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. 2018 May;141(5):1831-1843.e10.
doi: 10.1016/j.jaci.2017.07.024. Epub 2017 Aug 19.

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

Jorn J Heeringa  1 , A Faiz Karim  2 , Jan A M van Laar  2 , Robert M Verdijk  3 , Dion Paridaens  4 , P Martin van Hagen  2 , Menno C van Zelm  5
Affiliations

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

Jorn J Heeringa et al. J Allergy Clin Immunol. 2018 May.

Abstract

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.

Keywords: B cell; IgG(4); IgG(4)-related disease; T helper cell; flow cytometry; plasma cell; principal component analysis; regulatory T cell; sarcoidosis.

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  • Reply.
    Karim AF, Heeringa JJ, van Laar JAM, Verdijk RM, Dik WA, Paridaens AD, van Hagen PM, van Zelm MC. Karim AF, et al. J Allergy Clin Immunol. 2018 May;141(5):1958-1960.e4. doi: 10.1016/j.jaci.2017.11.016. Epub 2018 Jan 10. J Allergy Clin Immunol. 2018. PMID: 29329899 No abstract available.
  • The call for considering follicular helper T cells in IgG4-related disease.
    Akiyama M. Akiyama M. J Allergy Clin Immunol. 2018 May;141(5):1958. doi: 10.1016/j.jaci.2017.11.017. Epub 2018 Jan 10. J Allergy Clin Immunol. 2018. PMID: 29329900 No abstract available.

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