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

Research output: Contribution to journalArticleResearchpeer-review


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
JournalThe Journal of allergy and clinical immunology
Issue number5
Publication statusPublished - May 2018


  • Adolescent
  • Adult
  • Aged
  • B-Lymphocytes/immunology
  • Biomarkers/blood
  • Chemokines/immunology
  • Female
  • Humans
  • Immunoglobulin G/immunology
  • Immunologic Memory
  • Male
  • Middle Aged
  • Plasma Cells/immunology
  • Receptors, CXCR5/immunology
  • Sarcoidosis/blood
  • T-Lymphocytes, Regulatory/immunology
  • Th2 Cells/immunology
  • Tumor Necrosis Factor Receptor Superfamily, Member 7
  • Young Adult


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