A novel IgD-FcδR blocker, IgD-Fc-Ig fusion protein, effectively alleviates abnormal activation of T cells the disease progression in systemic lupus erythematosus

Abstract

Systemic lupus erythematosus (SLE) is a chronic, multi-organ autoimmune disease with complex pathogenesis and unclear causes. Elevated levels of IgD have been observed in the peripheral blood of SLE patients, suggesting a potential role for IgD through its interaction with the IgD Fc receptor (FcδR). This study aimed to explore the impact of IgD on T cell function in SLE and evaluate the therapeutic potential of targeting the IgD-FcδR pathway using an IgD-Fc-Ig fusion protein. In SLE patients, biomarkers such as BAFF, ESR, anti-dsDNA and SLEDAI-2k, which are used to assess disease activity and clinical presentations, were significantly correlated with sIgD levels. As an IgD-FcδR blocker, IgD-Fc-Ig effectively suppressed the activation and proliferation of CD4⁺ T cells stimulated by IgD, restored the balance between Th17 and Treg cell subsets, and reduced the expression and interaction of phosphorylated Lck (p-Lck) and JAK2 (p-JAK2). Moreover, in vivo study demonstrated that IgD-Fc-Ig may also ameliorates disease manifestations in MRL/lpr mice with lupus nephritis. IgD-Fc-Ig could reduce serum IgD levels, proteinuria level and the kidney deposition of immune complex C3, ameliorate histopathological changes in kidney and spleen tissue. Additionally, it reversed the state of excessive activation and imbalance of Th17/Treg cell subsets, reduced cytokine levels, and downregulated p-JAK2 and p-STAT3 expression. In conclusion, our study revealed a correlation between abnormally increased sIgD and SLE pathogenesis, IgD-FcδR-Lck-JAK2-STAT3 may act as an important mechanism contributing to T cell activation in SLE. IgD-Fc-Ig fusion protein may represent a promising targeted therapy for SLE.