The Discovery of Autoimmune Nodopathies and the Impact of IgG4 Antibodies in Autoimmune Neurology

In the past decade, significant progress has been made on the understanding of IgG4-mediated autoimmune diseases, of both the central and the peripheral CNS. In addition to the description of diverse antigenic targets, the description of IgG subclasses associated with specific pathogenic autoantibodies has provided useful insights into the pathophysiology and, more importantly, into the therapeutic implications of the autoantibody subclasses. This understanding has affected how myasthenia gravis, autoimmune encephalitis, and autoimmune neuropathies are treated. In the case of autoimmune neuropathies, the discovery of antigenic targets located at the node of Ranvier has led to the definition of a new diagnostic category, the autoimmune nodopathies, which differentiate them from the classical forms of Guillain-Barré syndrome and chronic inflammatory demyelinating polyradiculoneuropathy. These neuropathies including those caused by autoantibodies targeting contactin-1, contactin-associated protein 1, and neurofascin are mainly, though not always exclusively, mediated by IgG4 antibodies, and respond to therapies similarly to other IgG4-mediated neurologic and non-neurologic diseases, providing evidence that not only the antigenic target but also the autoantibody subclass play a role in understanding both the disease pathophysiology and response to therapies. In this article, we describe the history and main findings on autoimmune nodopathies; highlight the particularities and similarities of IgG4-mediated neurologic diseases, including autoimmune nodopathies and neuromuscular junction and certain CNS disorders; elaborate on the unique functional properties of IgG4 in influencing their specific response to immunotherapies stressing the rationale of the most suitable present and future targeted therapies; and discuss how best to apply and monitor maintenance therapies for inducing disease stability in all IgG4 neurologic autoimmunities including the need for potential future biomarkers.