Antibodies are produced when naive B cells differentiate into plasma cells within germinal centres (GCs) of lymphoid tissues. Patients with B cell lymphoma on effective immunotherapies exhibit diminished antibody production, leading to higher infection rates and reduced vaccine efficacy, even after B cell recovery. Current ex vivo models fail to sustain long-term GC reactions and effectively test B cell responses. Here we developed synthetic hydrogels mimicking the lymphoid tissue microenvironment, enabling human GCs from tonsils and peripheral blood mononuclear cell-derived B cells. Immune organoids derived from peripheral blood mononuclear cells maintain GC B cells and plasma cells longer than tonsil-derived ones and exhibit unique B cell programming, including GC compartments, somatic hypermutation, immunoglobulin class switching and B cell clones. Chemical inhibition of transcriptional and epigenetic processes enhances plasma cell formation. While integrating polarized CXCL12 protein in a lymphoid organ-on-chip modulates GC responses in healthy donor B cells, it fails with B cells derived from patients with lymphoma. Our system allows rapid, controlled modelling of immune responses and B cell disorders.

当初始 B 细胞在淋巴组织的生发中心 （GC） 内分化为浆细胞时，会产生抗体。接受有效免疫疗法的 B 细胞淋巴瘤患者表现出抗体产生减少，导致感染率更高和疫苗效力降低，即使在 B 细胞恢复后也是如此。目前的离体模型无法维持长期的 GC 反应并有效测试 B 细胞反应。在这里，我们开发了模拟淋巴组织微环境的合成水凝胶，使来自扁桃体和外周血单核细胞衍生 B 细胞的人类 GC 成为可能。来自外周血单核细胞的免疫类器官比扁桃体来源的免疫类器官维持 GC B 细胞和浆细胞的时间更长，并表现出独特的 B 细胞编程，包括 GC 区室、体细胞超突变、免疫球蛋白类别转换和 B 细胞克隆。转录和表观遗传过程的化学抑制促进了浆细胞的形成。虽然将极化 CXCL12 蛋白整合到淋巴器官芯片中可调节健康供体 B 细胞的 GC 反应，但淋巴瘤患者的 B 细胞则无法调节。我们的系统允许对免疫反应和 B 细胞疾病进行快速、受控的建模。