Neue Entität der Paranodopathien: eine Zielstruktur mit therapeutischen Konsequenzen

Zusammenfassung

Immunneuropathien mit Autoantikörpern gegen paranodale Proteine wurden erst in den letzten Jahren beschrieben. Es handelt sich dabei um eine Subgruppe der entzündlichen Neuropathien mit IgG4-Autoantikörpern gegen die Proteine Neurofascin-155, Contactin-1 und Caspr-1. Diese Gruppe macht in den meisten Studien zwar < 10 % der Patienten mit Diagnose einer chronisch-inflammatorischen demyelinisierenden Polyradikuloneuropathie (CIDP) aus, jedoch ist der Autoantikörpernachweis von diagnostischer Relevanz, da sich die Patienten im Ansprechen auf Therapien von anderen Patienten mit CIDP unterscheiden: Obwohl aufgrund der bislang begrenzten Fallzahl keine Therapiestudien vorliegen, ist in allen Fallberichten ein sehr gutes Ansprechen auf Behandlungen mit Rituximab beschrieben, meist kein Ansprechen auf die Standardtherapie der CIDP mit Immunglobulinen. Klinisch fallen die Patienten durch einen relativ akuten Erkrankungsbeginn, eine schwere motorisch-betonte Polyneuropathie, teilweise einen Aktionstremor und eine sensible Ataxie auf. Elektrophysiologisch finden sich Kennzeichen einer demyelinisierenden Neuropathie bei jedoch eher axonalem histologischen Phänotyp in der Nervenbiopsie. Erklärt werden kann letzteres durch das pathophysiologische Konzept einer „Paranodopathie/Nodopathie“, einer Schnürringerkrankung, bei der weder die Myelinscheide noch das Axon primärer Angriffspunkt der Immunantwort sind, sondern die Ranvierschen Schnürringe.

Abstract

Autoimmune neuropathies with autoantibodies against paranodal proteins have been described in the last few years. They comprise a subgroup of inflammatory neuropathies with IgG4 autoantibodies against the paranodal proteins neurofascin-155, contactin-1 and caspr-1. Although this subtype of autoimmune neuropathy represents just less than 10 % of all patients diagnosed with CIDP, it is of high interest as they show a different response to treatment. Even though there are no therapeutic studies available due to the limited number of patients identified so far, all case reports that have been published so far report an excellent response to treatment with rituximab, and in most cases no response to treatment with IVIG, the standard therapy of CIDP. The typical clinical picture of patients with autoantibodies against paranodal proteins is characterized by an acute onset of severe predominantly motor neuropathy, often accompanied by action tremor and sensory ataxia, with demyelinating features in the nerve conduction studies but an axonal histological phenotype. The latter may be explained by the pathogenetic concept of a paranodopathy/nodopathy, a disease of the paranode/node of Ranvier.

