Home Targeting complement system to treat myasthenia gravis
Article
Licensed
Unlicensed Requires Authentication

Targeting complement system to treat myasthenia gravis

  • Ruksana Huda , Erdem Tüzün and Premkumar Christadoss EMAIL logo
Published/Copyright: April 12, 2014
Become an author with De Gruyter Brill

Abstract

While the complement system is desired for protective immunity, antibody- and complement-mediated neuromuscular junction (NMJ) destruction, a hallmark of myasthenia gravis (MG) or experimental autoimmune MG (EAMG), is a significant concern. Evidence suggests that the binding of complement factors to the pathogenic anti-acetylcholine receptor (AChR) autoantibody induces the formation of membrane attack complexes (MAC), which ultimately lead to NMJ destruction and muscle weakness. Studies corroborating the evidence show that the complement (C3–C6)-deficient or complement inhibitor (anti-C1q, soluble CR1, anti-C6, and C5 inhibiting peptide)-treated animals are highly resistant to EAMG induction, whereas the deficiency of the naturally occurring complement inhibitors, such as the decay-accelerating factor (DAF), increases EAMG susceptibility. Notably, the complement-inhibited animals do not exhibit significant immunosuppression but only a marginal reduction in the production of certain cytokines and immunoglobulin isotypes. A preliminary clinical trial using antibody-based C5 inhibitor eculizumab has been shown to be of potential use for MG treatment. The inhibition of the classic complement pathway (CCP) alone appears to be enough to suppress EAMG, suggesting that the complement inhibitors targeting specifically the classic pathway could effectively treat MG without causing immunosuppressive and other side effects. For instance, a recent non-antibody-based therapeutic approach selectively targeting the CCP component C2 by small interfering RNA (siRNA) has proven useful in EAMG treatment. The treatment strategies developed for MG might also be beneficial for other complement-mediated autoimmune diseases.


Corresponding author: Premkumar Christadoss, Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA, e-mail:

References

Biesecker, G. and Gomez, C.M. (1989). Inhibition of acute passive transfer experimental autoimmune myasthenia gravis with Fab antibody to complement C6. J. Immunol. 142, 2654–2659.10.4049/jimmunol.142.8.2654Search in Google Scholar

Brodsky, R.A., Young, N.S., Antonioli, E., Risitano, A.M., Schrezenmeier, H., Schubert, J., Gaya, A., Coyle, L., de Castro, C., Fu, C.L., et al. (2008). Multicenter phase 3 study of the complement inhibitor eculizumab for the treatment of patients with paroxysmal nocturnal hemoglobinuria. Blood 111, 1840–1847.10.1182/blood-2007-06-094136Search in Google Scholar PubMed

Chamberlain-Banoub, J., Neal, J.W., Mizuno, M., Harris, C.L., and Morgan, B.P. (2006). Complement membrane attack is required for endplate damage and clinical disease in passive experimental myasthenia gravis in Lewis rats. Clin. Exp. Immunol. 146, 278–286.10.1111/j.1365-2249.2006.03198.xSearch in Google Scholar PubMed PubMed Central

Christadoss, P. (1988). C5 gene influences the development of murine myasthenia gravis. J. Immunol. 140, 2589–2592.10.4049/jimmunol.140.8.2589Search in Google Scholar

Conti-Fine, B.M., Milani, M., and Kaminski, H.J. (2006). Myasthenia gravis: past, present, and future. J. Clin. Invest. 116, 2843–2854.10.1172/JCI29894Search in Google Scholar PubMed PubMed Central

Conti-Fine, B.M., Milani, M., and Wang, W. (2008). CD4+ T cells and cytokines in the pathogenesis of acquired myasthenia gravis. Ann. NY. Acad. Sci. 1132, 193–209.10.1196/annals.1405.042Search in Google Scholar PubMed

Davis, J. (2008). Eculizumab. Am. J. Health Syst. Pharm. 65, 1609–1615.10.2146/ajhp080043Search in Google Scholar PubMed

de Zwaan, C., van Dieijen-Visser, M.P., and Hermens, W.T. (2003). Prevention of cardiac cell injury during acute myocardial infarction: possible role for complement inhibition. Am. J. Cardiovasc. Drugs 3, 245–251.10.2165/00129784-200303040-00003Search in Google Scholar PubMed

Drachman, D.B., Adams, R.N., Stanley, E.F., and Pestronk, A. (1980). Mechanisms of acetylcholine receptor loss in myasthenia gravis. J. Neurol. Neurosurg. Psychiatry 43, 601–610.10.1136/jnnp.43.7.601Search in Google Scholar PubMed PubMed Central

