Autoimmune Neurological Disorders with IgG4 Antibodies: a Distinct Disease Spectrum with Unique IgG4 Functions Responding to Anti-B Cell Therapies

The main IgG4 antibody–mediated neurological disorders (IgG4-ND) include MuSK myasthenia; CIDP with nodal/paranodal antibodies to Neurofascin-155, contactin-1/caspr-1, or pan-neurofascins; anti-LGI1 and CASPR2-associated limbic encephalitis, Morvan syndrome, or neuromyotonia; and several cases of the anti-IgLON5 and anti-DPPX-spectrum CNS diseases. The paper is centered on the clinical spectrum of IgG4-ND and their immunopathogenesis highlighting the unique functional effects of the IgG4 subclass compared to IgG1-3 antibody subclasses. The IgG4 antibodies exert pathogenic effects on their targeted antigens by blocking enzymatic activity or disrupting protein–protein interactions affecting signal transduction pathways, but not by activating complement, binding to inhibitory FcγRIIb receptor or engaging in cross-linking of the targeted antigen with immune complex formation as the IgG1-IgG3 antibody subclasses do. IgG4 can even inhibit the classical complement pathway by affecting the affinity of IgG1-2 subclasses to C1q binding. Because the IgG4 antibodies do not trigger inflammatory processes or complement-mediated immune responses, the conventional anti-inflammatory therapies, especially with IVIg, immunosuppressants, and plasmapheresis, are ineffective or not sufficiently effective in inducing long-term remissions. In contrast, aiming at the activated plasmablasts connected with IgG4 antibody production is a meaningful therapeutic target in IgG4-ND. Indeed, data from large series of patients with MuSK myasthenia, CIDP with nodal/paranodal antibodies, and anti-LGI1 and CASPR2-associated syndromes indicate that B cell depletion therapy with rituximab exerts long-lasting clinical remissions by targeting memory B cells and IgG4-producing CD20-positive short-lived plasma cells. Because IgG4 antibody titers seem reduced in remissions and increased in exacerbation, they may serve as potential biomarkers of treatment response supporting further the pathogenic role of self-reacting B cells. Controlled trials are needed in IgG4-ND not only with rituximab but also with the other anti-B cell agents that target CD19/20, especially those like obexelimab and obinutuzumab, that concurrently activate the inhibitory FcγRIIb receptors which have low binding affinity to IgG4, exerting a more prolonged anti-B cell action affecting also antigen presentation and cytotoxic T cells. Antibody therapies targeting FcRn, testing those anti-FcRn inhibitors that effectively catabolize the IgG4 antibody subclass, may be especially promising. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13311-022-01210-1.