Kidney international · 2026
Multi-omics analyses reveal the pathogenic role of terminal ileum-derived IgA+β7+ cells in IgA nephropathy.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Liu Xingzi, Wang Lan, Lin Miaomiao, Jia Niya, Liu Guanyi, Peng Jiawen, Wang Jingyu, Xie Tong, Dang Shaoqing, Wu Jingyi, Zhou Xujie, Liu Lijun, Shi Sufang, Lv Jicheng, Barratt Jonathan, Zhang Yuemiao, Zhang Hong
Аннотация
INTRODUCTION: Galactose-deficient IgA1 (Gd-IgA1) plays a key role in IgA nephropathy (IgAN), but the location of the plasma cells responsible for its production remain unknown.
METHODS: To locate Gd-IgA1-producing cells, we profiled intestinal and circulating immune cells from three independent cohorts totaling 99 IgAN cases and 121 healthy controls. The IgA phenotypes-including total IgA, Gd-IgA1, IgA-IgG complexes, secretory IgA, and polymeric IgA levels were measured in paired ileocecal and blood samples. Bulk RNA sequencing, cell deconvolution, and spatial profiling of biopsies identified Gd-IgA1-producing cells in ileocecal samples and blood. Functional studies employed anti-integrin α4β7 monoclonal antibodies in vitro and in a humanized IgAN mouse model.
RESULTS: We found significantly elevated levels of ileocecal IgA enriched for polymeric and Gd-IgA1 O-glycoforms in patients with IgAN. In parallel, terminal ileal rather than ascending colon IgA+ B cells were increased. Most of these cells expressed Gd-IgA1 and displayed dysregulation of enzymes involved in O-glycosylation. Furthermore, circulating IgA+ B cells in IgAN exhibited gene expression signatures more closely resembling that of terminal ileum-derived IgA+ B cells, rather than those from ascending colon or tonsil. Integrin β7 was identified as a biomarker for cells of terminal ileal origin, and there was an increase in IgA+β7+ plasmablasts/plasma cells, correlating with disease severity. In a mouse model of IgAN, anti-α4β7 monoclonal antibody reduced β7+ cells and Gd-IgA1 levels in vitro and induced attrition of Peyer's patches, decreased circulating β7+ plasmablasts/plasma cells, and prevented mesangial IgA deposition.
CONCLUSIONS: Our study highlights the importance of dysregulated B cell responses in the terminal ileum in IgAN and suggests the α4β7-MAdCAM-1 axis as a potential therapeutic target.
METHODS: To locate Gd-IgA1-producing cells, we profiled intestinal and circulating immune cells from three independent cohorts totaling 99 IgAN cases and 121 healthy controls. The IgA phenotypes-including total IgA, Gd-IgA1, IgA-IgG complexes, secretory IgA, and polymeric IgA levels were measured in paired ileocecal and blood samples. Bulk RNA sequencing, cell deconvolution, and spatial profiling of biopsies identified Gd-IgA1-producing cells in ileocecal samples and blood. Functional studies employed anti-integrin α4β7 monoclonal antibodies in vitro and in a humanized IgAN mouse model.
RESULTS: We found significantly elevated levels of ileocecal IgA enriched for polymeric and Gd-IgA1 O-glycoforms in patients with IgAN. In parallel, terminal ileal rather than ascending colon IgA+ B cells were increased. Most of these cells expressed Gd-IgA1 and displayed dysregulation of enzymes involved in O-glycosylation. Furthermore, circulating IgA+ B cells in IgAN exhibited gene expression signatures more closely resembling that of terminal ileum-derived IgA+ B cells, rather than those from ascending colon or tonsil. Integrin β7 was identified as a biomarker for cells of terminal ileal origin, and there was an increase in IgA+β7+ plasmablasts/plasma cells, correlating with disease severity. In a mouse model of IgAN, anti-α4β7 monoclonal antibody reduced β7+ cells and Gd-IgA1 levels in vitro and induced attrition of Peyer's patches, decreased circulating β7+ plasmablasts/plasma cells, and prevented mesangial IgA deposition.
CONCLUSIONS: Our study highlights the importance of dysregulated B cell responses in the terminal ileum in IgAN and suggests the α4β7-MAdCAM-1 axis as a potential therapeutic target.