Session Information
Date: Sunday, November 12, 2023
Title: (0001–0008) B Cell Biology & Targets in Autoimmune & Inflammatory Disease Poster
Session Type: Poster Session A
Session Time: 9:00AM-11:00AM
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.
To cite this abstract in AMA style:
Merino-Vico A, van Hamburg J, Tuijnenburg P, Al-Soudi A, Bonasia C, Helder B, Rutgers A, H. Abdulahad W, Stegeman C, Sanders J, Bergamaschi L, Lyons P, Bijma T, Van Keep L, wesenhagen K, Jongejan A, Olsson H, De Vries N, Kuijpers T, Heeringa P, Tas S. Targeting NF-κB Signalling in B Cells from ANCA-associated Vasculitis Impairs B Cell Biology as a Potential Novel Target [abstract]. Arthritis Rheumatol. 2023; 75 (suppl 9). 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/. Accessed .« Back to ACR Convergence 2023
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/