1. A human autoimmune organoid model reveals IL-7 function in coeliac disease.
- Author
-
Santos AJM, van Unen V, Lin Z, Chirieleison SM, Ha N, Batish A, Chan JE, Cedano J, Zhang ET, Mu Q, Guh-Siesel A, Tomaske M, Colburg D, Varma S, Choi SS, Christophersen A, Baghdasaryan A, Yost KE, Karlsson K, Ha A, Li J, Dai H, Sellers ZM, Chang HY, Dunn JCY, Zhang BM, Mellins ED, Sollid LM, Fernandez-Becker NQ, Davis MM, and Kuo CJ
- Subjects
- Humans, Autoantibodies immunology, Autoimmunity, B-Lymphocytes immunology, B-Lymphocytes metabolism, Biopsy, Epitopes immunology, Glutens immunology, Glutens metabolism, GTP-Binding Proteins metabolism, GTP-Binding Proteins immunology, HLA-DQ Antigens immunology, HLA-DQ Antigens metabolism, Killer Cells, Natural immunology, Myeloid Cells immunology, Protein Glutamine gamma Glutamyltransferase 2 immunology, Receptors, Antigen, B-Cell immunology, Receptors, Antigen, B-Cell metabolism, Receptors, Antigen, T-Cell immunology, Receptors, Antigen, T-Cell metabolism, T-Lymphocytes immunology, T-Lymphocytes metabolism, Celiac Disease immunology, Celiac Disease pathology, Celiac Disease metabolism, Duodenum immunology, Duodenum pathology, Duodenum metabolism, Interleukin-7 metabolism, Intestinal Mucosa immunology, Intestinal Mucosa metabolism, Intestinal Mucosa pathology, Models, Biological, Organoids immunology, Organoids metabolism, Organoids pathology
- Abstract
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
1-4 . 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., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)- Published
- 2024
- Full Text
- View/download PDF