Obraz immunologiczny MS a monitorowanie terapii Artykuł przeglądowy
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Opublikowane:
wrz 30, 2018
Słowa kluczowe:
limfocyty T, limfocyty B, komórki NK, stwardnienie rozsiane, terapie immunomodulujące
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Abstrakt
Stwardnienie rozsiane (MS, multiple sclerosis) to choroba autoimmunologiczna, której patogeneza nie jest w pełni poznana. Wprowadzane od 25 lat terapie immunomodulujące w znaczącym stopniu przyczyniły się zarówno do zmiany przebiegu choroby i jej rokowania, jak i do poznania podstaw procesu patologicznego zachodzącego w MS. W pracy przedstawiono zarówno znane, jak i nowe fakty dotyczące procesu autoimmunologicznego w MS w kontekście terapii immunomodulujących, koncentrując się głównie na roli limfocytów T i B.
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Bibliografia
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.