1. Liver Immune Profiling Reveals Pathogenesis and Therapeutics for Biliary Atresia.
- Author
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Wang J, Xu Y, Chen Z, Liang J, Lin Z, Liang H, Xu Y, Wu Q, Guo X, Nie J, Lu B, Huang B, Xian H, Wang X, Wu Q, Zeng J, Chai C, Zhang M, Lin Y, Zhang L, Zhao S, Tong Y, Zeng L, Gu X, Chen ZG, Yi S, Zhang T, Delfouneso D, Zhang Y, Nutt SL, Lew AM, Lu L, Bai F, Xia H, Wen Z, and Zhang Y
- Subjects
- Animals, Antigens, CD20 metabolism, B-Lymphocytes immunology, Biliary Atresia blood, Biliary Atresia drug therapy, Biopsy, CX3C Chemokine Receptor 1 metabolism, Cell Death, Cell Line, Cell Proliferation, Cell Transdifferentiation, Child, Child, Preschool, Cohort Studies, Cytotoxicity, Immunologic, Disease Models, Animal, Female, Humans, Immunoglobulin G metabolism, Infant, Inflammation pathology, Killer Cells, Natural immunology, Kupffer Cells pathology, Liver pathology, Liver Cirrhosis blood, Liver Cirrhosis complications, Liver Cirrhosis immunology, Liver Cirrhosis pathology, Lymphocyte Depletion, Lymphopoiesis, Male, Mice, Inbred BALB C, Phagocytosis, RNA metabolism, Rituximab administration & dosage, Rituximab pharmacology, Rituximab therapeutic use, Rotavirus physiology, Single-Cell Analysis, Th1 Cells immunology, Th17 Cells immunology, Biliary Atresia immunology, Biliary Atresia therapy, Liver immunology
- Abstract
Biliary atresia (BA) is a severe cholangiopathy that leads to liver failure in infants, but its pathogenesis remains to be fully characterized. By single-cell RNA profiling, we observed macrophage hypo-inflammation, Kupffer cell scavenger function defects, cytotoxic T cell expansion, and deficiency of CX3CR1
+ effector T and natural killer (NK) cells in infants with BA. More importantly, we discovered that hepatic B cell lymphopoiesis did not cease after birth and that tolerance defects contributed to immunoglobulin G (IgG)-autoantibody accumulation in BA. In a rhesus-rotavirus induced BA model, depleting B cells or blocking antigen presentation ameliorated liver damage. In a pilot clinical study, we demonstrated that rituximab was effective in depleting hepatic B cells and restoring the functions of macrophages, Kupffer cells, and T cells to levels comparable to those of control subjects. In summary, our comprehensive immune profiling in infants with BA had educed that B-cell-modifying therapies may alleviate liver pathology., Competing Interests: Declaration of Interests The authors declare an application of patents describing diagnosis and treatment of BA., (Copyright © 2020 Elsevier Inc. All rights reserved.)- Published
- 2020
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