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Open Access 01-12-2017 | Research

Increased cortical lesion load and intrathecal inflammation is associated with oligoclonal bands in multiple sclerosis patients: a combined CSF and MRI study

Authors: Gabriele Farina, Roberta Magliozzi, Marco Pitteri, Richard Reynolds, Stefania Rossi, Alberto Gajofatto, Maria Donata Benedetti, Francesco Facchiano, Salvatore Monaco, Massimiliano Calabrese

Published in: Journal of Neuroinflammation | Issue 1/2017

Abstract

Background

Although IgG oligoclonal bands (OCBs) in the cerebrospinal fluid (CSF) are a frequent phenomenon in multiple sclerosis (MS) patients, their relationship with grey matter lesions, intrathecal/meningeal inflammation and clinical evolution has not been clarified yet.

The aim of our study was to assess the relationship between the OCBs, the inflammatory/neurodegenerative CSF profile at diagnosis, the cortical lesion load and the clinical evolution after 10 years.

Methods

This is a 10-year observational, cross-sectional study based on a combined MRI, cognitive and CSF profiling of the examined patients.

Forty consecutive OCB-negative (OCB−) and 50 OCB-positive (OCB+) MS patients were included in this study. Both groups had mean disease duration of 10 years and were age and gender matched. Each patient underwent neurological and neuropsychological evaluation and 3-T MRI. Analysis of the presence and levels of 28 inflammatory mediators was performed in the CSF obtained from 10 OCB− MS, 11 OCB+ MS and 10 patients with other neurological conditions.

Results

Increased number of CLs was found in OCB+ compared to OCB− patients (p < 0.0001), whereas no difference was found in white matter lesion (WML) load (p = 0.36). The occurrence of OCB was also associated with increased levels of neurofilament light chains and of several inflammatory mediators linked to B lymphocyte activity and lymphoid-neogenesis (CXCL13, CXCL12, CXCL10, TNFSF13, TNFSF13B, IL6, IL10) and other pro-inflammatory molecules, such as IFN-γ, TNF, MMP2, GM-CSF, osteopontin and sCD163. Finally, the occurrence of OCB was found associated with poor prognosis, from both physical and cognitive points of view.

Conclusions

OCB at MS onset are associated with more severe GM pathology and with a more severe physical disability and cognitive impairment after 10 years. Increased levels of cytokines linked to B cell activation, lymphoid-neogenesis, and pro-inflammatory immune response in the CSF of OCB+ patients support the hypothesis of crucial role played by compartmentalized, intrathecal B cell response in the pathogenesis of CLs and OCB production.

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Kabat EA, Moore DH, Landow H. An electrophoretic study of the protein components in cerebrospinal fluid and their relationship to the serum proteins. J Clin Invest. 1942;21:571–7.CrossRefPubMedPubMedCentral

Villar LM, Masterman T, Casanova B, Gómez-Rial J, Espiño M, Sádaba MC, et al. CSF oligoclonal band patterns reveal disease heterogeneity in multiple sclerosis. J Neuroimmunol. 2009;211:101–4. Elsevier B.V.CrossRefPubMed

Dobson R, Ramagopalan S, Davis A, Giovannoni G. 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;84:909–14.CrossRefPubMed

Meinl E, Krumbholz M, Hohlfeld R. B lineage cells in the inflammatory central nervous system environment: migration, maintenance, local antibody production, and therapeutic modulation. Ann Neurol. 2006;59:880–92.CrossRefPubMed

Kanter JL, Narayana S, Ho PP, Catz I, Warren KG, Sobel RA, et al. Lipid microarrays identify key mediators of autoimmune brain inflammation. Nat Med. 2006;12:138–43.CrossRefPubMed

Blauth K, Owens GP, Bennett JL. The Ins and outs of B cells in multiple sclerosis. Front Immunol. 2015;6:565.CrossRefPubMedPubMedCentral

