TY - JOUR
T1 - Targeting NF-κB signaling in B cells as a potential new treatment modality for ANCA-associated vasculitis
AU - Merino-Vico, Ana
AU - van Hamburg, Jan Piet
AU - Tuijnenburg, Paul
AU - Frazzei, Giulia
AU - Al-Soudi, Aram
AU - Bonasia, Carlo G.
AU - Helder, Boy
AU - Rutgers, Abraham
AU - Abdulahad, Wayel H.
AU - Stegeman, Coen A.
AU - Sanders, Jan-Stephan
AU - Bergamaschi, Laura
AU - Lyons, Paul A.
AU - Bijma, Theo
AU - van Keep, Laura
AU - Wesenhagen, Kirsten
AU - Jongejan, Aldo
AU - Olsson, Henric
AU - de Vries, Niek
AU - Kuijpers, Taco W.
AU - Heeringa, Peter
AU - Tas, Sander W.
N1 - Funding Information: This project has received funding from the Dutch Arthritis Foundation (grant 18-1-404 ); and from the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement no. 847551 (A.M.-V.). Publisher Copyright: © 2023 The Authors
PY - 2024/1/1
Y1 - 2024/1/1
N2 - 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.
AB - 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.
KW - AAV
KW - B cell
KW - CD40
KW - NF-κB
KW - NIK
KW - Plasma cell
UR - http://www.scopus.com/inward/record.url?scp=85175552090&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.jaut.2023.103133
DO - https://doi.org/10.1016/j.jaut.2023.103133
M3 - Article
C2 - 37931331
SN - 0896-8411
VL - 142
JO - Journal of autoimmunity
JF - Journal of autoimmunity
M1 - 103133
ER -