Suppression of IgE Responses in CD23-Transgenic Animals Is Due to Expression of CD23 on Nonlymphoid Cells

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Although the causes of asthma vary, the severity of the disease correlates with the level of IgE produced. In this study we show that mice produced less IgE when they were depleted of the neurotransmitter norepinephrine (NE) before the administration of Ag. The suppression was prevented when a β2-adrenergic receptor (β2AR)-selective agonist was administered, suggesting that NE stimulated the β2AR to regulate the level of an IgE response in vivo. Although the cell targeted by NE to produce this effect in vivo is unknown, we show in vitro that the level of IgE increased on a per cell basis without an effect on class switch recombination when NE stimulated the β2AR on a B cell directly. The β2AR-induced increase in IgE depended on p38 MAPK but not protein kinase A activation, was due to an increased rate of mature IgE mRNA transcription, and was lost when β2AR-deficient B cells were used. Also, CD23 transcription was increased in a p38 MAPK-dependent manner and resulted in an increased level of soluble CD23 (sCD23). The β2AR-induced increase in sCD23 was associated with IgE up-regulation and possibly interacted with CD21/CD19. Using B cells from respective knockout mice, data showed that the β2AR-induced increase in IgE depended on B cell expression of CD23, CD21, and CD19. These findings suggest that at least one mechanism by which endogenous B cell activity in vivo is regulated by NE involves stimulation of the β2AR on the B cell alone to increase the level of IgE produced in a p38 MAPK- and sCD23-dependent manner.

Section: Discussionmentioning

confidence: 99%

The Level of IgE Produced by a B Cell Is Regulated by Norepinephrine in a p38 MAPK- and CD23-Dependent Manner

Pongratz

McAlees

Conrad

et al. 2006

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“…Whereas Ag-specific IgG is enhanced by CD23-mediated B cell responses, CD23 appears to be primarily a negative regulator of IgE in mice (12). This is highlighted by the observation that variants of CD23 expressed by New Zealand Black and 129/SvJ strains of mice fail to bind IgE, resulting in an excessive IgE response (13,14).…”

mentioning

confidence: 94%

CD23-Bound IgE Augments and Dominates Recall Responses through Human Naive B Cells

Griffith

Liang

Onguru

et al. 2011

Human peripheral blood BCRμ+ B cells express high levels of CD23 and circulate preloaded with IgE. The Ag specificity of CD23-bound IgE presumably differs from the BCR and likely reflects the Ag-specific mix of free serum IgE. CD23-bound IgE is thought to enhance B cell Ag presentation to T cells raising the question of how a B cell might respond when presented with a broad mix of Ags and CD23-bound IgE specificities. We recently reported that an increase in CD23+ B cells is associated with the development of resistance to schistosomiasis, highlighting the potential importance of CD23-bound IgE in mediating immunity. We sought to determine the relationship between BCR and CD23-bound IgE-mediated B cell activation in the context of schistosomiasis. We found that crude schistosome Ags downregulate basal B cell activation levels in individuals hyperexposed to infectious worms. Schistosome-specific IgE from resistant, occupationally exposed Kenyans recovered responses of B cells to schistosome Ag. Furthermore, cross-linking of CD23 overrode intracellular signals mediated via the BCR, illustrating its critical and dominating role in B cell activation. These results suggest that CD23-bound IgE augments and dominates recall responses through naive B cells.

“…Cleavage by metalloprotease(s) results in the release of the IgE-binding lectin domain and dissociation of the trimer (7). CD23 is known to enhance Ag processing of IgE-Ag complexes (8) and, more recently, it has been implicated, primarily through the use of CD23 KO and transgenic mice, in regulation of IgE synthesis (9,10).…”

mentioning

confidence: 99%

Temperature Effect on IgE Binding to CD23 Versus FcεRI

Chen

Kilmon

et al. 2003

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A chimeric soluble CD23, consisting of the extracellular domain of mouse CD23 and a modified leucine zipper (lz-CD23), has been shown to inhibit IgE binding to the FcεRI. A similar human CD23 construct was also shown to inhibit binding of human IgE to human FcεRI. In both systems, the inhibition was found to be temperature dependent; a 10-fold molar excess of lz-CD23 gave 90–98% inhibition at 4°C, dropping to 20–30% inhibition at 37°C. Surface plasmon resonance analysis of lz-CD23 binding to an IgE-coated sensor chip suggested that the effective concentration of lz-CD23 was lower at the higher temperatures. Analysis of 125I-IgE binding to CD23+-Chinese hamster ovary cells also indicated that increased temperature resulted in a lower percentage of IgE capable of interacting with CD23. In contrast, IgE interacts more effectively with FcεRI+-rat basophilic leukemia cells at 37°C compared with 4°C. The results support the concept that the open and closed IgE structures found by crystallography interact differently with the two IgE receptors and suggest that temperature influences the relative percentage of IgE in the respective structural forms. Changes in CD23 oligomerization also plays a role in the decreased binding seen at physiological temperatures.