Autoreactive IgG and IgA B Cells Evolve through Distinct Subclass Switch Pathways in the Autoimmune Disease Pemphigus Vulgaris

Cell Reports
Christoph T EllebrechtAimee S Payne

Abstract

Lineage analysis of autoreactive B cells can reveal the origins of autoimmunity. In the autoimmune disease pemphigus vulgaris (PV), desmoglein 3 (DSG3) and DSG1 autoantibodies are predominantly of the IgG4 subclass and less frequently of IgG1 and IgA subclasses, prompting us to investigate whether anti-DSG IgG4 B cells share lineages with IgG1, IgA1, and IgA2. Combining subclass-specific B cell deep sequencing with high-throughput antibody screening, we identified 80 DSG-reactive lineages from 4 PV patients. Most anti-DSG IgG4 B cells lacked clonal relationships to other subclasses and preferentially targeted DSG adhesion domains, whereas anti-DSG IgA frequently evolved from or to other subclasses and recognized a broader range of epitopes. Our findings suggest that anti-DSG IgG4 B cells predominantly evolve independently or diverge early from other subclasses and that IgA is most often not the origin of IgG autoreactivity in PV. These data provide insight into how autoreactivity diversifies across B cell subclasses.

Citations

Oct 5, 2019·Scientific Reports·Nancy ChaayaSéverine Padiolleau-Lefèvre
Feb 6, 2020·Nature Reviews. Immunology·Kang ChenAndrea Cerutti
Nov 22, 2019·Frontiers in Immunology·Michael OlbrichAnke Fähnrich
Sep 20, 2020·Journal of Lipid Research·Kazuya MiyashitaAnne P Beigneux
Jun 25, 2021·Expert Review of Clinical Immunology·Ali NiliMaryam Daneshpazhooh
Jul 6, 2021·Frontiers in Immunology·C ZografouP Stathopoulos
Jul 12, 2021·The Journal of Investigative Dermatology·Shirin EmtenaniChristoph M Hammers

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Methods Mentioned

BETA
phage
ELISA
PCR
immunoprecipitation

Software Mentioned

Perl script
IMGT
PEAR
USEARCH
customized
PHYLIP
HighV
Change
QUEST
iNEXT R package

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