IgG antibodies produced during subcutaneous allergen immunotherapy mediate inhibition of basophil activation via a mechanism involving both FcγRIIA and FcγRIIB

Abstract

1. Summary The majority of human subjects who receive subcutaneous allergen immunotherapy (IT) develop decreased sensitivity to their allergens. Multiple factors may explain the efficacy of IT, some evidence supports a role for allergen specific IgG antibodies. There is controversy whether such antibodies act by blocking allergen binding to IgE or initiation of active inhibitory signaling through low affinity IgG receptors (FcγRIIB) on mast cells and basophils. In this study, we addressed this question using peripheral blood from cat non-allergic, cat allergic, and immunotherapy-treated cat allergic subjects. Blood from subjects who received IT contain IgG antibodies that mediate inhibition of basophil activation by a mechanism that is blocked by antibodies specific for the inhibitory IgG receptor FcγRIIB. Surprisingly, inhibition was also blocked by aglycosylated, putatively non-FcR binding, antibodies that are specific for the FcγRIIA, suggesting a contribution of this receptor to the observed effect. Consistent with a cooperative effect, ex vivo basophils were found to express both IgG receptors. In other studies we found that basophils from subjects who were both chronically exposed to allergen and were producing both cat allergen specific IgE and IgG, are hypo-responsive to allergen. These studies confirm that IgG antibodies produced during IT act primarily by stimulation of inhibitory signaling, and suggest that FcγRIIA and FcγRIIB function cooperatively in activation of inhibitory signaling circuit. We suggest that under normal physiologic conditions in which only a small proportion of FcεRI are occupied by IgE of a single allergen specificity, FcγRIIA co-aggregation may, by providing activated Lyn, be required to fuel activation of inhibitory FcγRIIB function.

Previously undescribed grass pollen antigens are the major inducers of T helper 2 cytokine-producing T cells in allergic individuals

“…Thirdly, the regulation of PUTGA-specific Th2 responses may also result in downstream regulation of IgE and induction of blocking IgG antibody responses to known TG allergens, a hallmark of specific immunotherapy (SIT) treatment (27,28). Finally, induction of PUTGA-specific Th1 or Treg cells may lead to PUTGA-specific IgG production, which may interfere with IgE-induced mediator release and other immediate-type reactions by mechanisms such as steric hindrance, competition for antigen binding, and inhibitory signaling through FcγRIIB (29,30). Overall, our data suggest that the PUTGAs described in this work could present promising targets for a T-cell-focused specific immunotherapy, which could be safe for administration to higher-risk patients such as asthmatics.…”

Fcγ Receptors Inhibit Mouse and Human Basophil Activation

“…Supporting this in vivo observation, IgG anti-allergen Abs were reported to inhibit allergen-induced basophil activation (20,59). With this system, Cady et al (20) found that FcgRIIA was required for inhibition. We could not confirm a contribution of FcgRIIA in our experimental setting.…”

“…Immune complexes made of allergen and autologous Abs improved allergy to grass pollen (58). Supporting this in vivo observation, IgG anti-allergen Abs were reported to inhibit allergen-induced basophil activation (20,59). With this system, Cady et al (20) found that FcgRIIA was required for inhibition.…”

“…IgG receptors were described long ago on human basophils (18) and identified as FcgRIIA, FcgRIIB (19,20), and FcgRIIIB (22). FcgR were also observed on mouse basophils (25), but not identified.…”

“…IgG were long ago reported to bind to human basophils (18) on which two low-affinity IgG receptors were subsequently identified: FcgRIIA and FcgRIIB (19,20). FcgRIIA are single-chain ITAM-containing activating receptors, whereas FcgRIIB are singlechain ITIM-containing inhibitory receptors (21).…”