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Expansion of blood IgG4+ Bcells, Th2 and Tregulatory cells in IgG4-related disease.

J. Allergy Clin. Immunol. 2018, vol. 141, issue 5


IgG4-related disease (IgG4-RD) is a systemic fibro-inflammatory 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 elevated IgG4 serum levels. However, disease pathogenesis is still unclear and these cellular and molecular parameters are neither sensitive nor specific for diagnosis of IgG4-RD.


We here sought to develop a flowcytometric 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 individuals were included for 11-color flowcytometric analysis of peripheral blood for IgG4-expressing B cells and T-helper (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, IgG4-RD patients, but not patients with sarcoidosis, had increased numbers of circulating plasma blasts and CD21(low) B-cells, as well as Th2 and regulatory T-cells, indicating of a common disease pathogenesis in 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.

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