Journal
JOURNAL OF AUTOIMMUNITY
Volume 142, Issue -, Pages -Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jaut.2023.103133
Keywords
B cell; Plasma cell; NF-kappa B; AAV; NIK; CD40
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B lineage cells play a critical role in ANCA-associated vasculitis (AAV), and the transcription factor NF-kappa B may be a potential therapeutic target for AAV and other autoimmune diseases with prominent B cell involvement.
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-kappa B-associated gene signature. NF-kappa B 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-kappa B inducing kinase (NIK, non-canonical NF-kappa B signaling) and inhibitor-of-kappa B-kinase-beta (IKK beta, canonical NF-kappa B signaling) can effectively inhibit NF-kappa B 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-kappa B, particularly NIK, may be an effective, novel B lineage cell targeted therapy for AAV and other autoimmune diseases with prominent B cell involvement.
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