Chronic inflammatory demyelinating polyneuropathy (CIDP): change of serum IgG dimer levels during treatment with intravenous immunoglobulins

Journal of Neuroinflammation

Helmar C. Lehmann¹  Ilja Bobylev¹  Christian Ritter² 

[1] Center of Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany;Cognitive Neuroscience, Institute of Neuroscience and Medicine (INM-3), Research Centre Jülich, Jülich, Germany

关键词: Autoantibody;    Inflammation;    Surrogate marker;    Immune neuropathy;   

Others  :  1227079
DOI  :  10.1186/s12974-015-0361-1

 received in 2015-05-01, accepted in 2015-07-09,  发布年份 2015

【 摘 要 】

Background

Intravenous immunoglobulin (IVIg) is an effective treatment in chronic inflammatory demyelinating polyneuropathy (CIDP). In most patients, the optimal IVIg dose and regime is unknown. Polyvalent immunoglobulin (Ig) G form idiotypic/anti-idiotypic antibody pairs in serum and IVIg preparations. We determined IgG dimer levels before and after IVIg treatment in CIDP patients with the aim to explore their utility to serve as a surrogate marker for treatment response.

Methods

IgG was purified from serum of five controls without treatment, as well as from serum of 16 CIDP patients, two patients with Miller Fisher syndrome (MFS), and one patient with myasthenia gravis before and after treatment with IVIg. IgG dimer levels were determined by size exclusion chromatography. IgG dimer formation was correlated with clinical response to IVIg treatment in CIDP. Re-monomerized IgG dimer fractions were analyzed for immunoreactivity against peripheral nerve tissue.

Results

IgG dimer levels were significantly higher in post- compared to pre-IVIg infusion samples. Low post-treatment IgG dimer levels in CIDP patients were associated with clinical worsening during IVIg treatment. Re-monomerized IgG dimer fractions from CIDP patients showed immunoreactivity against peripheral nerve tissue, whereas similarly treated samples from MFS patients showed immunoreactivity against GQ1b.

Conclusion

Assessment of IgG dimer levels could be a novel approach to monitor CIDP patients during IVIg treatment, but further studies in larger cohorts are warranted to explore their utility to serve as a potential therapeutic biomarker for IVIg treatment response in CIDP.

【 授权许可】

   
2015 Ritter et al.

【 图 表 】

Fig. 1.

Fig. 2.

Fig. 3.

