Histamine Release from the Basophils of Control and Asthmatic Subjects and a Comparison of Gene Expression between “Releaser” and “Nonreleaser” Basophils

Abstract

Most human blood basophils respond to FcεRI cross-linking by releasing histamine and other inflammatory mediators. Basophils that do not degranulate after anti-IgE challenge, known as “nonreleaser” basophils, characteristically have no or barely detectable levels of the Syk tyrosine kinase. The true incidence of the nonreleaser phenotype, its relationship (if any) to allergic asthma, and its molecular mechanism are not well understood. In this study, we report statistical analyses of degranulation assays performed in 68 control and 61 asthmatic subjects that establish higher basal and anti-IgE-stimulated basophil degranulation among the asthmatics. Remarkably, 28% of the control group and 13% of the asthmatic group were nonreleasers for all or part of our 4-year long study and cycling between the releaser and nonreleaser phenotypes occurred at least once in blood basophils from 8 (of 8) asthmatic and 16 (of 23) control donors. Microarray analysis showed that basal gene expression was generally lower in nonreleaser than releaser basophils. In releaser cells, FcεRI cross-linking up-regulated >200 genes, including genes encoding receptors (the FcεRI α and β subunits, the histamine 4 receptor, the chemokine (C-C motif) receptor 1), signaling proteins (Lyn), chemokines (IL-8, RANTES, MIP-1α, and MIP-1β) and transcription factors (early growth response-1, early growth response-3, and AP-1). FcεRI cross-linking induced fewer, and quite distinct, transcriptional responses in nonreleaser cells. We conclude that “nonreleaser” and “cycler” basophils represent a distinct and reversible natural phenotype. Although histamine is more readily released from basophils isolated from asthmatics than controls, the presence of nonreleaser basophils does not rule out the diagnosis of asthma.

A Comparison of Inflammatory Mediators Released by Basophils of Asthmatic and Control Subjects in Response to High-Affinity IgE Receptor Aggregation

“…Although it is formally possible that the different yields of basophils from Percoll could result from a difference in density between the basophils of asthmatics and controls, basophils were not detectable in other gradient fractions. The increased numbers of basophils in blood from asthmatics complement a previous analysis of the larger data set showing that maximum percentage histamine released from asthmatics is also higher than control [11]. …”

“…We reported previously that basophils from asthmatics show a higher maximum percentage histamine than control basophils [11] and demonstrate here that more basophils are recovered after Percoll centrifugation from the blood of asthmatics than controls. Both characteristics may contribute to the onset or progression of disease.…”

Reduced FcεRI-Mediated Release of Asthma-Promoting Cytokines and Chemokines from Human Basophils during Omalizumab Therapy

“…This reduction in receptor levels occurs because IgE binding is required to stabilize FcεRI at the basophil membrane [14]. Signaling though the FcεRI causes the synthesis and release of substantial amounts of the Th2 cytokines IL-4 and IL-13 that are critical for initiating and maintaining allergic responses [15,16,17,18,19,20,21,22]. FcεRI signaling also stimulated the production of chemokines, particularly IL-8, that stimulate inflammatory cell chemotaxis [22].…”

Cysteinyl Leukotrienes Induce Macrophage Inflammatory Protein-1 in Human Monocytes/Macrophages

“…MIP-1α chemoattracts B cells, eosinophils and basophils, degranulates eosinophils and induces histamine release from basophils and mast cells whereas MIP-1β does not [22, 23]. MIP-1α and MIP-1β are expressed and produced in various cells and airways associated with asthma [6,7,8,9,10]. Therefore, it is believed that MIP-1α and MIP-1β modify the pathogenesis of asthma.…”

“…Previous studies have demonstrated that MIP-1α and MIP-1β modify the pathogenesis of asthma [6,7,8,9,10]. A previous paper revealed that MIP-1α production was stimulated by LTD 4 and lipopolysaccharides in alveolar macrophages of rats [11].…”