotstein D.L., Healy B.C., Malik M.T. et al.: Evaluation of no evidence of disease activity in a 7-year longitudinal multiple sclerosis cohort. JAMA Neurol. 2015; 72: 152-158.
51. Joseph F.G., Hirst C.L., Pickersgill T.P. et al.: CSF oligoclonal band status informs prognosis in multiple sclerosis: a case control study of 100 patients. J. Neurol. Neurosurg. Psychiatry 2009; 80: 292-296.
52. Harrer A., Tumani H., Niendorf S. et al.: Cerebrospinal fluid parameters of B cell-related activity in patients with active disease during natalizumab therapy. Mult. Scler. 2013; 19: 1209-1212.
53. Bankoti J., Apeltsin L., Hauser S.L. et al.: In multiple sclerosis, oligoclonal bands connect to peripheral B-cell responses. Ann. Neurol. 2014; 75(2): 266-276.
54. Kuhle J., Nourbakhsh B., Grant D. et al.: Serum neurofilament is associated with progression of brain atrophy and disability in early MS. Neurology 2017; 88: 826-831.
55. Kuhle J., Barro C., Disanto G. et al.: Serum neurofilament light chain in early relapsing remitting MS is increased and correlates with CSF levels and with MRI measures of disease severity. Mult. Scler. 2016; 22(12): 1550-1559.
56. Kuhle J., Disanto G., Lorscheider J. et al.: Fingolimod and CSF neurofilament light chain levels in relapsing-remitting multiple sclerosis. Neurology 2015; 84(16): 1639-1643.
57. Mellergård J., Tisell A., Blystad I. et al.: Cerebrospinal fluid levels of neurofilament and tau correlate with brain atrophy in natalizumab-treated multiple sclerosis. Eur. J. Neurol. 2017; 24(1): 112-121.
58. Novakova L., Axelsson M., Khademi M. et al.: Cerebrospinal fluid biomarkers as a measure of disease activity and treatment efficacy in relapsing-remitting multiple sclerosis. J. Neurochem. 2017; 141(2): 296-304.
59. Gandhi R., Healy B., Gholipour T. et al.: Circulating microRNAs as biomarkers for disease staging in multiple sclerosis. Ann. Neurol. 2013; 73: 729-740.
60. Ottoboni L., Keenan B.T., Tamayo P. et al.: An RNA profile identifies two subsets of multiple sclerosis patients differing in disease activity. Sci. Transl. Med. 2012; 4: 153ra131.
61. Housley W.J., Pitt D., Hafler D.A.: Biomarkers in multiple sclerosis. Clin. Immunol. 2015; 161(1): 51-58.