Smith JR, Braziel RM, Paoletti S, Lipp M, Uguccioni M, Rosenbaum JT. Expression of B-cell-attracting chemokine 1 (CXCL13) by malignant lymphocytes and vascular endothelium in primary central nervous system lymphoma. Blood. 2003;101:815–21.CrossRefPubMed

Magliozzi R, Columba-Cabezas S, Serafini B, Aloisi F. Intracerebral expression of CXCL13 and BAFF is accompanied by formation of lymphoid follicle-like structures in the meninges of mice with relapsing experimental autoimmune encephalomyelitis. J Neuroimmunol. 2004;148:11–23.CrossRefPubMed

Cyster JG. Chemokines, sphingosine-1-phosphate, and cell migration in secondary lymphoid organs. Annu Rev Immunol. 2005;23:127–59.CrossRefPubMed

10.

Magliozzi R, Howell O, Vora A, Serafini B, Nicholas R, Puopolo M, et al. Meningeal B-cell follicles in secondary progressive multiple sclerosis associate with early onset of disease and severe cortical pathology. Brain. 2007;130:1089–104.CrossRefPubMed

11.

Magliozzi R, Howell OW, Reeves C, Roncaroli F, Nicholas R, Serafini B, et al. A gradient of neuronal loss and meningeal inflammation in multiple sclerosis. Ann Neurol. 2010;68:477–93.CrossRefPubMed

12.

Howell OW, Reeves CA, Nicholas R, Carassiti D, Radotra B, Gentleman SM, et al. Meningeal inflammation is widespread and linked to cortical pathology in multiple sclerosis. Brain. 2011;134:2755–71.CrossRefPubMed

13.

Calabrese M, Magliozzi R, Ciccarelli O, Geurts JJG, Reynolds R, Martin R. Exploring the origins of grey matter damage in multiple sclerosis. Nat Rev Neurosci. 2015;16:147–58. Nature Publishing Group.CrossRefPubMed

14.

Rovaris M, Filippi M. MRI correlates of cognitive dysfunction in multiple sclerosis patients. J Neurovirol. 2000;6 Suppl 2:S172–5.PubMed

15.

Calabrese M, Poretto V, Favaretto A, Alessio S, Bernardi V, Romualdi C, et al. Cortical lesion load associates with progression of disability in multiple sclerosis. Brain. 2012;135:2952–61.CrossRefPubMed

16.

Filippi M, Preziosa P, Copetti M, Riccitelli G, Horsfield MA, Martinelli V, et al. Gray matter damage predicts the accumulation of disability 13 years later in MS. Neurology. 2013;81:1759–67.CrossRefPubMed

17.

Zivadinov R, Uher T, Hagemeier J, Vaneckova M, Ramasamy DP, Tyblova M, et al. A serial 10-year follow-up study of brain atrophy and disability progression in RRMS patients. Mult Scler. 2016;22(13):1709–18.

18.

Calabrese M, De Stefano N, Atzori M, Bernardi V, Mattisi I, Barachino L, et al. Detection of cortical inflammatory lesions by double inversion recovery magnetic resonance imaging in patients with multiple sclerosis. Arch Neurol. 2007;64:1416–22.CrossRefPubMed

19.

Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA, Filippi M, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011;69:292–302.CrossRefPubMedPubMedCentral

20.

Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology. 1983;33:1444–52.CrossRefPubMed

21.

Amato MP, Portaccio E, Goretti B, Zipoli V, Ricchiuti L, De Caro MF, et al. The Rao’s Brief Repeatable Battery and Stroop Test: normative values with age, education and gender corrections in an Italian population. Mult Scler. 2006;12:787–93.CrossRefPubMed

22.

Beck AT, Steer RA, Brown GK. Manual for the Beck depression inventory-II. San Antonio: TX Psychol. Corp; 1996. p. 1–82.

23.

Teunissen CE, Tumani H, Bennett JL, Berven FS, Brundin L, Comabella M, et al. Consensus guidelines for CSF and blood biobanking for CNS biomarker studies. Mult Scler Int. 2011;2011:246412.PubMedPubMedCentral

24.

