F(ab)'2-mediated neutralization of C3a and C5a anaphylatoxins: a novel effector function of immunoglobulins.
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.
Basta
Milan
M
Neuronal Excitability Section, National Institute for Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA. mb29r@nih.gov
Van Goor
Fredric
F
Luccioli
Stefano
S
Billings
Eric M
EM
Vortmeyer
Alexander O
AO
Baranyi
Lajos
L
Szebeni
Janos
J
Alving
Carl R
CR
Carroll
Michael C
MC
Berkower
Ira
I
Stojilkovic
Stanko S
SS
Metcalfe
Dean D
DD
D000818:Animals; D001249:Asthma / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D002118:Calcium; D002460:Cell Line; D002464:Cell Migration Inhibition; D015926:Complement C3a / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015936:Complement C5a / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006636:Histamine Release / Q000187:drug effects; D006801:Humans; D016756:Immunoglobulins, Intravenous / Q000494:pharmacology*; D008407:Mast Cells / Q000378:metabolism; D051379:Mice; D012128:Respiratory Distress Syndrome / Q000517:prevention & control; D013552:Swine; D013929:Thromboxane B2 / Q000378:metabolism; D005719:gamma-Globulins / Q000494:pharmacology*
D016756:Immunoglobulins, Intravenous; D005719:gamma-Globulins; C031151:pepsinated immunoglobulin G; D013929:Thromboxane B2; D015926:Complement C3a; D015936:Complement C5a; D002118:Calcium