期刊
GASTROENTEROLOGY
卷 137, 期 6, 页码 2018-2029出版社
W B SAUNDERS CO-ELSEVIER INC
DOI: 10.1053/j.gastro.2009.06.047
关键词
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资金
- Netherlands Organization for Scientific Research [VIDI 016.086.320]
BACKGROUND & AIMS: Exacerbations of ulcerative colitis (UC) are dominated by massive neutrophil influx in the lamina propria with concomitant mucosal ulceration. The prevalent antibody in this area is immunoglobulin A (IgA). Interestingly, the IgA Fc receptor (Fc alpha RI) potently activates neutrophils. As such, we investigated whether IgA-Fc alpha RI interaction contributes to tissue damage in UC. METHODS: Response of neutrophils to bovine serum albumin-, IgG-, or IgA-coated beads and Escherichia coli was investigated with 3-dimensional culture systems, real-time video microscopy, and (fluorescence) microscopy. In vivo studies were performed using human Fc alpha RI transgenic mice or nontransgenic litter-mates. Microscopic slides of UC patients were stained for IgA, Fc alpha RI, and neutrophils. RESULTS: In vitro and in vivo cross-linking of Fc alpha RI on neutrophils by serum IgA or uptake of IgA-coated E coli led to neutrophil migration. The responsible chemotactic factor was identified as leukotriene B4. Moreover, dimeric IgA (dIgA), which is produced in the lamina propria, but neither secretory IgA nor IgG, was equally capable of inducing neutrophil recruitment. We furthermore showed that Fc alpha RI+-neutrophils in the colon of UC patients had phagocytosed IgA-antigen complexes. CONCLUSIONS: Neutrophils are the first cells that arrive at inflammatory sites once pathogens have crossed the epithelial barrier. Fc alpha RI-dIgA interactions therefore may constitute an essential activation step to recruit more neutrophils' hereby eradicating impending infections. However, excessive IgA-antigen complexes can sustain a perpetuating inflammatory loop in UC, hereby seriously aggravating morbidity. Novel therapeutic strategies that block dIgA-Fc alpha RI interactions, and therefore diminish neutrophil migration and activation, may dampen the uncontrolled inflammatory processes in these patients.
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