Freedman MS, Thompson EJ, Deisenhammer F, Giovannoni G, Grimsley G, Keir G, et al. Recommended standard of cerebrospinal fluid analysis in the diagnosis of multiple sclerosis: a consensus statement. Arch Neurol. 2005;62:865–70.CrossRefPubMed

25.

Tanaka M, Matsushita T, Tateishi T, Ochi H, Kawano Y, Mei F-J, et al. Distinct CSF cytokine/chemokine profiles in atopic myelitis and other causes of myelitis. Neurology. 2008;71:974–81.CrossRefPubMed

26.

Studer V, Rossi S, Motta C, Buttari F, Centonze D. Peripheral B cell depletion and central proinflammatory cytokine reduction following repeated intrathecal administration of rituximab in progressive Multiple Sclerosis. J Neuroimmunol. 2014;276:229–31.CrossRefPubMed

27.

Geurts JJG, Roosendaal SD, Calabrese M, Ciccarelli O, Agosta F, Chard DT, et al. Consensus recommendations for MS cortical lesion scoring using double inversion recovery MRI. Neurology. 2011;76:418–24.CrossRefPubMed

28.

Haider L, Zrzavy T, Hametner S, Höftberger R, Bagnato F, Grabner G, et al. The topograpy of demyelination and neurodegeneration in the multiple sclerosis brain. Brain. 2016;139:807–15.CrossRefPubMedPubMedCentral

29.

Serafini B, Rosicarelli B, Magliozzi R, Stigliano E, Aloisi F. Detection of ectopic B-cell follicles with germinal centers in the meninges of patients with secondary progressive multiple sclerosis. Brain Pathol. 2004;14:164–74.CrossRefPubMed

30.

Ma N, He Y, Xiao H, Han G, Chen G, Wang Y, et al. BAFF maintains T-cell survival by inducing OPN expression in B cells. Mol Immunol. 2014;57:129–37.CrossRefPubMed

31.

Krumbholz M, Theil D, Cepok S, Hemmer B, Kivisäkk P, Ransohoff RM, et al. Chemokines in multiple sclerosis: CXCL12 and CXCL13 up-regulation is differentially linked to CNS immune cell recruitment. Brain. 2006;129:200–11.CrossRefPubMed

32.

Sellebjerg F, Börnsen L, Khademi M, Krakauer M, Olsson T, Frederiksen JL, et al. Increased cerebrospinal fluid concentrations of the chemokine CXCL13 in active MS. Neurology. 2009;73:2003–10.CrossRefPubMed

33.

Haas J, Bekeredjian-Ding I, Milkova M, Balint B, Schwarz A, Korporal M, et al. B cells undergo unique compartmentalized redistribution in multiple sclerosis. J Autoimmun. 2011;37:289–99.CrossRefPubMed

34.

Ferraro D, Galli V, Vitetta F, Simone AM, Bedin R, Del Giovane C, et al. Cerebrospinal fluid CXCL13 in clinically isolated syndrome patients: association with oligoclonal IgM bands and prediction of multiple sclerosis diagnosis. J Neuroimmunol. 2015;283:64–9.CrossRefPubMed

35.

Corcione A, Casazza S, Ferretti E, Giunti D, Zappia E, Pistorio A, et al. Recapitulation of B cell differentiation in the central nervous system of patients with multiple sclerosis. Proc Natl Acad Sci U S A. 2004;101:11064–9.CrossRefPubMedPubMedCentral

36.

Kornek B, Lassmann H. Axonal pathology in multiple sclerosis. A historical note. Brain Pathol. 1999;9:651–6.CrossRefPubMed

37.

Hesselgesser J, Taub D, Baskar P, Greenberg M, Hoxie J, Kolson DL, et al. Neuronal apoptosis induced by HIV-1 gp120 and the chemokine SDF-1 alpha is mediated by the chemokine receptor CXCR4. Curr Biol. 1998;8:595–8.CrossRefPubMed

38.

