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. ![Figure][1] ### Competing Interest Statement JV, SM, MH are coinventors on MuSK-related patents. LUMC and JV, SM and MH receive royalties from these patents. SM is a Board member for Renogenyx. LUMC receives royalties on a MuSK ELISA. JV is consultant for Argenx, Alexion, NMD Pharma. MH receives financial support from the LUMC (OIO 2017, Gisela Their Fellowship 2021), Top Sector Life Sciences & Health to Samenwerkende Gezondheidsfondsen (LSHM19130), Prinses Beatrix Spierfonds (W.OR 19.13). MJT is member of the European Reference Network for Rare Immunodeficiency, Autoinflammatory and Autoimmune Diseases-Project ID No 739543 (ERN-RITA; HCP Erasmus MC). MJT has filed a patent, on behalf of the Erasmus MC, for methods for typing neurological disorders and cancer, and devices for use therein, and has received research funds for serving on a scientific advisory board of Horizon Therapeutics, for consultation at Guidepoint Global LLC, for consultation at UCB, for teaching colleagues at Novartis. MJT has received an unrestricted research grant from Euroimmun AG, and from CSL Behring. JJMvD reports to be the chairman of the EuroFlow Consortium. JJMvD is also listed as inventor on the patent 'Means and methods for multiparameter cytometry based leukocyte subsetting' (PCT/NL2020/050688, filing date 5 November 2019), owned by the EuroFlow scientific consortium; JJMvD reports an Educational Services Agreement from BD Biosciences (San Jose, CA) and a Scientific Advisor Agreement with Cytognos/BD Biosciences; all related fees and honoraria are for the involved university departments at Leiden University Medical Center and University of Salamanca. The remaining authors declare no interests. The LUMC is part of the European Reference Network for Rare Neuromuscular Diseases [ERN-EURONMD] and the Netherlands Neuromuscular Center. The other authors have declared that no conflict of interest exists. [1]: pending:yes