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Immunologic Research
Published in: Immunologic Research 6/2017

01-12-2017 | Review

The complement system as a biomarker of disease activity and response to treatment in multiple sclerosis

Authors: Alexandru Tatomir, Anamaria Talpos-Caia, Freidrich Anselmo, Adam M. Kruszewski, Dallas Boodhoo, Violeta Rus, Horea Rus

Published in: Immunologic Research | Issue 6/2017

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Abstract

Multiple sclerosis (MS) is an inflammatory, demyelinating, and neurodegenerative disease of the central nervous system. The complement system has an established role in the pathogenesis of MS, and evidence suggests that its components can be used as biomarkers of disease-state activity and response to treatment in MS. Plasma C4a levels have been found to be significantly elevated in patients with active relapsing-remitting MS (RRMS), as compared to both controls and patients with stable RRMS. C3 levels are also significantly elevated in the cerebrospinal fluid (CSF) of patients with RRMS, and C3 levels are correlated with clinical disability. Furthermore, increased levels of factor H can predict the transition from relapsing to progressive disease, since factor H levels have been found to increase progressively with disease progression over a 2-year period in patients transitioning from RRMS to secondary progressive (SP) MS. In addition, elevations in C3 are seen in primary progressive (PP) MS. Complement components can also differentiate RRMS from neuromyelitis optica. Response gene to complement (RGC)-32, a novel molecule induced by complement activation, is a possible biomarker of relapse and response to glatiramer acetate (GA) therapy, since RGC-32 mRNA expression is significantly decreased during relapse and increased in responders to GA treatment. The predictive accuracy of RGC-32 as a potential biomarker (by ROC analysis) is 90% for detecting relapses and 85% for detecting a response to GA treatment. Thus, complement components can serve as biomarkers of disease activity to differentiate MS subtypes and to measure response to therapy.
Literature
1.
Compston DA, Morgan BP, Campbell AK, Wilkins P, Cole G, Thomas ND, et al. Immunocytochemical localization of the terminal complement complex in multiple sclerosis. Neuropathol Appl Neurobiol. 1989;15:307–16.CrossRefPubMed
2.
Lucchinetti C, Bruck W, Parisi J, Scheithauer B, Rodriguez M, Lassmann H. Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann Neurol. 2000;47:707–17.CrossRefPubMed
3.
Breij ECW, Brink BP, Veerhuis R, Van den Berg C, Vloet R, Yan R, Dijkstra CD, et al. Homogeneity of active demyelinating lesions in established multiple sclerosis. Ann Neurol. 2008;63:16–25.
4.
Tegla CA, Cudrici C, Patel S, Trippe R 3rd, Rus V, Niculescu F, et al. Membrane attack by complement: the assembly and biology of terminal complement complexes. Immunol Res. 2011;51:45–60.CrossRefPubMedPubMedCentral
5.
Rus H, Cudrici C, Niculescu F. C5b-9 complement complex in autoimmune demyelination: dual role in neuroinflammation and neuroprotection. Adv Exp Med Biol. 2006;586:139–51.CrossRefPubMed
6.
Barnett MH, Parratt JD, Cho ES, Prineas JW. Immunoglobulins and complement in postmortem multiple sclerosis tissue. Ann Neurol. 2009;65:32–46.CrossRefPubMed
7.
Barnett MH, Prineas JW. Relapsing and remitting multiple sclerosis: pathology of the newly forming lesion. Ann Neurol. 2004;55:458–68.CrossRefPubMed
8.
Lucchinetti C, Bruck W, Noseworthy J. Multiple sclerosis: recent developments in neuropathology, pathogenesis, magnetic resonance imaging studies and treatment. Curr Opin Neurol. 2001;14:259–69.CrossRefPubMed
