UCSF

Basophils represent a rare cell population involved in allergic responses and are one of the primary effector cells for IgE-induced inflammation. However, the basis for which certain IgE-antigen interactions trigger basophil activation and the downstream mechanisms for basophil-enhanced inflammation remain unclear. We examined how IgE affinity and overall antigen-IgE/Fc epsilon receptor I (FcεRI) binding differentially relate to basophil activation. Using IgE-loaded murine basophils, we observed that high affinity antigens promoted enhanced basophil degranulation and IL-4 production compared to low affinity antigens, even when the relative concentrations of these antigens were adjusted to achieve the same equilibrium binding to IgE/FcεRI. Similarly, antigen exposure of basophils in the lymph node also lead to enhanced basophil degranulation using high affinity antigen compared to low affinity antigen after adjusting for antigen surface binding. Subcutaneous exposure of high affinity antigen, but not low affinity antigen, promoted systemic basophil activation at distal sites and increased susceptibility to anaphylaxis. We propose that the affinity of IgE for antigen is a primary determinant of basophil degranulation and is a crucial factor in susceptibility to severe IgE-mediated responses such as anaphylaxis.

We also determined whether basophils promote IgE-induced responses in the lymph node. Exposure to a variety of stimuli leads to the accumulation of basophils into the draining lymph node. There, basophils have been proposed to act as critical initiators of the type II adaptive immune response, though more recent reports have challenged this hypothesis. Since then, a clear role for basophils in entering the lymph node has remained elusive. We investigated an alternative function for basophil accumulation into the lymph node: to participate in a local allergic inflammatory response. Through histological examination, basophils were observed to closely associate with dense inflammatory cell clusters comprised of eosinophils, alternatively activated macrophages, multinucleated giant cells, and a reorganized stromal cell population. These cell clusters increased upon antigen rechallenge. Testing basophil-deficient mice revealed that basophils were important contributors in both inflammatory cell recruitment and cell cluster formation. Moreover, IgE-induced activation of basophils was sufficient to promote the allergic inflammatory response in the lymph node. Behaviorally, basophils were observed to respond to incoming antigen by degranulating, producing IL-4, relocalizing closer to sites of antigen entry, and increasing in extended interactions with macrophages, suggesting important steps in the development of localized basophil-mediated responses. Finally, basophils associated with allergic inflammatory cell clusters that had formed in response to lymph node infiltration by the lymphatic-traversing helminth, Brugia pahangi, revealing the targeted and potentially defensive nature of the immune response. Altogether, we propose that a primary function for basophil entry into the lymph node is to participate in and promote a local allergic inflammatory response to protect against a perceived threat.