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Immunoglobulin G4+ clones identified by next‐generation sequencing dominate the B cell receptor repertoire in immunoglobulin G4 associated cholangitis
Author(s) -
Maillette de Buy Wenniger Lucas J.,
Doorenspleet Marieke E.,
Klarenbeek Paul L.,
Verheij Joanne,
Baas Frank,
Elferink Ronald P. Oude,
Tak Paul P.,
de Vries Niek,
Beuers Ulrich
Publication year - 2013
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.26232
Subject(s) - immunoglobulin d , antibody , immunology , breakpoint cluster region , biology , repertoire , b cell receptor , immunoglobulin g , immunoglobulin heavy chain , isotype , b cell , immunoglobulin class switching , receptor , genetics , monoclonal antibody , physics , acoustics
Immunoglobulin G4 (IgG4)‐associated cholangitis (IAC) is a manifestation of the recently discovered idiopathic IgG4‐related disease. The majority of patients have elevated serum IgG4 levels and/or IgG4‐positive B‐cell and plasma cell infiltrates in the affected tissue. We hypothesized that clonally expanded, class‐switched IgG4‐positive B cells and plasma cells could be causal to these poorly understood phenomena. In a prospective cohort of six consecutive IAC patients, six healthy controls, and six disease controls, we used a novel next‐generation sequencing approach to screen the B‐cell receptor (BCR) repertoires, in blood as well as in affected tissue, for IgG4+ clones. A full repertoire analysis of the BCR heavy chain was performed using GS‐FLX/454 and customized bioinformatics algorithms (>10,000 sequences/sample; clones with a frequency ≥0.5% were considered dominant). We found that the most dominant clones within the IgG+ BCR heavy repertoire of the peripheral blood at baseline were IgG4+ only in IAC patients. In all IAC patients, but none of the controls, IgG4+ BCR clones were among the 10 most dominant BCR clones of any immunoglobulin isotype (IgA, IgD, IgM, and IgG) in blood. The BCR repertoires of the duodenal papilla comprised the same dominant IgG4+ clones as the paired peripheral blood samples. In all IAC patients, after 4 and 8 weeks of corticosteroid therapy the contribution of these IgG4+ clones to the IgG+ repertoire as well as to total BCR repertoire was marginalized, mirroring sharp declines in serum IgG4 titers and regression of clinical symptoms. Conclusion: The novel finding of highly abundant IgG4+ BCR clones in blood and tissue of patients with active IAC, which disappear upon corticosteroid treatment, suggests that specific B cell responses are pivotal to the pathogenesis of IAC. (H EPATOLOGY 2013 )