B系细胞与ANCA相关性血管炎(AAV)密切相关,循环B细胞亚群的改变和利妥昔单抗(抗CD20)治疗的有益临床效果证明。这种治疗带来了长期的,外周B细胞耗竭,但允许长寿的浆细胞存活。因此,对更可逆和全B谱系细胞靶向方法存在未满足的需求。为了寻找潜在的新治疗靶点,对活动性AAV患者的CD27+记忆B细胞进行RNA测序,揭示了上调的NF-κB相关基因签名。NF-κB信号通路作用于各种B细胞表面受体的下游,包括BCR,CD40,BAFFR和TLRs,对B细胞反应至关重要。在这里,我们证明了NF-κB诱导激酶(NIK,非经典NF-κB信号传导)和κB激酶β抑制剂(IKKβ,典型的NF-κB信号)可以有效抑制B细胞中的NF-κB信号,而T细胞反应基本上不受影响。此外,两种抑制剂均显著降低B细胞增殖,抗体的分化和产生,包括蛋白酶-3(PR3)自身抗体,在AAV患者的B系细胞中。这些发现表明靶向NF-κB,尤其是NIK,可能是一个有效的,新型B系细胞靶向治疗AAV和其他具有突出B细胞参与的自身免疫性疾病。
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.