Background/Purpose: B cells have gained increased interest in ANCA-associated vasculitis (AAV) research, as the treatment of this autoimmune disease with rituximab (an anti-CD20 B cell targeted therapy) resulted in beneficial clinical outcomes. Despite its advantages, this treatment strategy results in long-term B cell depletion and fails in the targeting of long-lived plasma cells, rendering an unmet need for more reversible and combined B and plasma cell targeting approaches to achive long-term (drug-free) disease remission. This aim may be fullfilled upon targeting essential signaling pathways for B cell biology. The NF-κB signalling pathways regulate fundamental B and/or plasma cell responses, downstream of various B cell surface receptors, including the B cell receptor, CD40, and TLRs, making them potential targets. Furthermore, alterations in NF-κB have been described in other autoimmune diseases and in B cell malignancies. Our research aims to study the potential effects of inhibition of NF-κB signalling on B cell responses in general, and more specifically on plasmablast differentiation and (auto)antibody production in B cells from AAV patients as a novel therapeutic approach.

Methods: Memory B cells were obtained from patients with AAV and healthy donors (HD), and gene expression profiles were generated by RNA-sequencing. Functional assays were performed culturing PMBCs from AAV patients and HD with stimuli mimicking T cell-dependent (anti-CD40/IL-21) and T cell-independent (CpG/IL-2) conditions. Pharmacological inhibitors of NF-κB inducing kinase (NIK, non-canonical pathway) and Inhibitor-of-κB-kinase-β (IKKβ, canonical pathway) were added to the cultures. Downstream NF-κB signalling was determined by Western blot. After 6-day cultures, B cell proliferation and differentiation were determined by flow cytometry, and ELISA was performed for detection of (auto)antibody production.

Results: Memory B cells from AAV patients with active disease had an upregulated expression of NF-κB-associated genes compared to patients in remission and HD. Targeting of NIK and IKKβ in AAV and HD B cells effectively inhibited downstream non-canonical or canonical NF-κB signalling, respectively. NIK and IKKβ inhibition significantly reduced B cell proliferation in both stimulatory conditions in functional assays. In addition, NK and IKKβ inhibitors attenuated B cell differentiation into plasmablasts and antibody production, including anti-proteinase-3 (PR3) autoantibodies. Interestingly, the effects of NIK inhibition appeared to be B cell-specific, remdering T cell proliferation unaffected.

Conclusion: These data reveal that NF-κB-associated genes were highly expressed in memory B cells from AAV patients with active disease and that interfering with NF-κB signalling inhibits essential B cell responses that are important in the autoimmune process. These findings suggest that targeting NF-κB, particularly NIK, may be a more reversible and B cell directed novel treatment modality for AAV.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/targeting-nf-%ce%bab-signalling-in-b-cells-from-anca-associated-vasculitis-impairs-b-cell-biology-as-a-potential-novel-target/