Mediator Release from Basophils and Mast Cells and Its Relationship to Fcepsilon RI Expression and IgE-Suppressing Therapies

Self Cite

140

160

Plasmacytoid dendritic cells (pDC) express not only TLR9 molecules through which ligation with CpG DNA favors Th1 responses but also possess IgE receptors (FcεRI) implicated in allergen presentation and induction of Th2 responses. This dichotomy prompted an investigation to determine whether TLR9- and IgE receptor-mediated responses oppose one another in pDC by affecting receptor expression and associated functional responses. Results showed that IgE cross-linking reduced TLR9 in pDC and inhibited the capacity of these cells to secrete IFN-α when stimulated with the CpG oligodeoxynucleotide (ODN)-2216. In contrast, an ∼15-fold reduction in FcεRIα mRNA and a loss in surface protein were seen in pDC first exposed to TLR9 ligation with ODN-2216. Results indicated that type I IFNs partly mediated this effect, as rIFN-α also caused a significant ∼4-fold reduction in FcεRIα mRNA. Finally, this reduction in FcεRIα mediated by ODN-2216 correlated with a selective suppression of allergen-induced CD4+ T cell proliferation, but not of responses resulting from tetanus toxoid. Overall, these results imply mechanisms by which specific innate and IgE-dependent immune responses counterregulate one another at the dendritic cell level and may have significant impact on whether an ensuing response is either of Th1 or Th2 in nature.

Section: Discussionmentioning

confidence: 96%

TLR9- and FcεRI-Mediated Responses Oppose One Another in Plasmacytoid Dendritic Cells by Down-Regulating Receptor Expression

Schroeder

Bieneman

Xiao

et al. 2005

Self Cite

140

160

“…Therefore, IgE-mediated Fc⑀RI up-regulation is not an artifact observed in cultured cell lines. This is also true for human mast cells (16,17) as well as human and mouse basophils (18,19). Importantly, the IgE-mediated Fc⑀RI up-regulation was shown to result in critical enhancement of effector functions of those cells.…”

Section: Drastic Up-regulation Of Fc⑀ri On Mast Cells Is Induced By Imentioning

confidence: 86%

“…Two different mechanisms have been proposed to explain the IgE-mediated Fc⑀RI up-regulation (6,7,15,18). One is the suppression of loss of preformed Fc⑀RI expressed on the cell surface by protecting against the degradation of Fc⑀RI.…”

Section: Discussionmentioning

confidence: 99%

Drastic Up-Regulation of FcεRI on Mast Cells Is Induced by IgE Binding Through Stabilization and Accumulation of FcεRI on the Cell Surface

Kubo

Matsuoka

Taya³

et al. 2001

It has been shown that IgE binding to FcεRI on mast cells results in increased FcεRI expression, which in turn enhances IgE-dependent chemical mediator release from mast cells. Therefore, prevention of the IgE-mediated FcεRI up-regulation would be a promising strategy for management of allergic disorders. However, the mechanism of IgE-mediated FcεRI up-regulation has not been fully elucidated. In this study, we analyzed kinetics of FcεRI on peritoneal mast cells and bone marrow-derived mast cells. In the presence of brefeldin A, which prevented transport of new FcεRI molecules to the cell surface, levels of IgE-free FcεRI on mast cells decreased drastically during culture, whereas those of IgE-bound FcεRI were stable. In contrast, levels of FcγRIII on the same cells were stable even in the absence of its ligand, indicating that FcεRI α-chain, but not β- and γ-chains, was responsible for the instability of IgE-free FcεRI. As far as we analyzed, there was no evidence to support the idea that IgE binding to FcεRI facilitated synthesis and/or transport of FcεRI to the cell surface. Therefore, the stabilization and accumulation of FcεRI on the cell surface through IgE binding appears to be the major mechanism of IgE-mediated FcεRI up-regulation.

“…However, Fc⑀RI expression could be up-regulated by as much as 32-fold after in vitro incubation of mast cells with IgE or injection of IgE in vivo (12,17). Furthermore, IgE-transgenic mice had highly elevated levels of Fc⑀RI on mast cells, as has also been observed in patients with allergies (9,15,18). The IgE-mediated Fc⑀RI up-regulation was shown to enhance the ability of mast cells and basophils to release chemical mediators such as serotonin and cytokines (12,19).…”

mentioning

confidence: 89%

“…Two different mechanisms have been proposed to explain the IgE-mediated Fc⑀RI up-regulation (7,8,13,15). One mechanism involves the suppression of loss of preformed cell surface Fc⑀RI by protection against degradation of Fc⑀RI.…”

mentioning

confidence: 99%

Long Term Maintenance of IgE-Mediated Memory in Mast Cells in the Absence of Detectable Serum IgE

Kubo

Nakayama

Matsuoka

et al. 2003

Mast cells and basophils involved in allergic responses do not have clonotypic Ag receptors. However, they can acquire Ag specificity through binding of Ag-specific IgE to FcεRI expressed on their surface. Previous studies demonstrated that IgE binding induced the stabilization and accumulation of FcεRI on the cell surface and resulted in up-regulation of FcεRI. In this study we have further analyzed the maintenance of IgE-mediated memory in mast cells and basophils in vivo by comparing kinetics of serum IgE levels, FcεRI expression, and ability to induce systemic anaphylaxis. A single i.v. injection of trinitrophenyl-specific IgE induced 8-fold up-regulation of FcεRI expression on peritoneal mast cells in B cell-deficient (μm−/−) mice. Serum IgE levels became undetectable by day 6, but the treatment of mice with anti-IgE mAb induced a significant drop in body temperature on days 14, 28, and 42. The administration of trinitrophenyl -BSA, but not BSA, in place of anti-IgE mAb gave similar results, indicating the Ag specificity of the allergic response. This long term maintenance of Ag-specific reactivity in the allergic response was also observed in normal mice passively sensitized with IgE even though the duration was shorter than that in B cell-deficient mice. The appearance of IgE with a different specificity did not interfere with the maintenance of IgE-mediated memory of mast cells and basophils. These results suggest that IgE-mediated stabilization and up-regulation of FcεRI enables mast cells and basophils not only to acquire Ag specificity, but also to maintain memory in vivo for lengthy periods of time.