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

J Autoimmun. 2024 Jan:142:103133. doi: 10.1016/j.jaut.2023.103133. Epub 2023 Nov 8.

Abstract

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.

Keywords: AAV; B cell; CD40; NF-κB; NIK; Plasma cell.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis* / drug therapy
  • Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis* / metabolism
  • B-Lymphocytes / metabolism
  • Humans
  • NF-kappa B* / metabolism
  • NF-kappaB-Inducing Kinase
  • Signal Transduction

Substances

  • NF-kappa B
  • NF-kappaB-Inducing Kinase