Engel, A.G., Lambert, E.H., and Howard, F.M. (1977). Immune complexes (IgG and C3) at the motor end-plate in myasthenia gravis: ultrastructural and light microscopic localization and electrophysiologic correlations. Mayo Clin. Proc. 52, 267–280.Search in Google Scholar

Engel, A.G., Sahashi, K., and Fumagalli, G. (1981). The immunopathology of acquired myasthenia gravis. Ann. NY. Acad. Sci. 377, 158–174.10.1111/j.1749-6632.1981.tb33730.xSearch in Google Scholar PubMed

Heckmann, J.M., Uwimpuhwe, H., Ballo, R., Kaur, M., Bajic, V.B., and Prince, S. (2010). A functional SNP in the regulatory region of the decay-accelerating factor gene associates with extraocular muscle pareses in myasthenia gravis. Genes Immun. 11, 1–10.10.1038/gene.2009.61Search in Google Scholar PubMed PubMed Central

Hepburn, N.J., Chamberlain-Banoub, J.L., Williams, A.S., Morgan, B.P., and Harris, C.L. (2008). Prevention of experimental autoimmune myasthenia gravis by rat Crry-Ig: a model agent for long-term complement inhibition in vivo. Mol. Immunol. 45, 395–405.10.1016/j.molimm.2007.06.144Search in Google Scholar PubMed PubMed Central

Higuchi, O., Hamuro, J., Motomura, M., and Yamanashi, Y. (2011). Autoantibodies to low-density lipoprotein receptor-related protein 4 in myasthenia gravis. Ann. Neurol. 69, 418–422.10.1002/ana.22312Search in Google Scholar PubMed

Howard, J.F., Jr., Barohn, R.J., Cutter, G.R., Freimer, M., Juel, V.C., Mozaffar, T., Mellion, M.L., Benatar, M.G., Farrugia, M.E., Wang, J.J., et al. (2013). A randomized, double-blind, placebo-controlled phase II study of eculizumab in patients with refractory generalized myasthenia gravis. Muscle Nerve 48, 76–84.10.1002/mus.23839Search in Google Scholar PubMed

Huda, R., Tüzün, E., and Christadoss, P. (2013). Complement C2 siRNA mediated therapy of myasthenia gravis in mice. J. Autoimmun. 42, 94–104.10.1016/j.jaut.2013.01.003Search in Google Scholar PubMed

Kaminski, H.J., Li, Z., Richmonds, C., Lin, F., and Medof, M.E. (2004). Complement regulators in extraocular muscle and experimental autoimmune myasthenia gravis. Exp. Neurol. 189, 333–342.10.1016/j.expneurol.2004.06.005Search in Google Scholar PubMed

Kamolvarin, N., Hemachudha, T., Ongpipattanakul, B., Phanthumchinda, K., and Sueblinvong, T. (1991). Plasma C3c in immune-mediated neurological diseases: a preliminary report. Acta Neurol. Scand. 83, 382–387.10.1111/j.1600-0404.1991.tb03968.xSearch in Google Scholar PubMed

Klint, C., Gullstrand, B., Sturfelt, G., and Truedsson, L. (2000). Binding of immune complexes to erythrocyte CR1 (CD35): difference in requirement of classical pathway components and indication of alternative pathway-mediated binding in C2-deficiency. Scand. J. Immunol. 52, 103–108.10.1046/j.1365-3083.2000.00752.xSearch in Google Scholar PubMed

Klooster, R., Plomp, J.J., Huijbers, M.G., Niks, E.H., Straasheijm, K.R., Detmers, F.J., Hermans, P.W., Sleijpen, K., Verrips, A., Losen, M., et al. (2012). Muscle-specific kinase myasthenia gravis IgG4 autoantibodies cause severe neuromuscular junction dysfunction in mice. Brain 135, 1081–1101.10.1093/brain/aws025Search in Google Scholar PubMed

Knoll, B.M., Letendre, L., and Steensma, D.P. (2008). Life-threatening desquamating rash and hyperammonemia following administration of eculizumab for paroxysmal nocturnal hemoglobinuria. Am. J. Hematol. 83, 881–883.10.1002/ajh.21265Search in Google Scholar PubMed

Kumar, V. and Kaminski, H.J. (2011). Treatment of myasthenia gravis. Curr. Neurol. Neurosci. Rep. 11, 89–96.10.1007/s11910-010-0151-1Search in Google Scholar PubMed

