Abstract
IgA is the second most abundant antibody present in circulation and is enriched at mucosal surfaces. As such, IgA plays a key role in protection against a variety of mucosal pathogens including viruses. In addition to neutralizing viruses directly, IgA can also stimulate Fc-dependent effector functions via engagement of Fc alpha receptors (Fc-αRI) expressed on the surface of certain immune effector cells. Neutrophils are the most abundant leukocyte, express Fc-αRI, and are often the first to respond to sites of injury and infection. Here, we describe a function for IgA-virus immune complexes (ICs) during viral infections. We show that IgA-virus ICs potentiate NETosis-the programmed cell-death pathway through which neutrophils release neutrophil extracellular traps (NETs). Mechanistically, IgA-virus ICs potentiated a suicidal NETosis pathway via engagement of Fc-αRI on neutrophils through a toll-like receptor-independent, NADPH oxidase complex-dependent pathway. NETs also were capable of trapping and inactivating viruses, consistent with an antiviral function.
Highlights
IgA is the second most abundant antibody present in circulation and is enriched at mucosal surfaces
We show that IgA–virus immune complexes (ICs) potentiate NETosis—the programmed cell-death pathway through which neutrophils release neutrophil extracellular traps (NETs)
Neutrophils express FcαRI, and we have previously shown that IgA–influenza A virus (IAV) ICs stimulate reactive oxygen species (ROS) production in neutrophils; unlike IgG–influenza virus ICs, this could not be fully inhibited by cytochalasin D, indicating that IgA-mediated ROS production was not due to antibody-dependent cellular phagocytosis (ADCP) [24]
Summary
IgA is the second most abundant antibody present in circulation and is enriched at mucosal surfaces. Human neutrophils express the Fc alpha receptor (Fc-αRI/CD89) and are capable of exerting a variety of effector functions including phagocytosis, respiratory burst, antibody-dependent cellular phagocytosis (ADCP), and NETosis [3, 4]. Fc-dependent effector functions have been shown to play a central role in the protection conferred by broadly neutralizing antibodies (bnAbs) that bind to the hemagglutinin (HA) stalk domain of IAV [17,18,19]. These studies have only been performed in the context of monoclonal IgG antibodies. This is due, in large part, to the fact that mice do not express an Fc-αR homolog, which presents significant challenges for assessing the contributions of IgA to outcomes in vivo [1]
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