Defective interleukin-12/interferon-γ pathway in patients with hyperimmunoglobulinemia E syndrome

Borges, Wellington; Augustine, Nancy H.; Hill, Harry R.

doi:10.1016/s0022-3476(00)70098-9

Cited by 87 publications

(50 citation statements)

References 26 publications

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“…17 Thus, impaired production of IFN-␥ by T and NK cells with STAT3 mutations may favor elevated production of IgE in HIES ( Figure 6). A deficiency in IFN-␥-mediated regulation of B-cell activation in HIES is supported by several observations: 1) heightened expression of CD23 on HIES patients B cells ( Figure 5A,B), and increased serum soluble CD23 in HIES, 52 inasmuch that IFN-␥ can inhibit IL-4-induced up-regulation of CD23 expression on B cells 49 ; 2) reduced IFN-␥ production by HIES PBMCs 50,51,53,54 and CD4 ϩ T cells (Figure 5D) 61 ; 3) IFN-␥-mediated suppression of unusually high levels of IgE spontaneously produced by HIES PBMCs in vitro 52,62 ; and 4) administration of IFN-␥ reduced spontaneous IgE secretion by HIES patients B cells in vitro, and serum IgE levels. 62 Our hypothesis that reduced IFN-␥ production by CD4 ϩ T cells contributes to aberrant IgE production in HIES is supported by the findings that patients with mutations in IL-12 or IFN-␥R have significantly elevated serum IgE levels and increased incidence of clinical atopic disease compared with controls.…”

Section: Discussionmentioning

confidence: 63%

STAT3 is required for IL-21–induced secretion of IgE from human naive B cells

Avery

Cindy

Bryant

et al. 2008

Blood

124

111

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The production of immunoglobulin E (IgE) is tightly regulated. This is evidenced by the fact that it comprises less than 0.0001% of serum Ig, and aberrant production causes atopic conditions, including allergy, rhinitis, and anaphylaxis. Interleu IntroductionIn normal individuals, the concentration of serum immunoglobulin E (IgE) is approximately 100 ng/mL, 10 4 to 10 5 times lower than IgG and IgA, making it the least abundant serum Ig. 1 However, aberrant production of IgE, often resulting from dysregulated Th2 or deficient Th1 responses, is associated with numerous diseases, including atopy, allergy, asthma, eczema/ dermatitis, and parasitic infections. 2 Furthermore, extraordinarily high levels of IgE are present in patients with hyper-IgE syndrome (HIES), Ommen syndrome, Wiskott-Aldrich syndrome, Comel-Netherton syndrome, and immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome, diseases also associated with eczema, allergy, and atopy. 2,3 Thus, to maintain IgE at normal (nonpathogenic) levels, its production must be strictly regulated. Identification of modulators of IgE production is therefore critical for understanding the pathogenesis of, and designing novel therapeutics for, conditions such as allergy and atopy.It is well established that interleukin-4 (IL-4) induces IgE production by human and murine B cells. 4,5 Human B cells also produce IgE when stimulated with IL-13. 2,6,7 Several factors, such as interferon-␥ (IFN-␥), IFN-␣, transforming growth factor-␤, IL-10, and prostaglandins, have been identified that antagonize IL-4-induced IgE production by human and murine B cells. 2,4,5,[8][9][10] Recent studies have also revealed that IL-21 inhibits IL-4-induced IgE secretion by murine B cells. [11][12][13][14][15] The increased levels of serum IgE in IL-21R-or IL-21-deficient mice 11,13 most probably results from the ability of IL-21 to directly inhibit isotype switching to IgE by their B cells. 12 Despite these findings, the effects of IL-21 on IgE secretion by human B cells remain incompletely characterized. On one hand, IL-21 inhibited IL-4-induced IgE secretion in cultures of total peripheral blood mononuclear cells (PBMCs) 16,17 by inducing apoptosis of B cells committed to producing IgE and/or inducing IFN-␥ production by non-B cells in the PBMCs. 14,17 On the other hand, IL-21 had no effect on IgE secretion by human B cells stimulated with anti-CD40 monoclonal antibody (mAb), 18,19 yet it did enhance IgE secretion induced by anti-CD40 mAb and IL-4. [16][17][18]20 Because of conflicting reports on the role of IL-21 in switching to IgE by human B cells, and potential differences in regulating IgE by human and murine B cells, we examined the effect of IL-21 on IgE secretion by human naive B cells. IL-21 induced IgE secretion by CD40L-stimulated naive B cells. Furthermore, addition of both IL-4 and IL-21 to CD40L-stimulated human B cells resulted in potent synergy, inducing 10-to 100-fold higher levels of IgE than those induced by IL-4 or IL-21 alone. One explanation for the int...

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Section: Discussionmentioning

confidence: 63%

STAT3 is required for IL-21–induced secretion of IgE from human naive B cells

Avery

Cindy

Bryant

et al. 2008

Blood

124

111

View full text Add to dashboard Cite

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“…In fact, one study suggested that IL-12 expression is dysregulated and that the response (either greater or lesser than that of controls) depends on the stimulus. IFN-␥ deficits were also identified and the magnitude again depended on the stimulus (13). These studies suggest that the simple interpretation of Th1/Th2 im-balance is inadequate to explain the phenotypic manifestations of this syndrome.…”

Section: Introductionmentioning

confidence: 91%

“…For example, cell supernatants from patients with hyper-IgE syndrome have increased bone resorptive activity compared to those from controls (14). IL-12 stimulation of IFN-␥ has been reported as defective and treatment of cells in vitro with IFN-␥ has improved chemotactic activity (13,15), although treatment with IFN-␥ in vivo has been disappointing (16,17). This study was designed to examine various aspects of cytokine production in hyper-IgE syndrome.…”

Section: Introductionmentioning

confidence: 99%

Cytokine and Chemokine Dysregulation in Hyper-IgE Syndrome

Chehimi

Elder

Greene

et al. 2001

Clinical Immunology

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“…Recent evidence suggests that the defect may occur very early in the recognition of microbes. Cytokine and chemokine release after stimulation with microbial products is aberrant (43,54). The infections are characteristic of neutrophil disorders, with recurrent staphylococcal abscesses being a prominent feature (160).…”

Section: Functional Neutrophil Disordersmentioning

confidence: 99%

Infections in Patients with Inherited Defects in Phagocytic Function

2003

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Patients with defects in phagocytic function are predisposed to intracellular microorganisms and typically have early dissemination of the infection. Recognition of the underlying disorder and aggressive antimicrobial therapy has been beneficial for the patients. Improved understanding of the pathophysiology has also affected patient management by allowing specific, targeted immunomodulatory intervention. The disorders described in this review are not common but have had a significant impact on our understanding of the role of phagocytic cells in host defense. Conversely, understanding the role of the neutrophil and macrophage in infection has benefited not just the patients described in this review but also other patients with similar disease processes

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Defective interleukin-12/interferon-γ pathway in patients with hyperimmunoglobulinemia E syndrome

Cited by 87 publications

References 26 publications

STAT3 is required for IL-21–induced secretion of IgE from human naive B cells

STAT3 is required for IL-21–induced secretion of IgE from human naive B cells

Cytokine and Chemokine Dysregulation in Hyper-IgE Syndrome

Infections in Patients with Inherited Defects in Phagocytic Function

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