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

• Published in: Journal of allergy and clinical immunology Vol. 141; no. 5; pp. 1831 - 1843.e10
• Main Authors: Heeringa, Jorn J., Karim, A. Faiz, van Laar, Jan A.M., Verdijk, Robert M., Paridaens, Dion, van Hagen, P. Martin, van Zelm, Menno C.
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.05.2018
• Subjects: B cell; flow cytometry; IgG4; IgG4-related disease; plasma cell; principal component analysis; regulatory T cell; sarcoidosis; T helper cell; CSR; Treg; IgG4; sarcoidosis; regulatory T cell; IGH; T helper cell; PCA; CDR; B cell; IgG4-related disease; SHM; flow cytometry; plasma cell; TEM; principal component analysis; IgG4-RD
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2017.07.024

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. 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. 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. 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. 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. [Display omitted]