Advertisement
Original article| Volume 44, 102281, September 2020

Highly sensitive quantification of optic neuritis intrathecal biomarker CXCL13

      Highlights

      • Highly sensitive CXCL13 assay (Simoa) has higher accuracy than conventional ELISA.
      • Simoa assay facilitates early diagnosis of optic neuritis.
      • Intrathecal CXCL13 predicts development of MS in patients with acute optic neuritis.

      Abstract

      Background

      Elevation of CXCL13, a key regulator of B-cell recruitment in cerebrospinal fluid (CSF) is implicated in multiple sclerosis (MS).

      Objective

      to evaluate if measurement of CXCL13 using a highly sensitive assay is of value in acute optic neuritis (ON) patients for the prediction of later MS.

      Method

      CXCL13 was measured by Simoa in two independent treatment-naïve ON cohorts, a training cohort (TC, n = 33) originating from a population-based cohort, a validation cohort (VC, n = 30) consecutively collected following principles for population studies. Prospectively, 14/33 TC and 12/30 VC patients progressed to MS (MS-ON) while 19/33 TC and 18/30 VC patients, remained as isolated ON (ION).

      Results

      CXCL13 was detectable in all samples and were higher in ON compared with healthy controls (HC) (p = 0.012). In the TC, CSF levels in MS-ON were higher compared with ION patients and HC (p = 0.0001 and p<0.0001). In the VC, we confirmed the increase of CXCL13 in MS-ON compared to ION (p = 0.0091). Logistic regression analysis revealed an area under receiver operating characteristic curve of 0.83 [95% C.I: 0.73–0.93].

