In vitro models of autoimmunity are constrained by an inability to culture affected epithelium alongside the complex tissue-resident immune microenvironment. Coeliac disease (CeD) is an autoimmune disease in which dietary gluten-derived peptides bind to the major histocompatibility complex (MHC) class II human leukocyte antigen molecules (HLA)-DQ2 or HLA-DQ8 to initiate immune-mediated duodenal mucosal injury^1,2,3,4. Here, we generated air–liquid interface (ALI) duodenal organoids from intact fragments of endoscopic biopsies that preserve epithelium alongside native mesenchyme and tissue-resident immune cells as a unit without requiring reconstitution. The immune diversity of ALI organoids spanned T cells, B and plasma cells, natural killer (NK) cells and myeloid cells, with extensive T-cell and B-cell receptor repertoires. HLA-DQ2.5-restricted gluten peptides selectively instigated epithelial destruction in HLA-DQ2.5-expressing organoids derived from CeD patients, and this was antagonized by blocking MHC-II or NKG2C/D. Gluten epitopes stimulated a CeD organoid immune network response in lymphoid and myeloid subsets alongside anti-transglutaminase 2 (TG2) autoantibody production. Functional studies in CeD organoids revealed that interleukin-7 (IL-7) is a gluten-inducible pathogenic modulator that regulates CD8⁺ T-cell NKG2C/D expression and is necessary and sufficient for epithelial destruction. Furthermore, endogenous IL-7 was markedly upregulated in patient biopsies from active CeD compared with remission disease from gluten-free diets, predominantly in lamina propria mesenchyme. By preserving the epithelium alongside diverse immune populations, this human in vitro CeD model recapitulates gluten-dependent pathology, enables mechanistic investigation and establishes a proof of principle for the organoid modelling of autoimmunity.

自身免疫的体外模型受到无法与复杂的组织驻留免疫微环境一起培养受影响的上皮的限制。乳糜泻 (CeD) 是一种自身免疫性疾病，其中膳食麸质衍生肽与主要组织相容性复合物 (MHC) II 类人类白细胞抗原分子 (HLA)-DQ2 或 HLA-DQ8 结合，引发免疫介导的十二指肠粘膜损伤 ^1,2,3,4 。在这里，我们从内窥镜活检的完整碎片中生成了气液界面（ALI）十二指肠类器官，这些类器官将上皮与天然间充质和组织驻留免疫细胞作为一个单元保存，无需重建。 ALI 类器官的免疫多样性涵盖 T 细胞、B 细胞和浆细胞、自然杀伤 (NK) 细胞和骨髓细胞，并具有广泛的 T 细胞和 B 细胞受体库。 HLA-DQ2.5 限制性麸质肽选择性地引发来自 CeD 患者的表达 HLA-DQ2.5 的类器官的上皮破坏，并且通过阻断 MHC-II 或 NKG2C/D 来拮抗这种破坏。麸质表位刺激淋巴和骨髓亚群中的 CeD 类器官免疫网络反应，同时产生抗转谷氨酰胺酶 2 (TG2) 自身抗体。 CeD 类器官的功能研究表明，白细胞介素 7 (IL-7) 是一种麸质诱导型致病调节剂，可调节 CD8 ⁺ T 细胞 NKG2C/D 表达，并且对于上皮破坏是必要且充分的。此外，与无麸质饮食的缓解疾病相比，主动 CeD 患者活检中的内源性 IL-7 显着上调，主要是在固有层间充质中。 通过保留上皮细胞和不同的免疫群体，这种人体体外 CeD 模型重现了麸质依赖性病理学，实现了机制研究并为自身免疫类器官建模建立了原理证明。