Abstract
Some 10 years ago it emerged that at sufficiently high concentrations certain monoclonal mouse IgEs exert previously unsuspected effects on mast cells. Thus they can both promote survival and induce activation of mast cells without the requirement for antigens. This was a wake up call that appears to have been missed (or dismissed) by the majority of immunologists. The structural attributes responsible for the potency of the so-called “highly cytokinergic” or HC IgEs have not yet been determined, but the events that ensue when such IgEs bind to the high-affinity receptor, FcεRI, on mast cells have been thoroughly studied, and are strikingly similar to those engendered by antigens when they form cross-linked complexes with the receptors. We review the evidence for the cytokinergic activity of IgE, and the structural features and known properties of immunoglobulins, and of IgE in particular, most likely to be implicated in the phenomenon. We suggest that IgEs with cytokinergic activity may be generated by local germinal center reactions in the target organs of allergy. We consider also the important implications that the existence of cytokinergic IgE may have for a fuller understanding of adaptive immunity and of the action of IgE in asthma and other diseases.
Highlights
In the classical model for allergenic activation, a multivalent antigen – the allergen – enters the body and is captured by a pre-existing complex of an IgE antibody bound to its highaffinity receptor, FcεRI, on the membrane of mast cells, and basophils
We review the evidence for the cytokinergic activity of IgE, and the structural features and known properties of immunoglobulins, and of IgE in particular, most likely to be implicated in the phenomenon
QUESTIONS We hope we may have persuaded the reader that cytokinergic activity is no mere academic curiosity, relevant only to model haptenspecific mouse antibodies acting on cultured mast cells, but that it is likely to trouble humans
Summary
In the classical model for allergenic activation, a multivalent antigen – the allergen – enters the body and is captured by a pre-existing complex of an IgE antibody bound to its highaffinity receptor, FcεRI, on the membrane of mast cells, and basophils. Simultaneous binding and clustering of the IgE-FcεRI complexes by multivalent allergens may pass the threshold of stimulation required to induce cell degranulation; the signaling would be rapidly terminated by internalization of the complexes Later studies confirmed these observations, clarified the points at which the signaling pathways diverge and identified the resulting downstream events (Charles et al, 2004; Kitaura et al, 2004; Pandey et al, 2004; Sakurai et al, 2004;Yamasaki et al, 2004, 2007; Kohno et al, 2005; Nunomura et al, 2005; Sly et al, 2008). In the context of cytokinergic IgE activation of mast cells, conformational isomerism may provide a state with the capacity for additional protein-binding interactions This could be to a third protein, to free IgE, or to another self-protein, thereby bridging two IgE-FcεRI complexes (Figures 3B,C). Adjacent IgE-FcεRI complexes may contact each other directly (Figure 3A)
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