F(ab)'2-mediated neutralization of C3a and C5a anaphylatoxins: A novel effector function of immunoglobulins

Milan Basta, Fredric Van Goor, Stefano Luccioli, Eric M. Billings, Alexander O. Vortmeyer, Lajos Baranyi, Janos Szebeni, Carl R. Alving, Michael C. Carroll, Ira Berkower, Stanko S. Stojilkovic, Dean D. Metcalfe

Research output: Article

179 Citations (Scopus)

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 CSa, 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 CSa 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 CSa-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 CSa in inflammation.

Original languageEnglish
Pages (from-to)431-438
Number of pages8
JournalNature medicine
Volume9
Issue number4
DOIs
Publication statusPublished - ápr. 1 2003

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Basta, M., Van Goor, F., Luccioli, S., Billings, E. M., Vortmeyer, A. O., Baranyi, L., Szebeni, J., Alving, C. R., Carroll, M. C., Berkower, I., Stojilkovic, S. S., & Metcalfe, D. D. (2003). F(ab)'2-mediated neutralization of C3a and C5a anaphylatoxins: A novel effector function of immunoglobulins. Nature medicine, 9(4), 431-438. https://doi.org/10.1038/nm836