A role for C5a in augmenting IgG-dependent histamine release from basophils in chronic urticaria

Background: Histamine release in chronic urticaria is initiated by cross-linking of the a subunit of FcepsilonRI by means of IgG antibody, followed by complement activation. Objective: We sought to. further elucidate the mechanism by which complement augments histamine release and to assess the role of C5a. Methods: We first quantitated the ability of purified C5a to initiate basophil histamine release and to be inhibited by antibody directed to the C5a receptor. Using this antibody, we quantitated its ability to inhibit histamine release induced by sera from patients with chronic urticaria. We also compared the ability of normal serum, C5-depleted serum, and C5-depleted serum after reconstitution with C5 to augment histamine release by IgG isolated from patients with chronic urticaria. Results: As the concentration of C5a was increased up to 50 ng/mL, the percentage of histamine release increased and reached a plateau of 40% to 50%; this was inhibited by antibody to the C5a receptor. Preincubation of basophils with antibody to the C5a receptor inhibited basophil histamine release from 15 sera tested, with a range of 4% to 39%. Histamine release caused by patient IgG was augmented when normal serum was added but not when C5-depleted serum was substituted for normal serum. Augmentation of histamine release by patient IgG was again obtained when CS-depleted serum was reconstituted with C5. Conclusion: Our conclusion is that pathogenic IgG cross-links the IgE receptor directly to cause histamine release, and activation is augmented by complement. C5a is the complement agonist that is responsible for the augmented histamine release.