9.
Ingram G, Loveless S, Howell OW, Hakobyan S, Dancey B, Harris CL, et al. Complement activation in multiple sclerosis plaques: an immunohistochemical analysis. Acta Neuropathol Commun. 2014;2:53.CrossRefPubMedPubMedCentral
10.
Rus HG, Kim LM, Niculescu FI, Shin ML. Induction of C3 expression in astrocytes is regulated by cytokines and Newcastle disease virus. J Immunol. 1992;148:928–33.PubMed
11.
12.
Tegla CA, Cudrici C, Rozycka M, Soloviova K, Ito T, Singh AK, et al. C5b-9-activated, Kv1.3 channels mediate oligodendrocyte cell cycle activation and dedifferentiation. Exp Mol Pathol. 2011;91:335–45.CrossRefPubMedPubMedCentral
13.
Michailidou I, Naessens DM, Hametner S, Guldenaar W, Kooi EJ, Geurts JJ, et al. Complement C3 on microglial clusters in multiple sclerosis occur in chronic but not acute disease: implication for disease pathogenesis. Glia. 2017;65(2):264–77.CrossRefPubMed
14.
Rus H, Cudrici C, Niculescu F, Shin ML. Complement activation in autoimmune demyelination: dual role in neuroinflammation and neuroprotection. J Neuroimmunol. 2006;180:9–16.CrossRefPubMed
15.
Liu WT, Vanguri P, Shin ML. Studies on demyelination in vitro: the requirement of membrane attack components of the complement system. J Immunol. 1983;131:778–82.PubMed
16.
Liu Y, Given KS, Harlow DE, Matschulat AM, Macklin WB, Bennett JL, et al. Myelin-specific multiple sclerosis antibodies cause complement-dependent oligodendrocyte loss and demyelination. Acta Neuropathol Commun. 2017;5:25.CrossRefPubMedPubMedCentral
17.
Soane L, Cho HJ, Niculescu F, Rus H, Shin ML. C5b-9 terminal complement complex protects oligodendrocytes from death by regulating Bad through phosphatidylinositol 3-kinase/Akt pathway. J Immunol. 2001;167:2305–11.CrossRefPubMed
18.
Cudrici C, Niculescu F, Jensen T, Zafranskaia E, Fosbrink M, Rus V, et al. C5b-9 terminal complex protects oligodendrocytes from apoptotic cell death by inhibiting caspase-8 processing and up-regulating FLIP. J Immunol. 2006;176:3173–80.CrossRefPubMed
19.
Ingram G, Hakobyan S, Hirst CL, Harris CL, Loveless S, Mitchell JP, et al. Systemic complement profiling in multiple sclerosis as a biomarker of disease state. Mult Scler. 2012;18:1401–11.CrossRefPubMedPubMedCentral
20.
Lindblom RP, Aeinehband S, Strom M, Al Nimer F, Sandholm K, Khademi M, et al. Complement receptor 2 is increased in cerebrospinal fluid of multiple sclerosis patients and regulates C3 function. Clin Immunol. 2016;166-167:89–95.CrossRefPubMed
21.
Kwok JY, Vaida F, Augst RM, DY Y, Singh KK. Mannose binding lectin mediated complement pathway in multiple sclerosis. J Neuroimmunol. 2011;239:98–100.CrossRefPubMedPubMedCentral
22.
Ingram G, Hakobyan S, Robertson NP, Morgan BP. Elevated plasma C4a levels in multiple sclerosis correlate with disease activity. J Neuroimmunol. 2010;223:124–7.CrossRefPubMed
23.
Jongen PJ, Doesburg WH, Ibrahim-Stappers JL, Lemmens WA, Hommes OR, Lamers KJ. Cerebrospinal fluid C3 and C4 indexes in immunological disorders of the central nervous system. Acta Neurol Scand. 2000;101:116–21.CrossRefPubMed
24.
Hakobyan S, Luppe S, Evans DR, Harding K, Loveless S, Robertson NP, et al. Plasma complement biomarkers distinguish multiple sclerosis and neuromyelitis optica spectrum disorder. Mult Scler. 2017;23:946–55.CrossRefPubMed
25.
Nytrova P, Potlukova E, Kemlink D, Woodhall M, Horakova D, Waters P, et al. Complement activation in patients with neuromyelitis optica. J Neuroimmunol. 2014;274:185–91.CrossRefPubMed
26.
Ingram G, Hakobyan S, Hirst CL, Harris CL, Pickersgill TP, Cossburn MD, et al. Complement regulator factor H as a serum biomarker of multiple sclerosis disease state. Brain. 2010;133(Pt 6):1602–11.CrossRefPubMed
