Naz Farha, Hagspiel Nicholas, Young Mary K, Uddin Jashim, Tyus David, Boone Rachel, Brown Audrey C, Ramakrishnan Girija, Rigo Isaura, Madden Gregory R, Petri William A
Department of Medicine, Division of Infectious Diseases and International Health, Charlottesville, Virginia, USA.
Department of Microbiology, Immunology and Cancer Biology, Charlottesville, Virginia, USA.
bioRxiv. 2024 Nov 17:2024.11.16.623943. doi: 10.1101/2024.11.16.623943.
infection (CDI) recurs in one of five patients. Monoclonal antibodies targeting the virulence factor TcdB reduce disease recurrence, suggesting that an inadequate anti-TcdB response to CDI leads to recurrence. In patients with CDI, we discovered that IL-33 measured at diagnosis predicts future recurrence, leading us to test the role of IL-33 signaling in the induction of humoral immunity during CDI. Using a mouse recurrence model, IL-33 was demonstrated to be integral for anti-TcdB antibody production. IL-33 acted via ST2+ ILC2 cells, facilitating germinal center T follicular helper (GC-Tfh) cell generation of antibodies. IL-33 protection from reinfection was antibody-dependent, as μMT KO mice and mice treated with anti-CD20 mAb were not protected. These findings demonstrate the critical role of IL-33 in generating humoral immunity to prevent recurrent CDI.
艰难梭菌感染（CDI）在五分之一的患者中会复发。靶向毒力因子TcdB的单克隆抗体可降低疾病复发率，这表明对CDI的抗TcdB反应不足会导致复发。在CDI患者中，我们发现诊断时检测到的IL-33可预测未来的复发情况，这促使我们测试IL-33信号在CDI期间体液免疫诱导中的作用。使用小鼠复发模型，已证明IL-33对于抗TcdB抗体的产生不可或缺。IL-33通过ST2 + ILC2细胞发挥作用，促进生发中心T滤泡辅助（GC-Tfh）细胞产生抗体。IL-33对再感染的保护作用依赖于抗体，因为μMT基因敲除小鼠和用抗CD20单克隆抗体治疗的小鼠未得到保护。这些发现证明了IL-33在产生体液免疫以预防复发性CDI中的关键作用。
