Abstract
High-dose intravenous immunoglobulin (IVIG) prevents immune damage by scavenging complement fragments C3b and C4b. We tested the hypothesis that exogenous immunoglobulin molecules also bind anaphylatoxins C3a and C5a, thereby neutralizing their pro-inflammatory effects. Single-cell calcium measurements in HMC-1 human mast cells showed that a rise in intracellular calcium caused by C3a and C5a was inhibited in a concentration-dependent manner by IVIG, F(ab)′2-IVIG and irrelevant human monoclonal antibody. C3a- and C5a-induced thromboxane (TXB2) generation and histamine release from HMC-1 cells and whole-blood basophils were also suppressed by exogenous immunoglobulins. In a mouse model of asthma, immunoglobulin treatment reduced cellular migration to the lung. Lethal C5a-mediated circulatory collapse in pigs was prevented by pretreatment with F(ab)′2-IVIG. Molecular modeling, surface plasmon resonance (SPR) and western blot analyses suggested a physical association between anaphylatoxins and the constant region of F(ab)′2. This binding could interfere with the role of C3a and C5a in inflammation.
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Acknowledgements
The authors thank T. Semere for his help with HMC-1 cell cultures; M. Opperman for monoclonal antibodies against C3a and C5a; P. Gronski for purified F(ab)′2 immunoglobulin fragments and IVIG preparations (GammaVenin and Venimmun); R. Huber for the X-ray structures of the C3a molecule; E. Padlan for the X-ray and model structures of the Fab fragment of IgG; and B. Kelsall and P. Murphy for critical reading of the manuscript and helpful suggestions.
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Basta, M., Van Goor, F., Luccioli, S. et al. F(ab)′2-mediated neutralization of C3a and C5a anaphylatoxins: a novel effector function of immunoglobulins. Nat Med 9, 431–438 (2003). https://doi.org/10.1038/nm836
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DOI: https://doi.org/10.1038/nm836
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