Schlüsselwörter

Neuropathie - Schnürring - Autoantikörper - CIDP

Key words

neuropathy - node of Ranvier - autoantibody - CIDP

• Literatur

• 1 Mathey EK, Park SB, Hughes RA. et al. Chronic inflammatory demyelinating polyradiculoneuropathy: from pathology to phenotype. J Neurol Neurosurg Psychiatry 2015; 86: 973-985
• 2 Quarles RH, Weiss MD. Autoantibodies associated with peripheral neuropathy. Muscle Nerve 1999; 22: 800-822
• 3 Querol L, Illa I. Paranodal and other autoantibodies in chronic inflammatory neuropathies. Curr Opin Neurol 2015; 28: 474-479
• 4 Salzer JL, Brophy PJ, Peles E. Molecular domains of myelinated axons in the peripheral nervous system. Glia 2008; 56: 1532-1540
• 5 Rosenbluth J. Multiple functions of the paranodal junction of myelinated nerve fibers. J Neurosci Res 2009; 87: 3250-3258
• 6 Doppler K, Werner C, Sommer C. Disruption of nodal architecture in skin biopsies of patients with demyelinating neuropathies. J Peripher Nerv Syst 2013; 18: 168-176
• 7 Doppler K, Werner C, Henneges C. et al. Analysis of myelinated fibers in human skin biopsies of patients with neuropathies. J Neurol 2012; 259: 1879-1887
• 8 Li J, Bai Y, Ghandour K. et al. Skin biopsies in myelin-related neuropathies: bringing molecular pathology to the bedside. Brain 2005; 128: 1168-1177
• 9 Cifuentes-Diaz C, Dubourg O, Irinopoulou T. et al. Nodes of ranvier and paranodes in chronic acquired neuropathies. PLoS One 2011; 6: e14533
• 10 Peltier AC, Myers MI, Artibee KJ. et al. Evaluation of dermal myelinated nerve fibers in diabetes mellitus. J Peripher Nerv Syst 2013; 18: 162-167
• 11 Allt G, Cavanagh JB. Ultrastructural changes in the region of the node of ranvier in the rat caused by diphtheria toxin. Brain 1969; 92: 459-468
• 12 Allt G. Repair of segmental dehyelination in peripheral nerves: an electron microscope study. Brain 1969; 92: 639-646
• 13 Weller RO, Nester B. Early changes at the node of Ranvier in segmental demyelination. Histochemical and electron microscopic observations. Brain 1972; 95: 665-674
• 14 Devaux JJ, Odaka M, Yuki N. Nodal proteins are target antigens in Guillain-Barre syndrome. J Peripher Nerv Syst 2012; 17: 62-71
• 15 Devaux JJ. Antibodies to gliomedin cause peripheral demyelinating neuropathy and the dismantling of the nodes of Ranvier. Am J Pathol 2012; 181: 1402-1413
• 16 Querol L, Nogales-Gadea G, Rojas-Garcia R. et al. Antibodies to contactin-1 in chronic inflammatory demyelinating polyneuropathy. Ann Neurol 2013; 73: 370-380
• 17 Ng JK, Malotka J, Kawakami N. et al. Neurofascin as a target for autoantibodies in peripheral neuropathies. Neurology 2012; 79: 2241-2248
• 18 Pruss H, Schwab JM, Derst C. et al. Neurofascin as target of autoantibodies in Guillain-Barre syndrome. Brain 2011; 134: e173
• 19 Mathey EK, Derfuss T, Storch MK. et al. Neurofascin as a novel target for autoantibody-mediated axonal injury. J Exp Med 2007; 204: 2363-2372
• 20 Querol L, Nogales-Gadea G, Rojas-Garcia R. et al. Neurofascin IgG4 antibodies in CIDP associate with disabling tremor and poor response to IVIg. Neurology 2014; 82: 879-886
• 21 Devaux JJ, Miura Y, Fukami Y. et al. Neurofascin-155 IgG4 in chronic inflammatory demyelinating polyneuropathy. Neurology 2016; 86: 800-807
• 22 Ogata H, Yamasaki R, Hiwatashi A. et al. Characterization of IgG4 anti-neurofascin 155 antibody-positive polyneuropathy. Ann Clin Transl Neurol 2015; 2: 960-971
• 23 Kawamura N, Yamasaki R, Yonekawa T. et al. Anti-neurofascin antibody in patients with combined central and peripheral demyelination. Neurology 2013; 81: 714-722
• 24 Vural A, Gocmen R, Kurne AT. et al. Fulminant Central Plus Peripheral Nervous System Demyelination without Antibodies to Neurofascin. Can J Neurol Sci 2016; 43: 149-156
• 25 Doppler K, Appeltshauser L, Wilhelmi K. et al. Destruction of paranodal architecture in inflammatory neuropathy with anti-contactin-1 autoantibodies. J Neurol Neurosurg Psychiatry 2015; 86: 720-728
• 26 Miura Y, Devaux JJ, Fukami Y. et al. Contactin 1 IgG4 associates to chronic inflammatory demyelinating polyneuropathy with sensory ataxia. Brain 2015; 138: 1484-1491
• 27 Doppler K, Appeltshauser L, Villmann C. et al. Auto-antibodies to contactin-associated protein 1 (Caspr) in two patients with painful inflammatory neuropathy. Brain 2016; 139: 2617-2630
• 28 Cortese A, Devaux JJ, Zardini E. et al. Neurofascin-155 as a putative antigen in combined central and peripheral demyelination. Neurol Neuroimmunol Neuroinflamm 2016; 3: e238
• 29 Kadoya M, Kaida K, Koike H. et al. IgG4 anti-neurofascin155 antibodies in chronic inflammatory demyelinating polyradiculoneuropathy: Clinical significance and diagnostic utility of a conventional assay. J Neuroimmunol 2016; 301: 16-22
• 30 Uncini A. A common mechanism and a new categorization for anti-ganglioside antibody-mediated neuropathies. Exp Neurol 2012; 235: 513-516
• 31 Uncini A, Susuki K, Yuki N. Nodo-paranodopathy: beyond the demyelinating and axonal classification in anti-ganglioside antibody-mediated neuropathies. Clin Neurophysiol 2013; 124: 1928-1934
• 32 Labasque M, Hivert B, Nogales-Gadea G. et al. Specific contactin N-glycans are implicated in neurofascin binding and autoimmune targeting in peripheral neuropathies. J Biol Chem 2014; 289: 7907-7918
• 33 Tao MH, Smith RI, Morrison SL. Structural features of human immunoglobulin G that determine isotype-specific differences in complement activation. J Exp Med 1993; 178: 661-667
• 34 Vidarsson G, Dekkers G, Rispens T. IgG subclasses and allotypes: from structure to effector functions. Front Immunol 2014; 5: 520
• 35 Yuki N, Watanabe H, Nakajima T. et al. IVIG blocks complement deposition mediated by anti-GM1 antibodies in multifocal motor neuropathy. J Neurol Neurosurg Psychiatry 2011; 82: 87-91
• 36 Piepers S, Jansen MD, Cats EA. et al. IVIg inhibits classical pathway activity and anti-GM1 IgM-mediated complement deposition in MMN. J Neuroimmunol 2010; 229: 256-262
• 37 Appeltshauser L, Weishaupt A, Sommer C. et al. Complement deposition induced by binding of anti-contactin-1 auto-antibodies is modified by immunoglobulins. Exp Neurol 2017; 287: 84-89
• 38 Manso C, Querol L, Mekaouche M. et al. Contactin-1 IgG4 antibodies cause paranode dismantling and conduction defects. Brain 2016; 139: 1700-1712
• 39 Querol L, Rojas-Garcia R, Diaz-Manera J. et al. Rituximab in treatment-resistant CIDP with antibodies against paranodal proteins. Neurol Neuroimmunol Neuroinflamm 2015; 2: e149
• 40 Boyle ME, Berglund EO, Murai KK. et al. Contactin orchestrates assembly of the septate-like junctions at the paranode in myelinated peripheral nerve. Neuron 2001; 30: 385-397