27.
Aeinehband S, Lindblom RP, Al Nimer F, Vijayaraghavan S, Sandholm K, Khademi M, et al. Complement component C3 and butyrylcholinesterase activity are associated with neurodegeneration and clinical disability in multiple sclerosis. PLoS One. 2015;10(4):e0122048.CrossRefPubMedPubMedCentral
28.
Li Y, Qin Z, Yang M, Qin Y, Lin C, Liu S. Differential expression of complement proteins in cerebrospinal fluid from active multiple sclerosis patients. J Cell Biochem. 2011;112:1930–7.CrossRefPubMed
29.
Wang H, Wang K, Wang C, Qiu W, Lu Z, Hu X. Increased soluble C5b-9 in CSF of neuromyelitis optica. Scand J Immunol. 2014;79:127–30.CrossRefPubMed
30.
Sanders ME, Koski CL, Robbins D, Shin ML, Frank MM, Joiner KA. Activated terminal complement in cerebrospinal fluid in Guillain-Barre syndrome and multiple sclerosis. J Immunol. 1986;136:4456–9.PubMed
31.
Ingram G, Hakobyan S, Loveless S, Robertson N, Morgan BP. Complement regulator factor H in multiple sclerosis. J Cell Biochem. 2011;112:2653–4.CrossRefPubMed
32.
Sellebjerg F, Jaliashvili I, Christiansen M, Garred P. Intrathecal activation of the complement system and disability in multiple sclerosis. J Neurol Sci. 1998;157:168–74.CrossRefPubMed
33.
Tradtrantip L, Yao X, Su T, Smith AJ, Verkman AS. Bystander mechanism for complement-initiated early oligodendrocyte injury in neuromyelitis optica. Acta Neuropathol. 2017;134:35–44.CrossRefPubMed
34.
Badea TC, Niculescu FI, Soane L, Shin ML, Rus H. Molecular cloning and characterization of RGC-32, a novel gene induced by complement activation in oligodendrocytes. J Biol Chem. 1998;273:26977–81.CrossRefPubMed
35.
Badea T, Niculescu F, Soane L, Fosbrink M, Sorana H, Rus V, et al. RGC-32 increases p34CDC2 kinase activity and entry of aortic smooth muscle cells into S-phase. J Biol Chem. 2002;277:502–8.CrossRefPubMed
36.
Fosbrink M, Cudrici C, Tegla CA, Soloviova K, Ito T, Vlaicu S, et al. Response gene to complement 32 is required for C5b-9 induced cell cycle activation in endothelial cells. Exp Mol Pathol. 2009;86:87–94.CrossRefPubMedPubMedCentral
37.
Vlaicu SI, Tegla CA, Cudrici CD, Fosbrink M, Nguyen V, Azimzadeh P, et al. Epigenetic modifications induced by RGC-32 in colon cancer. Exp Mol Pathol. 2010;88:67–76.CrossRefPubMed
38.
Lopatinskaya L, van Boxel-Dezaire AH, Barkhof F, Polman CH, Lucas CJ, Nagelkerken L. The development of clinical activity in relapsing-remitting MS is associated with a decrease of FasL mRNA and an increase of Fas mRNA in peripheral blood. J Neuroimmunol. 2003;138(1–2):123–31.CrossRefPubMed
39.
Tegla CA, Cudrici CD, Azimzadeh P, Singh AK, Trippe R 3rd, Khan A, et al. Dual role of response gene to complement-32 in multiple sclerosis. Exp Mol Pathol. 2013;94:17–28.CrossRefPubMed
40.
Kruszewski AM, Rao G, Tatomir A, Hewes D, Tegla CA, Cudrici CD, et al. RGC-32 as a potential biomarker of relapse and response to treatment with glatiramer acetate in multiple sclerosis. Exp Mol Pathol. 2015;99:498–505.CrossRefPubMed
41.
Tatomir A, Cosmin T, Cudrici C, Boodhoo D, Martin A, Mekala A, et al. RGC-32 regulates TGF-β extracellular matrix production in multiple sclerosis. J Immunol. 2016;196:189.187.
Metadata
Title
The complement system as a biomarker of disease activity and response to treatment in multiple sclerosis
Authors
Alexandru Tatomir
Anamaria Talpos-Caia
Freidrich Anselmo
Adam M. Kruszewski
Dallas Boodhoo
Violeta Rus
Horea Rus
Publication date
01-12-2017
Publisher
Springer US
Published in
Immunologic Research / Issue 6/2017
Print ISSN: 0257-277X
Electronic ISSN: 1559-0755
DOI
https://doi.org/10.1007/s12026-017-8961-8

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