The importance of non-IgE and IgE-mediated controls and the enigma of non-responder basophils
The most frequently used stimulants in the BAT are allergens. However, basophils of approximately 10% of the population do not respond to stimulation through FcεRI even though they express normal densities of cell-surface IgE and upregulate CD63 well to a non–IgE-dependent stimulus. One cause of non-responsiveness is a low level of Syk phosphatase21-23, possibly in combination with elevated amounts of CD4513. The non-responder phase is transient; a patient may revert to a responsive state within months24,25. The non-responder state has also been reversed experimentally in vitro by culturing basophils in the presence of IL-326. In a large study performed in Singapore, basophil non-responsiveness was associated with lower amounts of basophil Syk, and an apparent reduction of the incidence of rhinitis; basophil non-responsiveness thus may be a final barrier of the immune system to prevent unwanted reactions against allergens24. As the amount of allergen-specific IgE increases, the amount of basophil Syk is transiently decreased by allergen exposure to limit the allergic response. It is not clear at this time, however, whether it is the clinically relevant allergen that is modulating this basophil response.
It is important to document that the blood basophils are alive and capable of mounting a response to a non-IgE stimulus to document, i.e. that the activation test is valid. The bacterial tripeptide fMLP that activates basophils through the G-protein coupled fMLP receptors to degranulate, is often used as a non-IgE mediated positive control1. Degranulation through fMLP occurs faster that the IgE-mediated response. It is insensitive to inhibitors like Staurosporine and Wortmannin, that inhibit IgE-mediated degranulation27. After confirming that blood basophils respond to fMLP, it is important to assess whether they respond to IgE-mediated controls. Blood basophils of non-responders do not get activated in response to a stimulus through IgE/FcεRI, i.e. they do not upregulate CD63 or release histamine.