AUTHOR=Endmayr Verena , Tunc Cansu , Ergin Lara , De Rosa Anna , Weng Rosa , Wagner Lukas , Yu Thin-Yau , Fichtenbaum Andreas , Perkmann Thomas , Haslacher Helmuth , Kozakowski Nicolas , Schwaiger Carmen , Ricken Gerda , Hametner Simon , Klotz Sigrid  , Dutra Lívia Almeida , Lechner Christian , de Simoni Désirée , Poppert Kai-Nicolas , Müller Georg Johannes , Pirker Susanne , Pirker Walter , Angelovski Aleksandra , Valach Matus , Maestri Michelangelo , Guida Melania , Ricciardi Roberta , Frommlet Florian , Sieghart Daniela , Pinter Miklos , Kircher Karl , Artacker Gottfried , Höftberger Romana , Koneczny Inga 

TITLE=Anti-Neuronal IgG4 Autoimmune Diseases and IgG4-Related Diseases May Not Be Part of the Same Spectrum: A Comparative Study

JOURNAL=Frontiers in Immunology

VOLUME=12

YEAR=2022

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.785247

DOI=10.3389/fimmu.2021.785247

ISSN=1664-3224

ABSTRACT=<sec><title>Background</title><p>IgG4 is associated with two emerging groups of rare diseases: 1) IgG4 autoimmune diseases (IgG4-AID) and 2) IgG4-related diseases (IgG4-RLD). Anti-neuronal IgG4-AID include MuSK myasthenia gravis, LGI1- and Caspr2-encephalitis and autoimmune nodo-/paranodopathies (CNTN1/Caspr1 or NF155 antibodies). IgG4-RLD is a multiorgan disease hallmarked by tissue-destructive fibrotic lesions with lymphocyte and IgG4 plasma cell infiltrates and increased serum IgG4 concentrations. It is unclear whether IgG4-AID and IgG4-RLD share relevant clinical and immunopathological features.</p></sec><sec><title>Methods</title><p>We collected and analyzed clinical, serological, and histopathological data in 50 patients with anti-neuronal IgG4-AID and 19 patients with IgG4-RLD.</p></sec><sec><title>Results</title><p>A significantly higher proportion of IgG4-RLD patients had serum IgG4 elevation when compared to IgG4-AID patients (52.63% vs. 16%, <italic>p</italic> = .004). Moreover, those IgG4-AID patients with elevated IgG4 did not meet the diagnostic criteria of IgG4-RLD, and their autoantibody titers did not correlate with their serum IgG4 concentrations. In addition, patients with IgG4-RLD were negative for anti-neuronal/neuromuscular autoantibodies and among these patients, men showed a significantly higher propensity for IgG4 elevation, when compared to women (<italic>p</italic> = .005). Last, a kidney biopsy from a patient with autoimmune paranodopathy due to CNTN1/Caspr1-complex IgG4 autoantibodies and concomitant nephrotic syndrome did not show fibrosis or IgG4<sup>+</sup> plasma cells, which are diagnostic hallmarks of IgG4-RLD.</p></sec><sec><title>Conclusion</title><p>Our observations suggest that anti-neuronal IgG4-AID and IgG4-RLD are most likely distinct disease entities.</p></sec>