Abstract
Neurofilaments are cytoskeletal proteins localized within axons, which may interact with the immune system during and following tissue destruction in multiple sclerosis (MS). Antibodies against the medium neurofilament subunit synthesized intrathecally may reflect axonal damage in MS patients. Both immunoglobulin G (IgG) and M (IgM) responses against the purified native medium subunit of neurofilaments (NFM) using enzyme-linked immunosorbent assay (ELISA) were determined in paired serum and cerebrospinal fluid samples obtained from 49 MS patients, 16 normal controls (CN), 21 control patients with miscellaneous diseases (CD) and 14 patients with neurodegenerative disorders (CDEG). Intrathecal production of IgM and IgG antibodies to NFM were elevated in MS patients compared with the CN or CD groups (p < 0.04 for IgM, p < 0.01 for IgG). The increase was present in all the MS courses (relapsing-remitting, primary and secondary progressive). Similar local anti-NFM IgG and IgM synthesis occurred in the MS and CDEG groups. MS patients with short and long disease duration did not differ in terms of their anti-NFM IgM and IgG responses. Repeated examinations showed stable intrathecal anti-NFM production. Intrathecal IgG and IgM antibodies against NFM were increased in MS patients and may serve as a potential marker for axonal pathology. The extent of anti-NFM levels did not correspond to any individualized clinical profiles of MS patients.
Similar content being viewed by others
References
Al-Chalabi A, Miller CC (2003) Neurofilaments and neurological disease. Bioessays 25: 346–55
Bitsch A, Kuhlmann T, Stadelmann C, Lassmann H, Lucchinetti C, Bruck W (2001) A longitudinal MRI study of histopathologically defined hypointense multiple sclerosis lesions. Ann Neurol. 49: 793–6
Couratier P, Yi FH, Preud’homme JL, Clavelou P, White A, Sindou P, Vallat JM, Jauberteau MO (1998) Serum autoantibodies to neurofilament proteins in sporadic amyotrophic lateral sclerosis. J Neurol Sci. 154: 137–45
Cross AH, Trotter JL, Lyons J (2001) B cells and antibodies in CNS demyelinating disease. J Neuroimmunol. 112: 1–14
De Stefano N, Narayanan S, Francis GS, Arnaoutelis R, Tartaglia MC, Antel JP, Matthews PM, Arnold DL (2001) Evidence of axonal damage in the early stages of multiple sclerosis and its relevance to disability. Arch Neurol. 58: 65–70
Evangelou N, Esiri MM, Smith S, Palace J, Matthews PM (2000) Quantitative pathological evidence for axonal loss in normal appearing white matter in multiple sclerosis. Ann Neurol. 47: 391–5
Fabriek BO, Zwemmer JN, Teunissen CE, Dijkstra CD, Polman CH, Laman JD, Castelijns JA (2005) In vivo detection of myelin proteins in cervical lymph nodes of MS patients using ultrasound-guided fine-needle aspiration cytology. J Neuroimmunol. 161: 190–4
Ferguson B, Matyszak MK, Esiri MM, Perry VH (1997) Axonal damage in acute multiple sclerosis lesions. Brain 120(Pt 3): 393–9
Filippi M (2001) In-vivo tissue characterization of multiple sclerosis and other white matter diseases using magnetic resonance based techniques. J Neurol 248: 1019–29
Filippi M, Bozzali M, Rovaris M, Gonen O, Kesavadas C, Ghezzi A, Martinelli V, Grossman RI, Scotti G, Comi G, Falini A (2003) Evidence for widespread axonal damage at the earliest clinical stage of multiple sclerosis. Brain 126: 433–7
Karcher D, Federsppiel BS, Lowenthal FD, Frank F, Lowenthal A (1986) Anti-neurofilament antibodies in blood of patients with neurological diseases. Acta Neuropathol (Berl) 72: 82–5
Kuhlmann T, Lingfeld G, Bitsch A, Schuchardt J, Bruck W (2002) Acute axonal damage in multiple sclerosis is most extensive in early disease stages and decreases over time. Brain 125: 2202–12
Kurtzke JF (1983) Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 33: 1444–52
Link H, Tibbling G (1977) Principles of albumin and IgG analyses in neurological disorders. III. Evaluation of IgG synthesis within the central nervous system in multiple sclerosis Scand. J Clin Lab Invest 37: 397–401
