Randall Centre for Cell & Molecular Biophysics, King's College London, London, UK.
Division of Asthma, Allergy and Lung Biology, King's College London, London, UK.
Immunology. 2023 Dec;170(4):483-494. doi: 10.1111/imm.13684. Epub 2023 Aug 2.
Phosphoinositide 3-kinase (PI3K) p110δ signalling negatively regulates the production of mouse IgE. However, there are disparities between the mouse and human IgE biology, and the role of PI3K p110δ in the production of human IgE is yet to be determined. To investigate the effect of PI3K p110δ inhibition in the production of human IgE we isolated human B cells from tonsil tissue and stimulated them with IL-4 and anti-CD40 antibody to induce class switching to IgE and IgG1 in the presence or absence of IC87114, a small molecule inhibitor of PI3K p110δ. Using FACS, RT-PCR and ELISA we examined the effect of PI3K p110δ inhibition on IgE production and determined the mechanisms involved. Unlike in mice, we observed that PI3K p110δ inhibition significantly reduces the number of IgE switched cells and the amounts of secreted IgE in IL4 and anti-CD40 cultures. However, the number of IgG1 cells and secreted IgG1 were largely unaffected by PI3K p110δ inhibition. The expression levels of AID, ε and γ1 germinal transcripts or other factors involved in the regulation of CSR to IgE and IgG1 were also unaffected by IC87114. However, we found that IC87114 significantly decreases the proliferation of tonsil B cells stimulated with IL-4 and anti-CD40, specifically reducing the frequency of cells that had undergone 4 divisions or more. In addition, PI3K p110δ inhibition reduced the levels of IRF4 expression in IgE germinal centre-like B cells leading to a block in plasma cell differentiation. In conclusion, PI3K p110δ signalling is required for the production of human IgE, which makes it a pharmacological target for the treatment of allergic disease.
磷酸肌醇 3-激酶（PI3K）p110δ信号负调控小鼠 IgE 的产生。然而，小鼠和人类 IgE 生物学之间存在差异，PI3K p110δ 在人类 IgE 产生中的作用尚未确定。为了研究 PI3K p110δ 抑制在人类 IgE 产生中的作用，我们从扁桃体组织中分离出人类 B 细胞，并用 IL-4 和抗 CD40 抗体刺激它们，在存在或不存在 PI3K p110δ 小分子抑制剂 IC87114 的情况下诱导 IgE 和 IgG1 的类别转换。我们通过 FACS、RT-PCR 和 ELISA 检测 PI3K p110δ 抑制对 IgE 产生的影响，并确定涉及的机制。与在小鼠中不同，我们观察到 PI3K p110δ 抑制显著减少 IgE 转换细胞的数量和 IL4 和抗 CD40 培养物中分泌的 IgE 的量。然而，PI3K p110δ 抑制对 IgG1 细胞的数量和分泌的 IgG1 影响不大。AID、ε 和 γ1 种系转录本的表达水平或参与 CSR 到 IgE 和 IgG1 调节的其他因素也不受 IC87114 的影响。然而，我们发现 IC87114 显著降低了 IL-4 和抗 CD40 刺激的扁桃体 B 细胞的增殖，特别是减少了经历 4 次或更多次分裂的细胞的频率。此外，PI3K p110δ 抑制降低了 IgE 生发中心样 B 细胞中 IRF4 表达水平，导致浆细胞分化受阻。总之，PI3K p110δ 信号对于人类 IgE 的产生是必需的，这使其成为治疗过敏疾病的药理学靶点。