Gardner C, Magliozzi R, Durrenberger PF, Howell OW, Rundle J, Reynolds R. Cortical grey matter demyelination can be induced by elevated pro-inflammatory cytokines in the subarachnoid space of MOG-immunized rats. Brain. 2013;136:3596–608.CrossRefPubMed

39.

Vogel DYS, Vereyken EJF, Glim JE, Heijnen PDAM, Moeton M, van der Valk P, et al. Macrophages in inflammatory multiple sclerosis lesions have an intermediate activation status. J Neuroinflammation. 2013;10:35.CrossRefPubMedPubMedCentral

40.

Zhang Z, Zhang Z-Y, Schittenhelm J, Wu Y, Meyermann R, Schluesener HJ. Parenchymal accumulation of CD163+ macrophages/microglia in multiple sclerosis brains. J Neuroimmunol. 2011;237:73–9.CrossRefPubMed

41.

Fabriek BO, Møller HJ, Vloet RPM, van Winsen LM, Hanemaaijer R, Teunissen CE, et al. Proteolytic shedding of the macrophage scavenger receptor CD163 in multiple sclerosis. J Neuroimmunol. 2007;187:179–86.CrossRefPubMed

42.

Boven LA, Van Meurs M, Van Zwam M, Wierenga-Wolf A, Hintzen RQ, Boot RG, et al. Myelin-laden macrophages are anti-inflammatory, consistent with foam cells in multiple sclerosis. Brain. 2005;129:517–26.CrossRefPubMed

43.

Stilund M, Reuschlein A-K, Christensen T, Møller HJ, Rasmussen PV, Petersen T. Soluble CD163 as a marker of macrophage activity in newly diagnosed patients with multiple sclerosis. PLoS One. 2014;9:e98588.CrossRefPubMedPubMedCentral

44.

Stilund M, Gjelstrup MC, Petersen T, Møller HJ, Rasmussen PV, Christensen T. Biomarkers of inflammation and axonal degeneration/damage in patients with newly diagnosed multiple sclerosis: contributions of the soluble CD163 CSF/serum ratio to a biomarker panel. PLoS One. 2015;10:e0119681.CrossRefPubMedPubMedCentral

45.

Komori M, Blake A, Greenwood M, Lin YC, Kosa P, Ghazali D, et al. Cerebrospinal fluid markers reveal intrathecal inflammation in progressive multiple sclerosis. Ann Neurol. 2015;78:3–20.CrossRefPubMed

46.

Choi SR, Howell OW, Carassiti D, Magliozzi R, Gveric D, Muraro PA, et al. Meningeal inflammation plays a role in the pathology of primary progressive multiple sclerosis. Brain. 2012;135:2925–37.CrossRefPubMed

47.

Lucchinetti CF, Popescu BFGG, Bunyan RF, Moll NM, Roemer SF, Lassmann H, et al. Inflammatory cortical demyelination in early multiple sclerosis. N Engl J Med. 2011;365:2188–97.CrossRefPubMedPubMedCentral

48.

Absinta M, Vuolo L, Rao A, Nair G, Sati P, Cortese ICM, et al. Gadolinium-based MRI characterization of leptomeningeal inflammation in multiple sclerosis.Neurology. 2015;85(1):18–28.

Title: Increased cortical lesion load and intrathecal inflammation is associated with oligoclonal bands in multiple sclerosis patients: a combined CSF and MRI study
Authors: Gabriele Farina
Roberta Magliozzi
Marco Pitteri
Richard Reynolds
Stefania Rossi
Alberto Gajofatto
Maria Donata Benedetti
Francesco Facchiano
Salvatore Monaco
Massimiliano Calabrese
Publication date: 01-12-2017
Publisher: BioMed Central
Published in: Journal of Neuroinflammation / Issue 1/2017
Electronic ISSN: 1742-2094
DOI: https://doi.org/10.1186/s12974-017-0812-y

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Increased cortical lesion load and intrathecal inflammation is associated with oligoclonal bands in multiple sclerosis patients: a combined CSF and MRI study

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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