RESUMO
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.
Assuntos
Atresia Biliar/imunologia , Atresia Biliar/terapia , Fígado/imunologia , Animais , Antígenos CD20/metabolismo , Linfócitos B/imunologia , Atresia Biliar/sangue , Atresia Biliar/tratamento farmacológico , Biópsia , Receptor 1 de Quimiocina CX3C/metabolismo , Morte Celular , Linhagem Celular , Proliferação de Células , Transdiferenciação Celular , Criança , Pré-Escolar , Estudos de Coortes , Citotoxicidade Imunológica , Modelos Animais de Doenças , Feminino , Humanos , Imunoglobulina G/metabolismo , Lactente , Inflamação/patologia , Células Matadoras Naturais/imunologia , Células de Kupffer/patologia , Fígado/patologia , Cirrose Hepática/sangue , Cirrose Hepática/complicações , Cirrose Hepática/imunologia , Cirrose Hepática/patologia , Depleção Linfocítica , Linfopoese , Masculino , Camundongos Endogâmicos BALB C , Fagocitose , RNA/metabolismo , Rituximab/administração & dosagem , Rituximab/farmacologia , Rituximab/uso terapêutico , Rotavirus/fisiologia , Análise de Célula Única , Células Th1/imunologia , Células Th17/imunologiaRESUMO
Pediatric-onset colitis and inflammatory bowel disease (IBD) have significant effects on the growth of infants and children, but the etiopathogenesis underlying disease subtypes remains incompletely understood. Here, we report single-cell clustering, immune phenotyping, and risk gene analysis for children with undifferentiated colitis, Crohn's disease, and ulcerative colitis. We demonstrate disease-specific characteristics, as well as common pathogenesis marked by impaired cyclic AMP (cAMP)-response signaling. Specifically, infiltration of PDE4B- and TNF-expressing macrophages, decreased abundance of CD39-expressing intraepithelial T cells, and platelet aggregation and release of 5-hydroxytryptamine at the colonic mucosae were common in colitis and IBD patients. Targeting these pathways by using the phosphodiesterase inhibitor dipyridamole restored immune homeostasis and improved colitis symptoms in a pilot study. In summary, comprehensive analysis of the colonic mucosae has uncovered common pathogenesis and therapeutic targets for children with colitis and IBD.
