Expansion of the immature B lymphocyte compartment in Graves' disease

Objective The specific mechanisms driving autoimmunity in Graves' disease (GD) remain largely unknown. Kappa-deleting recombination excision circles (KRECs) are circular DNA molecules generated during B cell maturation in the bone marrow which provide a measure of B cell production and proliferation. We aimed to investigate the association between KRECs and B cell subpopulations, with thyroid status and clinical outcome in GD patients. Methods Kappa-deleting recombination excision circles were measured by quantitative real-time PCR using a triple-insert plasmid control in 132 GD patients and 140 healthy controls. In addition, KRECs in GD patients on withdrawal of antithyroid drug (ATD) and 6-10 weeks later were analysed according to a clinical outcome at 1 year. Flow cytometry was performed on isolated CD19(+) B cells to quantitate 7 B lymphocyte subpopulations in 65 GD patients. Results Circulating KRECs were higher in GD vs. controls (P = 1.5 x 10(-9)) and demonstrated a positive correlation to thyroid hormones and autoantibodies (free thyroxine: P = 2.14 x 10(-5), rho = .30; free triiodothyronine: P = 1.99 x 10(-7), rho = .37; thyroid stimulating hormone receptor autoantibodies: P = 1.36 x 10(-5), rho = .23). Higher KRECs in GD patients 6-10 weeks after ATD withdrawal were associated with relapse of hyperthyroidism at 1 year (P = .04). The KRECs were positively correlated to the total CD19(+) B cell count (P = 3.2 x 10(-7)). Conclusions This study reports a robust association between KRECs and GD, highlighting the importance of B cells in the pathogenesis of GD and the influence of thyroid status on B cell activity. The findings indicate a potential role for KRECs as a marker of disease activity and outcome in GD.

Automated summary

The level of KRECs in circulating blood is significantly higher in GD patients compared to healthy controls, and it is positively correlated with thyroid hormones and autoantibodies. Higher KRECs levels in GD patients 6-10 weeks after withdrawal of ATD are associated with a higher risk of hyperthyroidism relapse at 1 year. These findings suggest that KRECs may serve as a marker of disease activity and outcome in GD.