Autoantibody subclass predominance is not driven by aberrant class switching or impaired B cell development

A subset of autoimmune diseases is characterized by predominant pathogenic IgG4 autoantibodies (IgG4-AIDs). Why IgG4 predominates in these disorders is unknown. We hypothesized that dysregulated B cell maturation or aberrant class switching causes overrepresentation of IgG4 + B cells and plasma cells. Therefore, we compared the B cell compartment of patients with muscle-specific kinase (MuSK) myasthenia gravis (MG), pemphigus, leucine-rich glioma inactivated (LGI1) encephalitis and contactin-associated protein-like 2 (CASPR2) encephalitis (four IgG4-AIDs) to patients with acetylcholine receptor (AChR) MG, Lambert-Eaton myasthenic syndrome (LEMS) (two IgG1-3-AIDs) and age-matched healthy donors, using flow cytometry. B cell subset relative abundance at all maturation stages was normal, except for a, possibly treatment-related, reduction in immature and naïve CD5 + cells in IgG4-AIDs. IgG4 + B cell and plasma cell fractions were normal in IgG4-AID patients, however they had an (sub)class-independent 8-fold increase in circulating mature CD20 - CD138 + plasma cells. No autoreactivity was found in this subset after sorting. In conclusion, patients with IgG4-AID do not show increased numbers of IgG4-expressing cells. These results argue against aberrant B cell development in these patients and rather suggest the autoantibody subclass predominance to be antigen-driven. The similarities between B cell subset numbers among these patients suggest that these IgG4-AIDs, despite displaying variable clinical phenotypes, share a similar underlying immune profile. Graphical abstract