Expansion of blood IgG₄⁺ B, T_H2, and regulatory T cells in patients with IgG₄-related disease.

Abstract

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 T_H 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 CD21^low B cells, as well as T_H2 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.