      Conclusions

      The highly sensitive CXCL13 Simoa assay demonstrated ability to identify ON patients and separate MS-ON from ION, and predictive diagnostic values indicates a promising potential of this assay.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Multiple Sclerosis and Related Disorders
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Alvarez E.
        • Piccio L.
        • Mikesell R.J.
        • Klawiter E.C.
        • Parks B.J.
        • Naismith R.T.
        • Cross A.H.
        CXCL13 is a Biomarker of Inflammation in Multiple sclerosis, Neuromyelitis optica, and Other Neurological Conditions. 19. Multiple sclerosis, Houndmills, Basingstoke, England2013: 1204-1208
        • Alvarez E.
        • Piccio L.
        • Mikesell R.J.
        • Trinkaus K.
        • Parks B.J.
        • Naismith R.T.
        • Cross A.H.
        Predicting optimal response to B-cell depletion with rituximab in multiple sclerosis using CXCL13 index, magnetic resonance imaging and clinical measures.
        Mult. Scler. J. Exp. Transl. Clin. 2015; 12055217315623800
        • Baecher-Allan C.
        • Kaskow B.J.
        • Weiner H.L.
        Multiple Sclerosis: mechanisms and immunotherapy.
        Neuron. 2018; 97: 742-768
        • Bai Z.
        • Chen D.
        • Wang L.
        • Zhao Y.
        • Liu T.
        • Yu Y.
        • Yan T.
        • Cheng Y.
        Cerebrospinal Fluid and Blood Cytokines as Biomarkers for Multiple Sclerosis: a Systematic Review and Meta-Analysis of 226 Studies With 13,526 Multiple Sclerosis Patients.
        Front. Neurosci. 2019; 13: 1026
        • Brettschneider J.
        • Czerwoniak A.
        • Senel M.
        • Fang L.
        • Kassubek J.
        • Pinkhardt E.
        • Lauda F.
        • Kapfer T.
        • Jesse S.
        • Lehmensiek V.
        • Ludolph A.C.
        • Otto M.
        • Tumani H.
        The chemokine CXCL13 is a prognostic marker in clinically isolated syndrome (CIS).
        PLoS ONE. 2010; 5: e11986
        • Denton A.E.
        • Innocentin S.
        • Carr E.J.
        • Bradford B.M.
        • Lafouresse F.
        • Mabbott N.A.
        • Morbe U.
        • Ludewig B.
        • Groom J.R.
        • Good-Jacobson K.L.
        • Linterman M.A.
        Type I interferon induces CXCL13 to support ectopic germinal center formation.
        J. Exp. Med. 2019; 216: 621-637
        • Edwards K.R.
        • Goyal J.
        • Plavina T.
        • Czerkowicz J.
        • Goelz S.
        • Ranger A.
        • Cadavid D.
        • Browning J.L.
        Feasibility of the use of combinatorial chemokine arrays to study blood and CSF in multiple sclerosis.
        PLoS ONE. 2013; 8: e81007
        • Festa E.D.
        • Hankiewicz K.
        • Kim S.
        • Skurnick J.
        • Wolansky L.J.
        • Cook S.D.
        • Cadavid D.
        Serum levels of CXCL13 are elevated in active multiple sclerosis.
        Multip. Sclero. J. 2009; 15: 1271-1279
        • Hytonen J.
        • Kortela E.
        • Waris M.
        • Puustinen J.
        • Salo J.
        • Oksi J.
        CXCL13 and neopterin concentrations in cerebrospinal fluid of patients with Lyme neuroborreliosis and other diseases that cause neuroinflammation.
        J. Neuroinflamm. 2014; 11: 103
        • Irani D.N.
        Regulated Production of CXCL13 within the Central Nervous System.
        J. Clin. Cell Immunol. 2016; 7
        • Iwanowski P.
        • Losy J.
        • Kramer L.
        • Wojcicka M.
        • Kaufman E.
        CXCL10 and CXCL13 chemokines in patients with relapsing remitting and primary progressive multiple sclerosis.
        J. Neurol. Sci. 2017; 380: 22-26
        • Khademi M.
        • Kockum I.
        • Andersson M.L.
        • Iacobaeus E.
        • Brundin L.
        • Sellebjerg F.
        • Hillert J.
        • Piehl F.
        • Olsson T.
        Cerebrospinal Fluid CXCL13 in Multiple sclerosis: a Suggestive Prognostic Marker For the Disease Course. 17. Multiple sclerosis, Houndmills, Basingstoke, England2011: 335-343
        • Krumbholz M.
        • Theil D.
        • Cepok S.
        • Hemmer B.
        • Kivisakk P.
        • Ransohoff R.M.
        • Hofbauer M.
        • Farina C.
        • Derfuss T.
        • Hartle C.
        • Newcombe J.
        • Hohlfeld R.
        • Meinl E.
        Chemokines in multiple sclerosis: CXCL12 and CXCL13 up-regulation is differentially linked to CNS immune cell recruitment.
        Brain. 2006; 129: 200-211
        • Li R.
        • Patterson K.R.
        • Bar-Or A.
        Reassessing B cell contributions in multiple sclerosis.
        Nat. Immunol. 2018; 19: 696-707
        • Liba Z.
        • Nohejlova H.
        • Capek V.
        • Krsek P.
        • Sediva A.
        • Kayserova J.
        Utility of chemokines CCL2, CXCL8, 10 and 13 and interleukin 6 in the pediatric cohort for the recognition of neuroinflammation and in the context of traditional cerebrospinal fluid neuroinflammatory biomarkers.
        PLoS ONE. 2019; 14e0219987
        • Magliozzi R.
        • Howell O.W.
        • Nicholas R.
        • Cruciani C.
        • Castellaro M.
        • Romualdi C.
        • Rossi S.
        • Pitteri M.
        • Benedetti M.D.
        • Gajofatto A.
        • Pizzini F.B.
        • Montemezzi S.
        • Rasia S.
        • Capra R.
        • Bertoldo A.
        • Facchiano F.
        • Monaco S.
        • Reynolds R.
        • Calabrese M.
        Inflammatory intrathecal profiles and cortical damage in multiple sclerosis.
        Ann. Neurol. 2018; 83: 739-755
        • Markowicz M.
        • Schotta A.M.
        • Kundi M.
        • Bogovic P.
        • Ogrinc K.
        • Strle F.
        • Stanek G.
        CXCL13 concentrations in cerebrospinal fluid of patients with Lyme neuroborreliosis and other neurological disorders determined by Luminex and ELISA.
        Ticks Tick. Borne Dis. 2018; 9: 1137-1142
        • Merkel B.
        • Butzkueven H.
        • Traboulsee A.L.
        • Havrdova E.
        • Kalincik T.
        Timing of high-efficacy therapy in relapsing-remitting multiple sclerosis: a systematic review.
        Autoimmun. Rev. 2017; 16: 658-665
        • Modvig S.
        • Degn M.
        • Horwitz H.
        • Cramer S.P.
        • Larsson H.B.
        • Wanscher B.
        • Sellebjerg F.
        • Frederiksen J.L.
        Relationship between cerebrospinal fluid biomarkers for inflammation, demyelination and neurodegeneration in acute optic neuritis.
        PLoS ONE. 2013; 8: e77163
      1. Modvig, S., Degn, M., Roed, H., Sorensen, T.L., Larsson, H.B., Langkilde, A.R., Frederiksen, J.L., Sellebjerg, F., 2015. Cerebrospinal fluid levels of chitinase 3-like 1 and neurofilament light chain predict multiple sclerosis development and disability after optic neuritis. Multiple sclerosis (Houndmills, Basingstoke, England) 21(14), 1761–1770.

