Expansion of blood IgG4 + B, TH2, and regulatory T cells in patients with IgG4-related disease

Jorn J. Heeringa, A. Faiz Karim, Jan A.M. van Laar, Robert M. Verdijk, Dion Paridaens, P. Martin van Hagen, Menno C. van Zelm

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35 Citations (Scopus)


Background: IgG4-related disease (IgG4-RD) is a systemic fibroinflammatory condition affecting various organs and has a diverse clinical presentation. Fibrosis and accumulation of IgG4 + plasma cells in tissue are hallmarks of the disease, and IgG4-RD is associated with increased IgG4 serum levels. However, disease pathogenesis is still unclear, and these cellular and molecular parameters are neither sensitive nor specific for the diagnosis of IgG4-RD. Objective: Here we sought to develop a flow cytometric gating strategy to reliably identify blood IgG4 + B cells to study their cellular and molecular characteristics and investigate their contribution in disease pathogenesis. Methods: Sixteen patients with histologically confirmed IgG4-RD, 11 patients with sarcoidosis, and 30 healthy subjects were included for 11-color flow cytometric analysis of peripheral blood for IgG4-expressing B cells and TH subsets. In addition, detailed analysis of activation markers and chemokine receptors was performed on IgG4-expressing B cells, and IgG4 transcripts were analyzed for somatic hypermutations. Results: Cellular and molecular analyses revealed increased numbers of blood IgG4 + memory B cells in patients with IgG4-RD. These cells showed reduced expression of CD27 and CXCR5 and increased signs of antibody maturation. Furthermore, patients with IgG4-RD, but not patients with sarcoidosis, had increased numbers of circulating plasmablasts and CD21low B cells, as well as TH2 and regulatory T cells, indicating a common disease pathogenesis in patients with IgG4-RD. Conclusion: These results provide new insights into the dysregulated IgG4 response in patients with IgG4-RD. A specific "peripheral lymphocyte signature" observed in patients with IgG4-RD, could support diagnosis and treatment monitoring.

Original languageEnglish
Pages (from-to)1831-1843.e10
Number of pages23
JournalJournal of Allergy and Clinical Immunology
Issue number5
Publication statusPublished - May 2018


  • B cell
  • Flow cytometry
  • IgG
  • IgG-related disease
  • Plasma cell
  • Principal component analysis
  • Regulatory T cell
  • Sarcoidosis
  • T helper cell

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