The regulation of immunoglobulin E class-switch recombination

Geha, Raif S.; Jabara, Haifa H.; Brodeur, Scott R.

doi:10.1038/nri1181

Cited by 408 publications

(435 citation statements)

References 129 publications

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“…Upon binding of IL-4 or IL-13 to IL-4Ra, STAT6 is phosphorylated. STAT6 function is critical for allergy, because STAT6-deficient mice have impaired Th2 function and B cell class switching to IgE (59). Numerous IL-4 and IL-13 gene variants were associated with elevated IgE levels and atopic conditions, including ocular allergy (6,60).…”

Section: Discussionmentioning

confidence: 99%

Role of CCL7 in Type I Hypersensitivity Reactions in Murine Experimental Allergic Conjunctivitis

Kuo

Collins

Boettner

et al. 2017

The Journal of Immunology

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Molecules that are necessary for ocular hypersensitivity reactions include the receptors CCR1 and CCR3; CCL7 is a ligand for these receptors. Therefore, we explored the role of CCL7 in mast cell activity and motility in vitro and investigated the requirement for CCL7 in a murine model of IgE-mediated allergic conjunctivitis. For mast cells treated with IgE and Ag, the presence of CCL7 synergistically enhanced degranulation and calcium influx. CCL7 also induced chemotaxis in mast cells. CCL7-deficient bone marrow–derived mast cells showed decreased degranulation following IgE and Ag treatment compared with wild-type bone marrow–derived mast cells, but there was no difference in degranulation when cells were activated via an IgE-independent pathway. In vivo, CCL7 was upregulated in conjunctival tissue during an OVA-induced allergic response. Notably, the early-phase clinical symptoms in the conjunctiva after OVA challenge were significantly higher in OVA-sensitized wild-type mice than in control challenged wild-type mice; the increase was suppressed in CCL7-deficient mice. In the OVA-induced allergic response, the numbers of conjunctival mast cells were lower in CCL7-deficient mice than in wild-type mice. Our results demonstrate that CCL7 is required for maximal OVA-induced ocular anaphylaxis, mast cell recruitment in vivo, and maximal FcεRI-mediated mast cell activation in vitro. A better understanding of the role of CCL7 in mediating ocular hypersensitivity reactions will provide insights into mast cell function and novel treatments for allergic ocular diseases.

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Section: Discussionmentioning

confidence: 99%

Role of CCL7 in Type I Hypersensitivity Reactions in Murine Experimental Allergic Conjunctivitis

Kuo

Collins

Boettner

et al. 2017

The Journal of Immunology

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“…These observations suggest the existence of an additional pathway to IgE, the exact nature of which remains to be elucidated. IL-4 or IL-13 interacts with a receptor form containing the IL-4R␣ chain, triggering the phosphorylation, dimerization, and nuclear translocation of STAT6, which promotes C⑀ gene expression and isotype switch recombination to IgE (14,15). It is conceivable that IgE could be produced in the absence of IL-4R␣ if another receptor form could interact with STAT6.…”

Section: Discussionmentioning

confidence: 99%

“…IL-4 may also act through IL-4R␣ complexed with the ␥ common chain. In either case, signal transduction through IL-4R␣ results in the phosphorylation, dimerization, and nuclear translocation of STAT-6, which binds to a specific response element in the C⑀ promoter region, providing an essential signal for IgE production (14,15).…”

Section: Ige Generation and Mast Cell Effector Function In Micementioning

confidence: 99%

“…IL-4 and IL-13 are critical cytokines for IgE production in response to Ag challenge (14,15). To investigate the requirement for these cytokines to support resting IgE levels in naive mice, serum was examined from wild-type mice and from mice genetically deficient in IL-4, IL-13, IL-4 ϩ IL-13, IL-4R␣, and IL-13R␣2.…”

Section: Mice Deficient In Il-4 And/or Il-13 Lack Serum Igementioning

confidence: 99%

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IgE Generation and Mast Cell Effector Function in Mice Deficient in IL-4 and IL-13

Fish¹,

Donaldson²,

Goldman³

et al. 2005

The Journal of Immunology

104

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IL-4 and IL-13 are potent cytokines that drive production of IgE, which is critical to the development of atopic disease. In this study, we directly compared IgE generation and IgE-dependent mast cell effector function in mouse strains lacking IL-4, IL-13, IL-4 + IL-13, or their common receptor component, IL-4Rα. Although serum IgE was undetectable under resting conditions in most animals deficient in one or both cytokines, peritoneal mast cells from mice lacking IL-4 or IL-13 had only partial reductions in surface IgE level. In contrast, peritoneal mast cells from IL-4/13−/− and IL-4Rα−/− animals were severely deficient in surface IgE, and showed no detectable degranulation following treatment with anti-IgE in vitro. Surprisingly, however, intradermal challenge with high concentrations of anti-IgE Ab induced an ear-swelling response in these strains, implying some capacity for IgE-mediated effector function in tissue mast cells. Furthermore, upon specific immunization with OVA, both IL-4/IL-13−/− and IL-4Rα−/− mice produced detectable levels of serum IgE and Ag-specific IgG1, and generated strong ear-swelling responses to intradermal administration of anti-IgE. These findings suggest that a mechanism for IgE production exists in vivo that is independent of IL-4 or IL-13.

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“…Repeated exposure to allergen then activates mast cells, which release mediators that facilitate recruitment of other cell types, including T H 2 cells, which mediate the inflammatory response in the airways (reviewed in Ref. 8). Thus, although the T H 2 axis plays a critical role in initiating the IgE response and airway inflammation, the presence of allergenspecific IgE does not necessarily culminate in asthma.…”

Section: Allergic Asthma: a Complex Syndromementioning

confidence: 99%

Allergic Asthma: Influence of Genetic and Environmental Factors

Mukherjee

Zhang

2011

Journal of Biological Chemistry

125

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Allergic asthma is a chronic airway inflammatory disease in which exposure to allergens causes intermittent attacks of breathlessness, airway hyper-reactivity, wheezing, and coughing. Allergic asthma has been called a "syndrome" resulting from a complex interplay between genetic and environmental factors. Worldwide, >300 million individuals are affected by this disease, and in the United States alone, it is estimated that >35 million people, mostly children, suffer from asthma. Although animal models, linkage analyses, and genome-wide association studies have identified numerous candidate genes, a solid definition of allergic asthma has not yet emerged; however, such studies have contributed to our understanding of the multiple pathways to this syndrome. In contrast with animal models, in which T-helper 2 (T H 2) cell response is the dominant feature, in human asthma, an initial exposure to allergen results in T H 2 cell-dependent stimulation of the immune response that mediates the production of IgE and cytokines. Re-exposure to allergen then activates mast cells, which release mediators such as histamines and leukotrienes that recruit other cells, including T H 2 cells, which mediate the inflammatory response in the lungs. In this minireview, we discuss the current understanding of how associated genetic and environmental factors increase the complexity of allergic asthma and the challenges allergic asthma poses for the development of novel approaches to effective treatment and prevention.

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The regulation of immunoglobulin E class-switch recombination

Cited by 408 publications

References 129 publications

Role of CCL7 in Type I Hypersensitivity Reactions in Murine Experimental Allergic Conjunctivitis

Role of CCL7 in Type I Hypersensitivity Reactions in Murine Experimental Allergic Conjunctivitis

IgE Generation and Mast Cell Effector Function in Mice Deficient in IL-4 and IL-13

Allergic Asthma: Influence of Genetic and Environmental Factors

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