        • Novakova L.
        • Axelsson M.
        • Khademi M.
        • Zetterberg H.
        • Blennow K.
        • Malmestrom C.
        • Piehl F.
        • Olsson T.
        • Lycke J.
        Cerebrospinal fluid biomarkers as a measure of disease activity and treatment efficacy in relapsing-remitting multiple sclerosis.
        J. Neurochem. 2017; 141: 296-304
        • Olesen M.N.
        • Soelberg K.
        • Debrabant B.
        • Nilsson A.C.
        • Lillevang S.T.
        • Grauslund J.
        • Brandslund I.
        • Madsen J.S.
        • Paul F.
        • Smith T.J.
        • Jarius S.
        • Asgari N.
        Cerebrospinal fluid biomarkers for predicting development of multiple sclerosis in acute optic neuritis: a population-based prospective cohort study.
        J. Neuroinflamm. 2019; 16: 59
        • Piccio L.
        • Naismith R.T.
        • Trinkaus K.
        • Klein R.S.
        • Parks B.J.
        • Lyons J.A.
        • Cross A.H.
        Changes in B- and T-lymphocyte and chemokine levels with rituximab treatment in multiple sclerosis.
        Arch. Neurol. 2010; 67: 707-714
        • Pilz G.
        • Sakic I.
        • Wipfler P.
        • Kraus J.
        • Haschke-Becher E.
        • Hitzl W.
        • Trinka E.
        • Harrer A.
        Chemokine CXCL13 in serum, CSF and blood-CSF barrier function: evidence of compartment restriction.
        Fluids Barriers CNS. 2020; 17: 7
        • 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 J.S.
        Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria.
        Ann. Neurol. 2011; 69: 292-302
        • Reiber H.
        • Peter J.B.
        Cerebrospinal fluid analysis: disease-related data patterns and evaluation programs.
        J. Neurol. Sci. 2001; 184: 101-122
        • Remy M.M.
        • Schobi N.
        • Kottanattu L.
        • Pfister S.
        • Duppenthaler A.
        • Suter-Riniker F.
        Cerebrospinal fluid CXCL13 as a diagnostic marker of neuroborreliosis in children: a retrospective case-control study.
        J. Neuroinflamm. 2017; 14: 173
        • Rubenstein J.L.
        • Wong V.S.
        • Kadoch C.
        • Gao H.X.
        • Barajas R.
        • Chen L.
        • Josephson S.A.
        • Scott B.
        • Douglas V.
        • Maiti M.
        • Kaplan L.D.
        • Treseler P.A.
        • Cha S.
        • Hwang J.H.
        • Cinque P.
        • Cyster J.G.
        • Lowell C.
        CXCL13 plus interleukin 10 is highly specific for the diagnosis of CNS lymphoma.
        Blood. 2013; 121: 4740-4748
        • Rupprecht T.A.
        • Lechner C.
        • Tumani H.
        • Fingerle V.
        [CXCL13: a biomarker for acute Lyme neuroborreliosis: investigation of the predictive value in the clinical routine].
        Nervenarzt. 2014; 85: 459-464
        • Soelberg K.
        • Jarius S.
        • Skejoe H.
        • Engberg H.
        • Mehlsen J.J.
        • Nilsson A.C.
        • Madsen J.S.
        • Reindl M.
        • Wildemann B.
        • Grauslund J.
        • Kyvik K.O.
        • Smith T.J.
        • Lillevang S.T.
        • Paul F.
        • Weinshenker B.G.
        • Asgari N.
        A Population-Based Prospective Study of Optic Neuritis. 23. Multiple sclerosis, Houndmills, Basingstoke, England2017: 1893-1901
        • Sospedra M.
        B cells in multiple sclerosis.
        Curr Opin Neurol. 2018; 31: 256-262
        • Thompson A.J.
        • Banwell B.L.
        • Barkhof F.
        • Carroll W.M.
        • Coetzee T.
        • Comi G.
        • Correale J.
        • Fazekas F.
        • Filippi M.
        • Freedman M.S.
        • Fujihara K.
        • Galetta S.L.
        • Hartung H.P.
        • Kappos L.
        • Lublin F.D.
        • Marrie R.A.
        • Miller A.E.
        • Miller D.H.
        • Montalban X.
        • Mowry E.M.
        • Sorensen P.S.
        • Tintore M.
        • Traboulsee A.L.
        • Trojano M.
        • Uitdehaag B.M.J.
        • Vukusic S.
        • Waubant E.
        • Weinshenker B.G.
        • Reingold S.C.
        • Cohen J.A.
        Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria.
        Lancet Neurol. 2018; 17: 162-173