Macrophages are the dominant effector cells responsible for IgG-mediated passive systemic anaphylaxis challenged by natural protein antigen in BALB/c and C57BL/6 mice

IgG-induced passive systemic anaphylaxis (PSA), a serious adverse effect of passive immune therapy using therapeutic monoclonal antibodies, has been greatly emphasized. However, controversy exists regarding the type of effector cells involved in IgG-induced anaphylaxis as a result of the induction of PSA by different IgG subtypes or the use of mice with varying genetic backgrounds. To clarify the effector cells for PSA, the PSA model with serious hypothermia was established by IgG monoclonal antibody (mAb) against natural protein or complete antigen, not hapten conjugate, in BALB/c and C57BL/6 mice. The results indicated that PSA could be remarkably inhibited by the depletion of macrophages but not by the depletion of whole leukocytes, basophils, neutrophils or monocytes. We further confirmed that macrophages are indispensable for the PSA induced by all six IgG-natural antigen complexes in both strains of mice. Additionally, platelet-activating factor (PAF) was found to be the major effector mediator for IgG-induced anaphylaxis. Moreover, gene knock-out of the third component of complement (C3) did not affect PSA-related hypothermia in C57BL/6 mice. These results indicate that macrophages and PAF act as dominant effector cells and mediator molecules, respectively, and are indispensable components in the induction of IgG-mediated PSA induced by IgG mAb and natural protein antigen. Based on the above results, we hypothesize that inconsistencies in effector cells for PSA may be associated with different features of the mAb-antigen system that might affect the magnitude of FcγRs cross-linking on effector cells.