Background The pivotal role of B cells in the pathogenesis autoimmune diseases such as ANCA-associated vasculitis (AAV) is well-established and further substantiated by beneficial therapeutic effects of rituximab (anti-CD20 B cell targeted therapy). However, this results in prolonged B cell depletion while long-lived plasma cells are not targeted. Thus, there is a need for novel therapeutics targeting the B-cell lineage in AAV. NF-κB signalling pathways that act downstream of various B cell surface receptors, including the B cell antigen receptor, CD40, BAFFR and TLRs, are crucially involved in B cell responses and may be suitable as novel targets.

Objectives To identify whether inhibition of NF-κB signalling by novel pharmacological inhibitors is effective in targeting B cell responses in general and more specifically blocks (auto)antibody production and plasmablast differentiation in B cells from AAV patients.

Methods PBMC and sorted B cells from AAV patients and healthy donors were cultured with T cell-dependent (anti-IgM +anti CD40+IL-21) and T cell-independent (CpG +IL-2) stimuli. NF-κB signalling was targeted in these cultures by small molecule inhibitors of NF-κB inducing kinase (NIK, non-canonical NF-κB signalling) and Inhibitor of κB kinase β (IKKβ, canonical NF-κB signalling). Downstream NF-κB signalling and nuclear NF-κB translocation was determined by Western blot and confocal imaging. Effects on B cell proliferation and differentiation were determined by CFSE dilution assays and flow cytometric analysis of B cell markers. (Auto)antibody production was measured by ELISA.

Results In B cells of AAV patients and healthy donors, targeting of NIK and IKKβ effectively inhibited downstream non-canonical or canonical NF-κB signalling, respectively. In a B cell stimulation assay, NIK and IKKβ inhibition significantly reduced T cell-dependent (anti-IgM +anti CD40+IL-21) and T cell-independent (CpG +IL-2) B cell proliferation. In addition, B cell differentiation towards plasmablasts (CD27⁺⁺/CD38⁺) and functional antibody production was attenuated by both NIK and IKKβ inhibitors. Interestingly, the effects of NIK inhibition appeared to be B cell-specific as T cell proliferation was largely unaffected.

Conclusions These data demonstrate that inhibition of NF-κB signalling in AAV B cells results in the modulation of various B cell responses. Ongoing studies will indicate whether targeting of NF-κB signalling in B cells may be an effective novel treatment modality for AAV.

Disclosure of Interest None declared