Kusner, L.L., Satija, N., Cheng, G., and Kaminski, H.J. (2013). Targeting therapy to the neuromuscular junction: proof of concept. Muscle Nerve. doi:10.1002/mus.24057.10.1002/mus.24057Search in Google Scholar PubMed PubMed Central

Leite, M.I., Jacob, S., Viegas, S., Cossins, J., Clover, L., Morgan, B.P., Beeson, D., Willcox, N., and Vincent, A. (2008). IgG1 antibodies to acetylcholine receptors in ‘seronegative’ myasthenia gravis. Brain 131, 1940–1952.10.1093/brain/awn092Search in Google Scholar

Lennon, V.A., Seybold, M.E., Lindstrom, J.M., Cochrane, C., and Ulevitch, R. (1978). Role of complement in the pathogenesis of experimental autoimmune myasthenia gravis. J. Exp. Med. 147, 973–983.10.1084/jem.147.4.973Search in Google Scholar

Li, J., Qi, H., Tüzün, E., Allman, W., Yilmaz, V., Saini, S.S., Deymeer, F., Saruhan-Direskeneli, G., and Christadoss, P. (2009). Mannose-binding lectin pathway is not involved in myasthenia gravis pathogenesis. J. Neuroimmunol. 208, 40–45.10.1016/j.jneuroim.2008.12.013Search in Google Scholar

Liang, S., Krauss, J.L., Domon, H., McIntosh, M.L., Hosur, K.B., Qu, H., Li, F., Tzekou, A., Lambris, J.D., and Hajishengallis, G. (2011). The C5a receptor impairs IL-12-dependent clearance of Porphyromonas gingivalis and is required for induction of periodontal bone loss. J. Immunol. 186, 869–877.10.4049/jimmunol.1003252Search in Google Scholar

Lin, F., Kaminski, H.J., Conti-Fine, B.M., Wang, W., Richmonds, C., and Medof, M.E. (2002). Markedly enhanced susceptibility to experimental autoimmune myasthenia gravis in the absence of decay-accelerating factor protection. J. Clin. Invest. 110, 1269–1274.10.1172/JCI0216086Search in Google Scholar

Liszewski, M.K., Kolev, M., Le Friec, G., Leung, M., Bertram, P.G., Fara, A.F., Subias, M., Pickering, M.C., Drouet, C., Meri, S., et al. (2013). Intracellular complement activation sustains T cell homeostasis and mediates effector differentiation. Immunity 39, 1143–1157.10.1016/j.immuni.2013.10.018Search in Google Scholar

Liu, A., Lin, H., Liu, Y., Cao, X., Wang, X., and Li, Z. (2009). Correlation of C3 level with severity of generalized myasthenia gravis. Muscle Nerve 40, 801–808.10.1002/mus.21398Search in Google Scholar

Mori, S., Kubo, S., Akiyoshi, T., Yamada, S., Miyazaki, T., Hotta, H., Desaki, J., Kishi, M., Konishi, T., Nishino, Y., et al. (2012). Antibodies against muscle-specific kinase impair both presynaptic and postsynaptic functions in a murine model of myasthenia gravis. Am. J. Pathol. 180, 798–810.10.1016/j.ajpath.2011.10.031Search in Google Scholar

Nastuk, W.L., Plescia, O.J., and Osserman, K.E. (1960). Changes in serum complement activity in patients with myasthenia gravis. Proc. Soc. Exp. Biol. Med. 105, 177–184.10.3181/00379727-105-26050Search in Google Scholar

Piddlesden, S.J., Jiang, S., Levin, J.L., Vincent, A., and Morgan, B.P. (1996). Soluble complement receptor 1 (sCR1) protects against experimental autoimmune myasthenia gravis. J. Neuroimmunol. 71, 173–177.10.1016/S0165-5728(96)00144-0Search in Google Scholar

Plomp, J.J., Huijbers, M.G., van der Maarel, S.M., and Verschuuren, J.J. (2012). Pathogenic IgG4 subclass autoantibodies in MuSK myasthenia gravis. Ann. NY Acad. Sci. 1275, 114–122.10.1111/j.1749-6632.2012.06808.xSearch in Google Scholar PubMed

Qi, H., Tüzün, E., Allman, W., Saini, S.S., Penabad, Z.R., Pierangeli, S., and Christadoss, P. (2008). C5a is not involved in experimental autoimmune myasthenia gravis pathogenesis. J. Neuroimmunol. 196, 101–106.10.1016/j.jneuroim.2008.03.007Search in Google Scholar PubMed PubMed Central

