Journal
JOURNAL OF IMMUNOLOGY
Volume 189, Issue 4, Pages 1594-1601Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1101763
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- Netherlands Organization for Scientific Research [VIDI 016.086.320]
- Deutsche Forschungsgemeinschaft [SI-1281/4-1]
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IgA represents the most prominent Ab class at mucosal surfaces and the second most prevalent Ab in human blood after IgG. We recently demonstrated that cross-linking of the granulocyte IgA FcR (Fc alpha RI) by IgA induces a chemotactic-driven positive-feedback migration loop, hereby amplifying recruitment of granulocytes to IgA deposits. Therefore, we postulated that aberrant IgA-Ag complexes, which can be found in tissues in IgA-mediated diseases, are responsible for tissue damage by inducing continuous granulocyte migration and activation. Using an IgA-dependent skin-blistering disease as a model system, we demonstrated colocalization of FcaRI-positive granulocyte infiltrates with IgA in cryosections of lesional skin of patients suffering from this disease. Furthermore, we showed granulocyte migration to IgA deposits injected in human skin explants and in murine skin of Fc alpha RI transgenic mice in vivo. Importantly, ex vivo migration and tissue damage were inhibited by blocking FcaRI, indicating that these events are dependent on the interaction of IgA autoantibodies with Fc alpha RI. Thus, interrupting the granulocyte migration loop by blocking FcaRI reduces tissue damage in diseases with aberrant IgA-immune complexes. As such, our results may lead to development of new therapies for IgA-mediated chronic inflammatory diseases, hereby decreasing severe morbidity and improving quality of life for these patients. The Journal of Immunology, 2012, 189: 1594-1601.
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