A human autoimmune organoid model reveals IL-7 function in coeliac disease.

Autor: Santos AJM; Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA., van Unen V; Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.; Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA.; Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, CA, USA., Lin Z; Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA., Chirieleison SM; Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA., Ha N; Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA., Batish A; Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA., Chan JE; Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA., Cedano J; Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA., Zhang ET; Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA., Mu Q; Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA., Guh-Siesel A; Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA., Tomaske M; Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA., Colburg D; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA., Varma S; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA., Choi SS; Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA., Christophersen A; K. G. Jebsen Coeliac Disease Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.; Department of Immunology, Oslo University Hospital, Oslo, Norway.; Department of Rheumatology, Dermatology and Infectious Diseases, Oslo University Hospital, Oslo, Norway., Baghdasaryan A; Department of Chemistry, Stanford University School of Medicine, Stanford, CA, USA., Yost KE; Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA, USA.; Department of Dermatology, Stanford University School of Medicine, Stanford, CA, USA., Karlsson K; Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.; Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.; Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA., Ha A; Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA., Li J; Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, CA, USA., Dai H; Department of Chemistry, Stanford University School of Medicine, Stanford, CA, USA., Sellers ZM; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA., Chang HY; Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA, USA.; Department of Dermatology, Stanford University School of Medicine, Stanford, CA, USA.; Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA., Dunn JCY; Department of Pediatric Surgery, Stanford University School of Medicine, Stanford, CA, USA., Zhang BM; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA., Mellins ED; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA., Sollid LM; K. G. Jebsen Coeliac Disease Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.; Department of Immunology, Oslo University Hospital, Oslo, Norway., Fernandez-Becker NQ; Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA., Davis MM; Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA.; Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, CA, USA.; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA., Kuo CJ; Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA. cjkuo@stanford.edu.
Jazyk: angličtina
Zdroj: Nature [Nature] 2024 Aug; Vol. 632 (8024), pp. 401-410. Date of Electronic Publication: 2024 Jul 24.
DOI: 10.1038/s41586-024-07716-2
Abstrakt: 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.)
Databáze: MEDLINE
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