IgE Nonresponders in Basophil Activation Tests: A Narrative Review From Mechanistic Insights to Clinical Implications and Future Directions.

It has been known for about 50 years that a proportion of human basophils does not release histamine or leukotrienes or upregulates activation markers in response to IgE-dependent stimuli. This group of so-called nonresponders with unresponsive basophils is found in up to 20% of tests conducted. There seems to be no relation to clinical symptoms. The nonresponder status is not defined in a standardized manner, but basophils are often considered nonresponsive if they release less than 5% to 10% of their histamine content or show activation of less than or equal to 10% CD63+ basophils after FcεRI cross-linking. Results from nonresponder patients should be regarded as false negatives. Different genetic factors between reactive and anergic basophils appear to play a minor role because various other factors allow a conversion from the nonresponder status to the responder status in one individual (IL-3, low-Na+ medium, natural changes over time, etc.). In most studies reduced levels of Lyn and Syk proteins in nonreleasers were observed. Therefore, it was assumed that translational or posttranslational regulatory mechanisms (proteasomal degradation), especially specific to the Lyn and Syk levels, are responsible for the nonresponder status. Further biochemical studies, along with mechanistic experiments and multiomics approaches, should be conducted to clarify IgE unresponsiveness.