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.

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Keywords B cell, Flow cytometry, IgG4, IgG4-related disease, Plasma cell, Principal component analysis, Regulatory T cell, Sarcoidosis, T helper cell
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Journal Journal of Allergy and Clinical Immunology
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Heeringa, J.J, Karim, A.F, van Laar, J.A.M, Verdijk, R.M, Paridaens, A.D.A, van Hagen, P.M, & van Zelm, M.C. (2017). Expansion of blood IgG4 + B, TH2, and regulatory T cells in patients with IgG4-related disease. Journal of Allergy and Clinical Immunology. doi:10.1016/j.jaci.2017.07.024