Blocking Fcα receptor I on granulocytes prevents tissue damage induced by IgA autoantibodies.
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 (FcαRI) 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 FcαRI-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 FcαRI transgenic mice in vivo. Importantly, ex vivo migration and tissue damage were inhibited by blocking FcαRI, indicating that these events are dependent on the interaction of IgA autoantibodies with FcαRI. Thus, interrupting the granulocyte migration loop by blocking FcαRI 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.
Department of Molecular Cell Biology and Immunology, VU University Medical Center, 1081 BT Amsterdam, The Netherlands.
Lydia P
LP
van der Steen
Jantine E
JE
Bakema
Alina
A
Sesarman
Florina
F
Florea
Cornelis W
CW
Tuk
Gudula
G
Kirtschig
J Joris
JJ
Hage
Cassian
C
Sitaru
Marjolein
M
van Egmond
D000818:Animals; D001323:Autoantibodies / Q000276:immunology* / Q000378:metabolism; D001327:Autoimmune Diseases / Q000276:immunology* / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005455:Fluorescent Antibody Technique; D006098:Granulocytes / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007070:Immunoglobulin A / Q000276:immunology* / Q000378:metabolism; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D017452:Receptors, IgG / Q000276:immunology* / Q000378:metabolism; D012872:Skin Diseases, Vesiculobullous / Q000276:immunology / Q000378:metabolism
D001323:Autoantibodies; C489017:FCGR1A protein, human; C485701:Fcgr1 protein, mouse; D007070:Immunoglobulin A; D017452:Receptors, IgG