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Autoantibodies in chronic inflammatory neuropathies: diagnostic and therapeutic implications

Key Points

  • Discovery of the antigenic targets associated with nerve-specific autoimmune diseases is a crucial step in understanding their pathogenesis

  • The identification of highly disease-specific autoantibodies in patients with inflammatory neuropathies has considerable clinical utility, even when the proportion of antibody-positive patients is low

  • IgG4 antibodies against contactin-1 and neurofascin splice variant 155 characterize a subtype of chronic inflammatory demyelinating polyradiculoneuropathy with distinct clinical features, including poor response to intravenous immunoglobulin

  • Autoantibodies linked to multifocal motor neuropathy, polyneuropathy associated with monoclonal gammopathy of unknown significance and paraneoplastic peripheral nerve disorders provide important clinical information and their presence should be investigated in all patients with inflammatory neuropathies

Abstract

The chronic inflammatory neuropathies (CINs) are rare, very disabling autoimmune disorders that generally respond well to immune therapies such as intravenous immunoglobulin (IVIg). The most common forms of CIN are chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), multifocal motor neuropathy, and polyneuropathy associated with monoclonal gammopathy of unknown significance. The field of CIN has undergone a major advance with the identification of IgG4 autoantibodies directed against paranodal proteins in patients with CIDP. Although these autoantibodies are only found in a small subset of patients with CIDP, they can be used to guide therapeutic decision-making, as these patients have a poor response to IVIg. These observations provide proof of concept that identifying the target antigens in tissue-specific antibody-mediated autoimmune diseases is important, not only to understand their underlying pathogenic mechanisms, but also to correctly diagnose and treat affected patients. This state-of-the-art Review focuses on the role of autoantibodies against nodes of Ranvier in CIDP, a clinically relevant emerging field of research. The role of autoantibodies in other immune-mediated neuropathies, including other forms of CIN, primary autoimmune neuropathies, neoplasms, and systemic diseases that resemble CIN, are also discussed.

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Figure 1: The node of Ranvier.
Figure 2: Pathogenic mechanisms involving antibodies associated with autoimmune neuropathies.
Figure 3: Immunological findings in patients with CIDP and anti-NF155 antibodies.
Figure 4: Features of CIDP associated with autoantibodies that target NF155.

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Acknowledgements

The authors thank the Agence Nationale pour la Recherche and Instituto de Salud Carlos III CIBERER for their funding of the collaborative Antibodies against Cell Adhesion Molecules in Inflammatory Neuropathies (ACAMIN) project under the E-Rare-2 (ERA-Net for Research on Rare Diseases) framework (grant to J.J.D., L.Q. and I.I). The authors also acknowledge funding from the Association Française contre les Myopathies (grant MNM1 2012–14580 to J.J.D., L.Q. and I.I.) and the Fondo de Investigaciones Sanitarias, Ministry of Economy and Competitiveness, Instituto de Salud Carlos III, Subprograma Juan Rodés (grants JR13/00014 and PI16/000627 to L.Q. and PI13/00937 to I.I.).

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L.Q. and J.J.D. contributed to researching data for the article, discussions of its content, writing and review or editing of the manuscript. L.Q. wrote the first draft of the manuscript focusing on chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and the clinical implications of autoantibodies. J.J.D. reviewed the basic aspects of the topic, molecular descriptions, animal models and pathogenicity. R.R.-G. researched data for the article, contributed to discussions of its content, and reviewed the sections on multifocal motor neuropathy and paraproteinaemic neuropathy. I.I. researched data for the article, contributed to discussions of its content and reviewed the clinical implications of antibodies in CIDP, as well as providing the general perspective and historical background.

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Correspondence to Luis Querol.

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Querol, L., Devaux, J., Rojas-Garcia, R. et al. Autoantibodies in chronic inflammatory neuropathies: diagnostic and therapeutic implications. Nat Rev Neurol 13, 533–547 (2017). https://doi.org/10.1038/nrneurol.2017.84

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