Expansion of blood IgG(4)(+) B, T(H)2, and regulatory T cells in patients with IgG(4)-related disease

Background: IgG(4)-related disease (IgG(4)-RD) is a systemic fibroinflammatory condition affecting various organs and has a diverse clinical presentation. Fibrosis and accumulation of IgG(4)(+) plasma cells in tissue are hallmarks of the disease, and IgG(4)-RD is associated with increased IgG(4) serum levels. However, disease pathogenesis is still unclear, and these cellular and molecular parameters are neither sensitive nor specific for the diagnosis of IgG(4)-RD. Objective: Here we sought to develop a flow cytometric gating strategy to reliably identify blood IgG(4)(+) B cells to study their cellular and molecular characteristics and investigate their contribution in disease pathogenesis. Methods: Sixteen patients with histologically confirmed IgG(4)-RD, 11 patients with sarcoidosis, and 30 healthy subjects were included for 11-color flow cytometric analysis of peripheral blood for IgG(4)-expressing B cells and T-H subsets. In addition, detailed analysis of activation markers and chemokine receptors was performed on IgG(4)-expressing B cells, and IgG(4) transcripts were analyzed for somatic hypermutations. Results: Cellular and molecular analyses revealed increased numbers of blood IgG(4)(+) memory B cells in patients with IgG(4)-RD. These cells showed reduced expression of CD27 and CXCR5 and increased signs of antibody maturation. Furthermore, patients with IgG(4)-RD, but not patients with sarcoidosis, had increased numbers of circulating plasmablasts and CD21(low) B cells, as well as T(H)2 and regulatory T cells, indicating a common disease pathogenesis in patients with IgG(4)-RD. Conclusion: These results provide new insights into the dysregulated IgG(4) response in patients with IgG(4)-RD. A specific peripheral lymphocyte signature observed in patients with IgG(4)-RD, could support diagnosis and treatment monitoring.