Qin, X., Ferris, S., Hu, W., Guo, F., Ziegeler, G., and Halperin, J.A. (2006). Analysis of the promoters and 5′-UTR of mouse Cd59 genes, and of their functional activity in erythrocytes. Genes Immun. 7, 287–297.10.1038/sj.gene.6364296Search in Google Scholar PubMed

Ricklin, D. and Lambris, J.D. (2013). Complement in immune and inflammatory disorders: pathophysiological mechanisms. J. Immunol. 190, 3831–3838.10.4049/jimmunol.1203487Search in Google Scholar PubMed PubMed Central

Rioux, P. (2001). TP-10 (AVANT Immunotherapeutics). Curr. Opin. Investig. Drugs 2, 364–371.Search in Google Scholar

Risitano, A.M. (2013). Paroxysmal nocturnal hemoglobinuria and the complement system: recent insights and novel anticomplement strategies. Adv. Exp. Med. Biol. 735, 155–172.10.1007/978-1-4614-4118-2_10Search in Google Scholar PubMed

Rodgaard, A., Nielsen, F.C., Djurup, R., Somnier, F., and Gammeltoft, S. (1987). Acetylcholine receptor antibody in myasthenia gravis: predominance of IgG subclasses 1 and 3. Clin. Exp. Immunol. 67, 82–88.Search in Google Scholar

Romi, F., Kristoffersen, E.K., Aarli, J.A., and Gilhus, N.E. (2005). The role of complement in myasthenia gravis: serological evidence of complement consumption in vivo. J. Neuroimmunol. 158, 191–194.10.1016/j.jneuroim.2004.08.002Search in Google Scholar PubMed

Roumenina, L.T., Sène, D., Radanova, M., Blouin, J., Halbwachs-Mecarelli, L., Dragon-Durey, M.A., Fridman, W.H., and Fremeaux-Bacchi, V. (2011). Functional complement C1q abnormality leads to impaired immune complexes and apoptotic cell clearance. J. Immunol. 187, 4369–4373.10.4049/jimmunol.1101749Search in Google Scholar PubMed

Ruiz-Argüelles, A. and Llorente, L. (2007). The role of complement regulatory proteins (CD55 and CD59) in the pathogenesis of autoimmune hemocytopenias. Autoimmun. Rev. 6, 155–161.10.1016/j.autrev.2006.09.008Search in Google Scholar PubMed

Sahashi, K., Engel, A.G., Lambert, E.H., and Howard, F.M., Jr. (1980). Ultrastructural localization of the terminal and lytic ninth complement component (C9) at the motor end-plate in myasthenia gravis. J. Neuropathol. Exp. Neurol. 39, 160–172.10.1097/00005072-198003000-00005Search in Google Scholar PubMed

Shen, C., Lu, Y., Zhang, B., Figueiredo, D., Bean, J., Jung, J., Wu, H., Barik, A., Yin, D.M., Xiong, W.C., et al. (2013). Antibodies against low-density lipoprotein receptor-related protein 4 induce myasthenia gravis. J. Clin. Invest. 123, 5190–5202.10.1172/JCI66039Search in Google Scholar PubMed PubMed Central

Shiraishi, H., Motomura, M., Yoshimura, T., Fukudome, T., Fukuda, T., Nakao, Y., Tsujihata, M., Vincent, A., and Eguchi, K. (2005). Acetylcholine receptors loss and postsynaptic damage in MuSK antibody-positive myasthenia gravis. Ann. Neurol. 57, 289–293.10.1002/ana.20341Search in Google Scholar PubMed

Soltys, J. and Wu, X. (2012). Complement regulatory protein Crry deficiency contributes to the antigen specific recall response in experimental autoimmune myasthenia gravis. J. Inflamm. (Lond.) 9, 20.10.1186/1476-9255-9-20Search in Google Scholar PubMed PubMed Central

Soltys, J., Gong, B., Kaminski, H.J., Zhou, Y., and Kusner, L.L. (2008). Extraocular muscle susceptibility to myasthenia gravis: unique immunological environment? Ann. N. Y. Acad. Sci. 1132, 220–224.10.1196/annals.1405.037Search in Google Scholar PubMed PubMed Central

Soltys, J., Kusner, L.L., Young, A., Richmonds, C., Hatala, D., Gong, B., Shanmugavel, V., and Kaminski, H.J. (2009). Novel complement inhibitor limits severity of experimentally myasthenia gravis. Ann. Neurol. 65, 67–75.10.1002/ana.21536Search in Google Scholar PubMed PubMed Central