【 参考文献 】

• [1]Nobile-Orazio E: Chronic inflammatory demyelinating polyradiculoneuropathy and variants: where we are and where we should go. J Peripher Nerv Syst 2014, 19:2-13.
• [2]Dalakas MC: Advances in the diagnosis, pathogenesis and treatment of CIDP. Nat Rev Neurol 2011, 7:507-17.
• [3]Vallat JM, Sommer C, Magy L: Chronic inflammatory demyelinating polyradiculoneuropathy: diagnostic and therapeutic challenges for a treatable condition. Lancet Neurol 2010, 9:402-12.
• [4]Köller H, Kieseier BC, Jander S, Hartung HP: Chronic inflammatory demyelinating neuropathy. N Engl J Med 2005, 352:1343-56.
• [5]Lehmann HC, Hughes RA, Hartung HP: Treatment of chronic inflammatory demyelinating polyradiculoneuropathy. Handb Clin Neurol 2013, 115:415-27.
• [6]Eftimov F, Winer JB, Vermeulen M, de Haan R, van Schaik IN: Intravenous immunoglobulin for chronic inflammatory demyelinating polyradiculoneuropathy. Cochrane Database Syst Rev 2013., 12Article ID CD001797
• [7]Hughes RA, Donofrio P, Bril V, Dalakas MC, Deng C, Hanna K, et al.: Intravenous immune globulin (10% caprylate-chromatography purified) for the treatment of chronic inflammatory demyelinating polyradiculoneuropathy (ICE study): a randomised placebo-controlled trial. Lancet Neurol 2008, 7:136-44.
• [8]Buttmann M, Kaveri S, Hartung HP: Polyclonal immunoglobulin G for autoimmune demyelinating nervous system disorders. Trends Pharmacol Sci 2013, 34:445-57.
• [9]Lehmann HC, Hartung HP: Plasma exchange and intravenous immunoglobulins: mechanism of action in immune-mediated neuropathies. J Neuroimmunol 2011, 231:61-9.
• [10]Ritter C, Förster D, Albrecht P, Hartung HP, Kieseier BC, Lehmann HC: IVIG regulates BAFF expression in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). J Neuroimmunol 2014, 274:225-9.
• [11]Shoenfeld Y, Rauova L, Gilburd B, Kvapil F, Goldberg I, Kopolovic J, et al.: Efficacy of IVIG affinity-purified anti-double-stranded DNA anti-idiotypic antibodies in the treatment of an experimental murine model of systemic lupus erythematosus. Int Immunol 2002, 14:1303-11.
• [12]Mimouni D, Blank M, Payne AS, Anhalt GJ, Avivi C, Barshack I, et al.: Efficacy of intravenous immunoglobulin (IVIG) affinity-purified anti-desmoglein anti-idiotypic antibodies in the treatment of an experimental model of pemphigus vulgaris. Clin Exp Immunol 2010, 162:543-9.
• [13]Zandman-Goddard G, Blank M, Shoenfeld Y: Intravenous immunoglobulins in systemic lupus erythematosus: from the bench to the bedside. Lupus 2009, 18:884-8.
• [14]Caccavo D, Vaccaro F, Ferri GM, Amoroso A, Bonomo L: Anti-idiotypes against antiphospholipid antibodies are present in normal polyspecific immunoglobulins for therapeutic use. J Autoimmun 1994, 7:537-48.
• [15]Vassilev TL, Bineva IL, Dietrich G, Kaveri SV, Kazatchkine MD: Variable region-connected, dimeric fraction of intravenous immunoglobulin enriched in natural autoantibodies. J Autoimmun 1995, 8:405-13.
• [16]Schaub A, von Gunten S, Vogel M, Wymann S, Rüegsegger M, Stadler BM, et al.: Dimeric IVIG contains natural anti-Siglec-9 autoantibodies and their anti-idiotypes. Allergy 2011, 66:1030-7.
• [17]Schaub A, Wymann S, Heller M, Ghielmetti M, Beleznay Z, Stadler BM, et al.: Self-reactivity in the dimeric intravenous immunoglobulin fraction. Ann N Y Acad Sci 2007, 1110:681-93.
• [18]Bolli R, Woodtli K, Bärtschi M, Höfferer L, Lerch P: L-Proline reduces IgG dimer content and enhances the stability of intravenous immunoglobulin (IVIG) solutions. Biologicals 2010, 38:150-7.
• [19]Teeling JL, Jansen-Hendriks T, Kuijpers TW, de Haas M, van de Winkel JG, Hack CE, et al.: Therapeutic efficacy of intravenous immunoglobulin preparations depends on the immunoglobulin G dimers: studies in experimental immune thrombocytopenia. Blood 2001, 98:1095-9.
• [20]Morgan AC, Rossen RD, Twomey JJ: Naturally occurring circulating immune complexes: normal human serum contains idiotype-anti-idiotype complexes dissociable by certain IgG antiglobulins. J Immunol 1979, 122:1672-80.
• [21]Roux KH, Tankersley DL: A view of the human idiotypic repertoire. Electron microscopic and immunologic analyses of spontaneous idiotype-anti-idiotype dimers in pooled human IgG. J Immunol 1990, 144:1387-95.
• [22]Joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society: European Federation of Neurological Societies/Peripheral Nerve Society Guideline on management of chronic inflammatory demyelinating polyradiculoneuropathy: report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society - first revision J Peripher Nerv Syst 2010, 15:1-9.
• [23]Hughes R, Bensa S, Willison H, Van den Bergh P, Comi G, Illa I, et al.: Randomized controlled trial of intravenous immunoglobulin versus oral prednisolone in chronic inflammatory demyelinating polyradiculoneuropathy. Ann Neurol 2001, 50:195-201.
• [24]Tankersley DL: Dimer formation in immunoglobulin preparations and speculations on the mechanism of action of intravenous immune globulin in autoimmune diseases. Immunol Rev 1994, 139:159-72.
• [25]Tankersley DL, Preston MS, Finlayson JS: Immunoglobulin G dimer: an idiotype-anti-idiotype complex. Mol Immunol 1988, 25:41-8.
• [26]Bleeker WK, Teeling JL, Verhoeven AJ, Rigter GM, Agterberg J, Tool AT, et al.: Vasoactive side effects of intravenous immunoglobulin preparations in a rat model and their treatment with recombinant platelet-activating factor acetylhydrolase. Blood 2000, 95:1856-61.
• [27]Dietrich G, Kazatchkine MD: Normal immunoglobulin G (IgG) for therapeutic use (intravenous Ig) contain antiidiotypic specificities against an immunodominant, disease-associated, cross-reactive idiotype of human anti-thyroglobulin autoantibodies. J Clin Invest 1990, 85:620-5.
• [28]Rossi F, Jayne DR, Lockwood CM, Kazatchkine MD: Anti-idiotypes against anti-neutrophil cytoplasmic antigen autoantibodies in normal human polyspecific IgG for therapeutic use and in the remission sera of patients with systemic vasculitis. Clin Exp Immunol 1991, 83:298-303.
• [29]Sanvito L, Makowska A, Mahdi-Rogers M, Hadden R, Peakman M, Gregson N, et al.: Humoral and cellular immune responses to myelin protein peptides in chronic inflammatory demyelinating polyradiculoneuropathy. J Neurol Neurosurg Psychiatry 2009, 80:333-8.
• [30]Melendez-Vasquez C, Redford J, Choudhary PP, Gray IA, Maitland P, Gregson NA, et al.: Immunological investigation of chronic inflammatory demyelinating polyradiculoneuropathy. J Neuroimmunol 1997, 73:124-34.
• [31]Querol L, Nogales-Gadea G, Rojas-Garcia R, Martinez-Hernandez E, Diaz-Manera J, Suárez-Calvet X, et al.: Antibodies to contactin-1 in chronic inflammatory demyelinating polyneuropathy. Ann Neurol 2013, 73:370-80.
• [32]Ng JK, Malotka J, Kawakami N, Derfuss T, Khademi M, Olsson T, et al.: Neurofascin as a target for autoantibodies in peripheral neuropathies. Neurology 2012, 79:2241-8.
• [33]Nobile-Orazio E, Giannotta C, Briani C: Anti-ganglioside complex IgM antibodies in multifocal motor neuropathy and chronic immune-mediated neuropathies. J Neuroimmunol 2010, 219:119-22.