%0 Journal Article
%T A human autoimmune organoid model reveals IL-7 function in coeliac disease.
%A Santos AJM
%A van Unen V
%A Lin Z
%A Chirieleison SM
%A Ha N
%A Batish A
%A Chan JE
%A Cedano J
%A Zhang ET
%A Mu Q
%A Guh-Siesel A
%A Tomaske M
%A Colburg D
%A Varma S
%A Choi SS
%A Christophersen A
%A Baghdasaryan A
%A Yost KE
%A Karlsson K
%A Ha A
%A Li J
%A Dai H
%A Sellers ZM
%A Chang HY
%A Dunn JCY
%A Zhang BM
%A Mellins ED
%A Sollid LM
%A Fernandez-Becker NQ
%A Davis MM
%A Kuo CJ
%J Nature
%V 632
%N 8024
%D 2024 Aug 24
%M 39048815
%F 69.504
%R 10.1038/s41586-024-07716-2
%X 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 injury1-4. 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.