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bioRxiv · 10.1101/2023.06.30.546522

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

Paardekooper, L. M.·Fillie-Grijpma, Y. E.·van der Sluijs-Gelling, A. J.·Zlei, M.·van Doorn, R.·Vermeer, M. H.·Paunovic, M.·Titulaer, M. J.·van der Maarel, S. M.·van Dongen, J. J. M.·Verschuuren, J. J.·Huijbers, M. G.
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Abstract

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 naive 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 O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=119 SRC="FIGDIR/small/546522v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@1444429org.highwire.dtl.DTLVardef@d70867org.highwire.dtl.DTLVardef@168a7c0org.highwire.dtl.DTLVardef@1dd4483_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Paardekooper, L. M., Fillie-Grijpma, Y. E., van der Sluijs-Gelling, A. J., Zlei, M., van Doorn, R., Vermeer, M. H., Paunovic, M., Titulaer, M. J., van der Maarel, S. M., van Dongen, J. J. M., Verschuuren, J. J., Huijbers, M. G.. 2023-06-30. Autoantibody subclass predominance is not driven by aberrant class switching or impaired B cell development. https://doi.org/10.1101/2023.06.30.546522

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