Demyelination diseases involving the central and peripheral nervous systems are etiologically heterogeneous with both cell-mediated and humoral immunities playing pathogenic roles. Recently, autoantibodies against nodal and paranodal proteins, such as neurofascin186 (NF186), neurofascin155 (NF155), contactin-1 (CNTN1), contactin-associated protein 1 (CASPR1) and gliomedin, have been discovered in not only chronic demyelinating conditions, such as multiple sclerosis (MS) and chronic inflammatory demyelinating polyradiculoneuropathy, but also in acute demyelinating conditions, such as Guillain-Barré syndrome. Only a minority of these patients harbor anti-nodal/paranodal protein antibodies; however, these autoantibodies, especially IgG4 subclass autoantibodies to paranodal proteins, are associated with unique features and these conditions are collectively termed nodopathy or paranodopathy. Establishing a concept of IgG4-related nodopathy/paranodopathy contributes to diagnosis and treatment strategy because IgG4 autoantibody-related neurological diseases are often refractory to conventional immunotherapies. IgG4 does not fix complements, or internalize the target antigens, because IgG4 exists in a monovalent bispecific form in vivo. IgG4 autoantibodies can bock protein-protein interaction. Thus, the primary role of IgG4 anti-paranodal protein antibodies may be blockade of interactions between NF155 and CNTN1/CASPR1, leading to conduction failure, which is consistent with the sural nerve pathology presenting paranodal terminal loop detachment from axons with intact internodes in the absence of inflammation. However, it still remains to be elucidated how these autoantibodies belonging to the same IgG4 subclass can cause each IgG4 autoantibody-specific manifestation. Another important issue is to clarify the mechanism by which IgG4 antibodies to nodal/paranodal proteins emerge. IgG4 antibodies develop on chronic antigenic stimulation and can block antibodies that alleviate allergic inflammation by interfering with the binding of allergen-specific IgE to allergens. Thus, environmental antigens cross-reacting with nodal and paranodal proteins may warrant future study.
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