Targeting NF-κB signaling in B cells as a potential new treatment modality for ANCA-associated vasculitis

Ana Merino-Vico, Jan Piet van Hamburg, Paul Tuijnenburg, Giulia Frazzei, Aram Al-Soudi, Carlo G Bonasia, Boy Helder, Abraham Rutgers, Wayel H Abdulahad, Coen A Stegeman, Jan-Stephan Sanders, Laura Bergamaschi, Paul A Lyons, Theo Bijma, Laura van Keep, Kirsten Wesenhagen, Aldo Jongejan, Henric Olsson, Niek de Vries, Taco W KuijpersPeter Heeringa, Sander W Tas

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B lineage cells are critically involved in ANCA-associated vasculitis (AAV), evidenced by alterations in circulating B cell subsets and beneficial clinical effects of rituximab (anti-CD20) therapy. This treatment renders a long-term, peripheral B cell depletion, but allows for the survival of long-lived plasma cells. Therefore, there is an unmet need for more reversible and full B lineage cell targeting approaches. To find potential novel therapeutic targets, RNA sequencing of CD27 + memory B cells of patients with active AAV was performed, revealing an upregulated NF-κB-associated gene signature. NF-κB signaling pathways act downstream of various B cell surface receptors, including the BCR, CD40, BAFFR and TLRs, and are essential for B cell responses. Here we demonstrate that novel pharmacological inhibitors of NF-κB inducing kinase (NIK, non-canonical NF-κB signaling) and inhibitor-of-κB-kinase-β (IKKβ, canonical NF-κB signaling) can effectively inhibit NF-κB signaling in B cells, whereas T cell responses were largely unaffected. Moreover, both inhibitors significantly reduced B cell proliferation, differentiation and production of antibodies, including proteinase-3 (PR3) autoantibodies, in B lineage cells of AAV patients. These findings indicate that targeting NF-κB, particularly NIK, may be an effective, novel B lineage cell targeted therapy for AAV and other autoimmune diseases with prominent B cell involvement.

Original languageEnglish
Article number103133
Number of pages13
JournalJournal of Autoimmunity
Early online date4-Nov-2023
Publication statusPublished - Jan-2024

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