Antibodies mediate natural and vaccine-induced immunity against viral and bacterial pathogens, whereas fungi represent a widespread kingdom of pathogenic species for which neither vaccine nor neutralizing antibody therapies are clinically available. Here, using a multi-kingdom antibody profiling (multiKAP) approach, we explore the human antibody repertoires against gut commensal fungi (mycobiota). We identify species preferentially targeted by systemic antibodies in humans, with Candida albicans being the major inducer of antifungal immunoglobulin G (IgG). Fungal colonization of the gut induces germinal center (GC)-dependent B cell expansion in extraintestinal lymphoid tissues and generates systemic antibodies that confer protection against disseminated C. albicans or C. auris infection. Antifungal IgG production depends on the innate immunity regulator CARD9 and CARD9⁺CX3CR1⁺ macrophages. In individuals with invasive candidiasis, loss-of-function mutations in CARD9 are associated with impaired antifungal IgG responses. These results reveal an important role of gut commensal fungi in shaping the human antibody repertoire through CARD9-dependent induction of host-protective antifungal IgG.

抗体介导对病毒和细菌病原体的天然免疫和疫苗诱导的免疫，而真菌代表了广泛的病原体物种王国，临床上既没有疫苗也没有中和抗体疗法。在这里，我们使用多领域抗体分析 (multiKAP) 方法，探索针对肠道共生真菌 (mycobiota) 的人类抗体库。我们确定了人类全身抗体优先靶向的物种，白色念珠菌是抗真菌免疫球蛋白 G (IgG) 的主要诱导物。肠道的真菌定植诱导肠外淋巴组织中的生发中心 (GC) 依赖性 B 细胞扩增，并产生全身性抗体，从而保护免受播散性白色念珠菌或C. 耳感染。抗真菌 IgG 的产生取决于先天免疫调节剂 CARD9 和 CARD9 ⁺ CX3CR1 ⁺巨噬细胞。在侵袭性念珠菌病患者中， CARD9功能丧失突变与抗真菌 IgG 反应受损有关。这些结果揭示了肠道共生真菌通过 CARD9 依赖性诱导宿主保护性抗真菌 IgG 在塑造人类抗体库中的重要作用。