Immunoglobulin A: FcαRI Interactions Induce Neutrophil Migration Through Release of Leukotriene B4

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 (FcαRI) potently activates neutrophils. As such, we investigated whether IgA-FcαRI 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 FcαRI transgenic mice or nontransgenic littermates. Microscopic slides of UC patients were stained for IgA, FcαRI, and neutrophils.

Results

In vitro and in vivo cross-linking of FcαRI 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 FcαRI⁺-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. FcαRI-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-FcαRI interactions, and therefore diminish neutrophil migration and activation, may dampen the uncontrolled inflammatory processes in these patients.

Abbreviations used in this paper: BSA, bovine serum albumin, dIgA, dimeric IgA, FcαRI, IgA Fc receptor, IBD, inflammatory bowel diseases, IL, interleukin, ITAM, tyrosine-based activation motif, LTB4, leukotriene B4, mAb, monoclonal antibody, PBS, phosphate-buffered saline, PE, phycoerythrin, SIgA, secretory IgA, UC, ulcerative colitis