Lublin FD, Reingold SC (1996) Defining the clinical course of multiple sclerosis: results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Neurology 46: 907–11
Lycke JN, Karlsson JE, Andersen O, Rosengren LE (1998) Neurofilament protein in cerebrospinal fluid: a potential marker of activity in multiple sclerosis. J Neurol Neurosurg Psychiatry 64: 402–4
Malmestrom C, Haghighi S, Rosengren L, Andersen O, Lycke J (2003) Neurofilament light protein and glial fibrillary acidic protein as biological markers in MS Neurology 61: 1720–5
Miller DH, Barkhof F, Frank JA, Parker GJ, Thompson AJ (2002) Measurement of atrophy in multiple sclerosis: pathological basis, methodological aspects and clinical relevance. Brain 125: 1676–95
Miller DH, Thompson AJ, Filippi M (2003) Magnetic resonance studies of abnormalities in the normal appearing white matter and grey matter in multiple sclerosis. J Neurol. 250: 1407–19
Norgren N, Sundstrom P, Svenningsson A, Rosengren L, Stigbrand T, Gunnarsson M (2004) Neurofilament and glial fibrillary acidic protein in multiple sclerosis. Neurology 63: 1586–90
Petzold A, Eikelenboom MJ, Keir G, Grant D, Lazeron RH, Polman CH, Uitdehaag BM, Thompson EJ, Giovannoni G (2005) Axonal damage accumulates in the progressive phase of multiple sclerosis: three year follow up study. J Neurol Neurosurg Psychiatry 76: 206–11
Poser CM, Paty DW, Scheinberg L, McDonald WI, Davis FA, Ebers GC, Johnson KP, Sibley WA, Silberberg DH, Tourtellotte WW (1983) New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol. 13: 227–31
Prat A, Antel J (2005) Pathogenesis of multiple sclerosis. Curr Opin Neurol 18: 225–30
Reiber H, Peter JB (2001) Cerebrospinal fluid analysis: disease-related data patterns and evaluation programs. J Neurol Sci 184: 101–22
Roxburgh RH, Seaman SR, Masterman T, Hensiek AE, Sawcer SJ, Vukusic S, Achiti I, Confavreux C, Coustans M, le Page E, Edan G, McDonnell GV, Hawkins S, Trojano M, Liguori M, Cocco E, Marrosu MG, Tesser F, Leone MA, Weber A, Zipp F, Miterski B, Epplen JT, Oturai A, Sorensen PS, Celius EG, Lara NT, Montalban X, Villoslada P, Silva AM, Marta M, Leite I, Dubois B, Rubio J, Butzkueven H, Kilpatrick T, Mycko MP, Selmaj KW, Rio ME , Sa M, Salemi G, Savettieri G, Hillert J, Compston DA (2005) Multiple Sclerosis Severity Score: using disability and disease duration to rate disease severity. Neurology 64: 1144–51
Semra YK, Seidi OA, Sharief MK (2002) Heightened intrathecal release of axonal cytoskeletal proteins in multiple sclerosis is associated with progressive disease and clinical disability. J Neuroimmunol. 122: 132–9
Silber E, Semra YK, Gregson NA, Sharief MK (2002) Patients with progressive multiple sclerosis have elevated antibodies to neurofilament subunit. Neurology 58: 1372–81
Terryberry JW, Thor G, Peter JB (1998) Autoantibodies in neurodegenerative diseases: antigen-specific frequencies and intrathecal analysis. Neurobiol Aging 19: 205–16
Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mork S, Bo L (1998) Axonal transection in the lesions of multiple sclerosis. N Engl J Med. 338: 278–85
van Walderveen MA, Kamphorst W, Scheltens P, van Waesberghe JH, Ravid R, Valk J, Polman CH, Barkhof F (1998) Histopathologic correlate of hypointense lesions on T1-weighted spin-echo MRI in multiple sclerosis. Neurology 50: 1282–8
Acknowledgement
The study was supported by the research project MSM 0021620816. We thank Dr. Benáková for albumin and total IgG measurements of all of our specimens. Additionally, we thank Dr. Ridzon and Dr. Rusina for providing samples from ALS patients.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Bartoš, A., Fialová, L., Soukupová, J. et al. Elevated intrathecal antibodies against the medium neurofilament subunit in multiple sclerosis. J Neurol 254, 20–25 (2007). https://doi.org/10.1007/s00415-006-0185-0
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00415-006-0185-0