Immunoglobulin A: Fc alpha RI Interactions Induce Neutrophil Migration Through Release of Leukotriene B4

L.P.E. van der Steen, C.W. Tuk, J.E. Bakema, G. Kooij, A. Reijerkerk, G. Vidarsson, G. Bouma, G. Kraal, H.E. de Vries, R.H.J. Beelen, M. van Egmond

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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 littermates. 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
Original languageUndefined/Unknown
Pages (from-to)2018-2029
Issue number6
Publication statusPublished - 2009

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