Strait RT, Morris SC, Finkelman FD. J Clin Invest. 2006;116:833–841
PURPOSE OF THE STUDY. It has been hypothesized that at least part of the mechanism of successful allergen immunotherapy is the induction of specific immunoglobulin (Ig) G that can “block” IgE-dependent responses by competitively preventing IgE binding and/or by signaling via inhibitory FcγRIIb on basophils and mast cells, thereby downregulating FcεRI-dependent signaling. In vivo evidence of this blocking function has been lacking. The authors of this study carefully addressed whether and how specific IgG can inhibit IgE-mediated anaphylaxis by using a murine model.
METHODS. The authors had previously established a model of anaphylaxis by immunizing BALB/c mice with goat anti-mouse IgD antibody (GαMD), which elicits a strong T-helper 2 response with high levels of IgE, IgG1, and mastocytosis. In this study they very cleverly modified the model by conjugating GαMD with the hapten trinitrophenyl to generate a trinitrophenyl-specific IgG and IgE response to allow for more detailed evaluation of the role of different antibody isotypes with the same epitope specificity. They used a number of tools including antibody blocking of FcγRs, FcRIII-deficient knockout mice, and pharmacologic inhibition to discriminate between IgE- and IgG-dependent anaphylaxis. Assessment of anaphylaxis was by temperature drop and hemoconcentration. IgG-trinitrophenyl antibody complexes were measured by enzyme-linked immunosorbent assay (ELISA). In some experiments, interleukin 4 secretion was measured from whole blood by ELISA.
RESULTS. In immunized mice, the authors showed that IgE-dependent anaphylaxis is primarily inhibited by IgG preventing antigen-induced cross-linking of cell-associated IgE. In FcγRIII-deficient mice (ie, those capable of only IgE-dependent anaphylaxis), blockade of the FcγRIIb inhibitory receptors did not exacerbate antigen-induced anaphylaxis, and IgG–antigen complexes could be detected in whole blood within 5 minutes of antigen administration. Furthermore, animals passively sensitized with IgE in the absence of IgG reacted with 1000-fold lower doses of antigen. Epitope density was inversely correlated with threshold dose for inducing reactivity. Finally, by adding back increasing amounts of IgG to the passively IgE-sensitized animals, they showed that FcRIIb does inhibit IgE responses when IgG levels are low.
CONCLUSIONS. Antigen-specific IgG does block IgE-mediated reactions in vivo by both direct competition and signaling via the inhibitory IgG receptor, FcγRIIb.
REVIEWER COMMENTS. This was the first in vivo demonstration of specific IgG's ability to block IgE-dependent reactions, which has been suggested for many years by the frequently observed rise in allergen-specific IgG titer during successful immunotherapy. There are potentially important large differences between the mouse model and IgG induction in the context of allergen immunotherapy, including the fact that IgG-dependent anaphylaxis is well established in mice but uncertain to even exist in humans. It is also unclear from the article how the ratio of IgG to IgE in this model compares to the ratio of IgG and IgE specific to a particular allergen in human patients. However, the authors carefully and elegantly demonstrated the capacity and mechanistic details of IgG blocking antibody in vivo and strongly support the concept of blocking IgG in the context of immunotherapy.
- Copyright © 2007 by the American Academy of Pediatrics