Soltys, J., Halperin, J.A., and Xuebin, Q. (2012). DAF/CD55 and Protectin/CD59 modulate adaptive immunity and disease outcome in experimental autoimmune myasthenia gravis. J. Neuroimmunol. 244, 63–69.10.1016/j.jneuroim.2012.01.003Search in Google Scholar PubMed

Tüzün, E., Scott, B.G., Goluszko, E., Higgs, S., and Christadoss, P. (2003). Genetic evidence for involvement of classical complement pathway in induction of experimental autoimmune myasthenia gravis. J. Immunol. 171, 3847–3854.10.4049/jimmunol.171.7.3847Search in Google Scholar PubMed

Tüzün, E., Saini, S.S., Yang, H., Alagappan, D., Higgs, S., and Christadoss, P. (2006a). Genetic evidence for the involvement of Fcgamma receptor III in experimental autoimmune myasthenia gravis pathogenesis. J. Neuroimmunol. 174, 157–167.10.1016/j.jneuroim.2006.01.015Search in Google Scholar PubMed

Tüzün, E., Saini, S.S., Ghosh, S., Rowin, J., Meriggioli, M.N., and Christadoss, P. (2006b). Predictive value of serum anti-C1q antibody levels in experimental autoimmune myasthenia gravis. Neuromuscul. Disord. 16, 137–143.10.1016/j.nmd.2005.11.005Search in Google Scholar PubMed

Tüzün, E., Saini, S.S., Morgan, B.P., and Christadoss, P. (2006c). Complement regulator CD59 deficiency fails to augment susceptibility to actively induced experimental autoimmune myasthenia gravis. J. Neuroimmunol. 181, 29–33.10.1016/j.jneuroim.2006.07.016Search in Google Scholar PubMed

Tüzün, E., Li, J., Saini, S.S., Yang, H., and Christadoss, P. (2007). Pros and cons of treating murine myasthenia gravis with anti-C1q antibody. J. Neuroimmunol. 182, 167–176.10.1016/j.jneuroim.2006.10.014Search in Google Scholar PubMed

Tüzün, E., Huda, R., and Christadoss, P. (2011). Complement and cytokine based therapeutic strategies in myasthenia gravis. J. Autoimmun. 37, 136–143.10.1016/j.jaut.2011.05.006Search in Google Scholar PubMed

Viegas, S., Jacobson, L., Waters, P., Cossins, J., Jacob, S., Leite, M.I., Webster, R., and Vincent, A. (2012). Passive and active immunization models of MuSK-Ab positive myasthenia: electrophysiological evidence for pre and postsynaptic defects. Exp. Neurol. 234, 506–512.10.1016/j.expneurol.2012.01.025Search in Google Scholar PubMed

Vincent, A. and Drachman, D.B. (2002). Myasthenia gravis. Adv. Neurol. 88, 159–188.Search in Google Scholar

Wu, X., Tuzun, E., Li, J., Xiao, T., Saini, S.S., Qi, H., Allman, W., and Christadoss, P. (2012). Ocular and generalized myasthenia gravis induced by human acetylcholine receptor γ subunit immunization. Muscle Nerve 45, 209–216.10.1002/mus.22273Search in Google Scholar PubMed

Yang, H., Wu, B., Tüzün, E., Saini, S.S., Li, J., Allman, W., Higgs, S., Xiao, T.L., and Christadoss, P. (2007). A new mouse model of autoimmune ocular myasthenia gravis. Invest. Ophthalmol. Vis. Sci. 48, 5101–5111.10.1167/iovs.07-0271Search in Google Scholar PubMed

Zachrau, B., Finke, D., Kropf, K., Gosink, H.J., Kirchner, H., and Goerg, S. (2004). Antigen localization within the splenic marginal zone restores humoral immune response and IgG class switch in complement C4-deficient mice. Int. Immunol. 16, 1685–1690.10.1093/intimm/dxh159Search in Google Scholar PubMed

Zhou, Y., Gong, B., Lin, F., Rother, R.P., Medof, M.E., and Kaminski, H.J. (2007). Anti-C5 antibody treatment ameliorates weakness in experimentally acquired myasthenia gravis. J. Immunol. 179, 8562–8567.10.4049/jimmunol.179.12.8562Search in Google Scholar PubMed

Received: 2014-3-6
Accepted: 2014-3-26
Published Online: 2014-4-12
Published in Print: 2014-8-1

© 2014 by De Gruyter

Downloaded on 3.10.2025 from https://www.degruyterbrill.com/document/doi/10.1515/revneuro-2014-0021/html
Scroll to top button