Targeting NF-kappaB-inducing kinase shapes B-cell homeostasis in myasthenia gravis.

BACKGROUND

B cell immune dysregulation plays a critical role in myasthenia gravis (MG). However, targeted B-cell therapy such as rituximab may result in long-term peripheral B cell clearance and allow for the survival of plasma cells, contributing to frequent infections and relapses. Therefore, we aimed to identify potential novel therapeutic targets that preserve part of B cell function while inhibiting antibody-secreting cells (ASCs).

METHODS

The transcriptome of sorted CD19B cells obtained from MG patients in active and remission state was performed by RNA sequencing. The hallmark gene NF-kappaB-inducing kinase (NIK/MAP3K14) associated with NF-κB and TNF signaling was identified, and the expression levels of NIK in CD19B cells, CD4T cells and serum from new-onset MG patients and controls were validated by flow cytometry, qPCR and ELISA. In vitro and in vivo, the effects of NIK inhibitor (B022) on the function of CD19B cells and CD4T cells were detected under the MG PBMCs, sorted B cells and experimental autoimmune MG (EAMG) rat model, respectively.

RESULTS

The expression levels of NIK were upregulated in CD19B cells, CD4T cells and serum from new-onset MG patients. Notably, increased serum NIK levels were positively correlated with disease severity and decreased with disease remission. NIK inhibitor B022 significantly reduced B-cell activation, proliferation, ASCs differentiation and pathogenic function, as well as CD4T cell activation and Th17 cells differentiation in vitro. Intraperitoneal injection of B022 ameliorated the severity of EAMG rats, and reduced proportion of pathogenic B and T cell subsets, antibody levels and postsynaptic membrane damage.

CONCLUSIONS

Targeting NIK with small molecule kinase inhibitors can effectively shape B cell homeostasis, and exhibit protective effects in the EAMG rat model, which may be an effective novel treatment strategy for MG.